DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

LIDOCAINE MATRIX ADHESIVE PATCH AND IT’S PROCESS

We, AZISTA INDUSTRIES PVT LTD,
a company incorporated under the company’s Act, 1956 having address at
Sy.No. 80-84, 4th Floor, C Wing, Melange Towers, Patrika Nagar, Madhapur, Hyderabad, Telangana- 500081, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF INVENTION
The present invention relates to non-aqueous matrix adhesive patch composition.

The present invention specifically relates to a composition of low amount Lidocaine non-aqueous matrix adhesive patch.

The present invention also relates to a composition of low amount Lidocaine non-aqueous matrix adhesive patch comprising topical anesthetic as active ingredient and pharmaceutically acceptable excipients.

The present invention also relates to a composition of low amount Lidocaine as topical anesthetic and pharmaceutically acceptable excipients for relieving muscular pain, sprains, strain and post-herpetic neuralgic pain.

The present invention also relates to process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.

BACKGROUND OF INVENTION
Local anaesthetics are widely used both independently for regional anaesthesia and in combination with general anaesthesia. They play a major role in the management of acute and chronic pain.

Local anaesthetics are a heterogeneous group of compounds that block voltage-gated sodium channels (VGSCs). Their molecular structure shares common features, with a hydrophobic aromatic group, an amide group and the connecting intermediary chain. This gives the molecule both hydrophobic and hydrophilic properties. Local anaesthetics are often categorised into ester-linked and amide-linked compounds according to the type of the intermediary chain. They can also be divided into short-acting (e.g. chloroprocaine), intermediate-acting (e.g. mepivacaine, lidocaine) and long-acting (e.g. bupivacaine, ropivacaine) compounds.

A topical anesthetic is a local anesthetic that is used to numb the surface of a body part. Topical anesthetic composition is provided for administration to the skin, eye, ear, nose, mouth and other mucous membranes to reduce pain or discomfort caused by minor skin irritations, cold sores or fever blisters, sunburn or other minor burns, insect bites or stings, poison ivy or oak rashes, and other sources of minor pain on a surface of the body. As compared to conventional topical anesthetics, the subject anesthetic composition has demonstrated improved efficacy, potency, convenience and duration when applied to the mucosa of a patient.

Lidocaine is an anesthetic; anesthetics have a numbing effect and are used to block pain. Topical (intended to be used on body surfaces such as the skin) lidocaine is a common medicine. Topical anesthetics like lidocaine are available as gels, creams, liquids, sprays, eye drops, and patches. Examples of patch include aqueous base patches (Hydrogel) and non-aqueous patch (tapes).

Lidocaine topical anesthetics works by blocking nerves from sending pain signals to the brain. The result is temporary numbness of the area on which they are applied (a "local" anesthetic). Because of their numbing effect, topical anesthetics are effective in treating pain such as sunburns, cuts or scrapes, insect bites, cold sores, rashes, hemorrhoids, injuries of the eye, or a sore throat.

JP Patent No. 3159688 B2 discloses transdermal absorption tape suitable for sustained percutaneous absorption of a local anesthetic, and more particularly, to a stable local anesthetic such as lidocaine. Transdermal absorption tape can be absorbed from the skin for a long time and can be used to reduce the pain of shingles or postherpetic neuralgia. Non-aqueous percutaneous absorption preparation can exhibit long-lasting effects of a local anesthetic such as lidocaine for a long time and can be repeatedly used for a long time without peeling keratin. It also discloses non-aqueous plaster containing 5 to 50% by weight of styrene-isoprene-styrene block copolymer, 1 to 60% by weight of alicyclic saturated hydrocarbon resin, 5 to 60% by weight of liquid paraffin and 1 to 30% by weight of butyl rubber, a transdermal absorption tape agent characterized in that backing is prepared by mixing 100 parts by weight of a base with 1 to 30 parts by weight of a local anesthetic as an active ingredient is carried on a support.

US Patent No. 5,827,529 A discloses external preparation for application to the skin containing lidocaine which comprises a drug-retaining layer placed on a support, wherein said drug-retaining layer comprises an adhesive gel base and 1 to 10% by weight of lidocaine, said base comprising a water-soluble high molecular weight substance, water and a water-retaining agent, which can release the active lidocaine gradually and constantly so that lidocaine is transdermally absorbed for a long period of time.

US Patent No. 8,722,065 B2 discloses novel tape preparation containing lidocaine at a high concentration. It also discloses tape preparation containing lidocaine at a high content, which has a lidocaine content of 10 w/w % or more, can be produced by using a lactic acid salt of lidocaine, while preventing the precipitation of a crystal of lidocaine.

US Patent No. 9,283,174 B2 discloses non-aqueous patches comprising lidocaine, which is not dissolved and is present in a crystalline state, have poor permeability to the skin. It also discloses non-aqueous patch comprising 0.5 to 7 mass % lidocaine and/or its reactant, and a dissolving agent consisting of an organic acid and a polyalcohol, which are contained in a plaster, wherein the amount of lidocaine and/or its reactant is 0.1 to 1 mg/cm2 of the plaster, and wherein the proportion of dissolving agent to lidocaine and/or its reactant is 0.5 to 5 mass % of dissolving agent relative to 1 mass % of lidocaine and/or its reactant. It also discloses that non-aqueous patch further comprises tackifier resin selected from the group consisting of terpene resin, rosin-based resin, alicyclic petroleum resin, phenolic resin and combinations thereof. Plaster is held by a substrate selected from the group consisting of nonwoven fabric, woven fabric, knitted fabric or a combination thereof.

US Publication No. 2013/0184351 A1 discloses transdermal delivery patch comprising local anesthetic agent and optionally a permeation enhancement agent for reducing neuropathic pain. It also discloses patch for transdermal delivery of lidocaine for reducing pain comprising, a patch comprising a composition comprising a therapeutically effective amount of lidocaine, wherein said amount of lidocaine is less than 4 percent by weight, and wherein said pain is selected from neuropathic pain, osteoarthritis pain, back pain, pain associated with fibromyalgia, pain associated with carpal tunnel syndrome, pain associated with muscle strain, pain associated with muscle sprain or degenerative bone pain, or any combination thereof.

US Publication No. 2014/0356412 A1 discloses non-aqueous patch comprising lidocaine and/or its reactant, and a dissolving agent which are contained in a base of plaster, the plaster being hold by a support, of which strength of 50% stretched to longitudinal direction is less than 2,000 g/50 mm and of biaxially-oriented stretch cloth. It also discloses dissolving agent includes organic acid and polyalcohol. The proportion of dissolving agent and lidocaine is 0.5 to 5 mass % of dissolving agent relative to 1 mass % of lidocaine.

US Publication No. 2018/0256495 A1 discloses formulation for a novel external preparation having excellent transdermal absorption of a basic pharmacologically active component contained therein. It also discloses nonaqueous external preparation comprising a lidocaine, an organic acid, and an alcohol solvent in a base of the external preparation. It also discloses that organic acid is selected from the group consisting of acetic acid, propionic acid, butyric acid, hexanoic acid, glycolic acid, methoxyacetic acid, lactic acid, stearic acid, isostearic acid, levulinic acid, benzoic acid, salicylic acid, acetylsalicylic acid, 3-hydroxybutyric acid and alcohol solvent is one or more selected from the group consisting of propylene glycol, 2-propanol, 1,3-butanediol, and ethylene glycol.

US Publication No. 2018/0177742 A1 discloses non-aqueous patches containing lidocaine. Non-aqueous tapes and patches containing lidocaine and methods of administering these tapes and patches so that patients receive an effective amount of lidocaine without causing undue side effects. Non-aqueous tapes and patches contain less lidocaine but are bioequivalent to aqueous lidocaine patches. It also discloses non-aqueous tapes and patches that contain less lidocaine than aqueous patches but have one or more pharmacokinetic parameters of the formulation is within 70% to 125% of that of an aqueous patch containing 5% lidocaine. The most effective proportion of dissolving agent and lidocaine is 0.5 to 5 wt % of dissolving agent relative to 1 wt % of lidocaine. In this proportion, lidocaine can be stably mixed in a dissolved state, increasing the release rate of the lidocaine to the skin, and causing the drug to effectively permeate into the muscle.

All the prior art references shows transdermal absorption tape suitable for sustained percutaneous absorption of lidocaine as local anesthetic, external preparation for application to the skin containing 1 to 10% by weight of lidocaine, tape preparation containing lidocaine at a high concentration i.e., 10 w/w % or more, non-aqueous patch comprising 0.5 to 7 mass % lidocaine and/or its reactant, and 0.5 to 5 mass % dissolving agent consisting of an organic acid and a polyalcohol, patch for transdermal delivery of lidocaine for reducing pain comprising therapeutically effective amount of less than 4 percent by weight of lidocaine, non-aqueous patch comprising lidocaine and/or its reactant, and a dissolving agent which are contained in a base of plaster and nonaqueous external preparation comprising a lidocaine, an organic acid, an alcohol solvent in a base of the external preparation. However, the inventors of the present invention have developed low amount local anesthetic non-aqueous matrix adhesive patch comprising Lidocaine as topical anesthetic, low concentration of dissolving agent relative to amount of lidocaine, adhesive material and pharmaceutically acceptable excipients for relieving muscular pain, sprains, strain and post-herpetic neuralgic pain. The inventors of present invention also provide process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a composition of low amount local anesthetic non-aqueous matrix adhesive patch.

Another objective of the present invention is to provide a composition of low amount Lidocaine non-aqueous matrix adhesive patch comprising topical anesthetic as active ingredient and pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a composition of low amount Lidocaine as topical anesthetic, dissolving agent, adhesive material and pharmaceutically acceptable excipients for relieving muscular pain, sprains, strain and post-herpetic neuralgic pain.

Still another objective of the present invention is to provide a composition of low amount Lidocaine as topical anesthetic, dissolving agent, adhesive material andtackifying agent, plasticizer, penetration enhancers, antioxidants as pharmaceutically acceptable excipients.

Still another objective of the present invention is to provide a composition of low amount Lidocaine as topical anesthetic, low concentration of dissolving agent, adhesive material, and tackifying agent, plasticizer, penetration enhancers, antioxidants as pharmaceutically acceptable excipients.

Still another objective of the present invention is to provide process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.

Still another objective of the present invention is to provide process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting adhesive materials, dissolving active ingredient in dissolving agent, adding active ingredient solution, penetration enhancer, antioxidant, plasticizer into adhesive mixture, coating, drying, laminating and cutting into desired size.

Still another objective of the present invention is to provide process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) which is a solvent-free technique, faster and more economic coating process. In addition, HMC technique has several advantages including drug release, adhesiveness (tack) and physical properties of patch can be tuned relatively easy compared to solvent based coating technique.

In yet another objective of the present invention is to provide relief from muscular pain, sprains, strain and post-herpetic neuralgic pain by application of low amount Lidocaine non-aqueous matrix adhesive patch.

SUMMARY OF INVENTION
Accordingly, the present invention provides a composition of low amount Lidocaine non-aqueous matrix adhesive patch useful in facilitating and relieving muscular pain, sprains, strain and post-herpetic neuralgic pain.

Another embodiment of the present invention relates to a composition of low amount Lidocaine as local anesthetic, low concentration of dissolving agent, adhesive material and pharmaceutically acceptable excipients for relieving muscular pain, sprains, strain and post-herpetic neuralgic pain.

In another embodiment, the present invention provides a composition of low amount Lidocaine as topical anesthetic, dissolving agent, adhesive material andtackifying agent, plasticizer, penetration enhancers, antioxidants as pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a composition of low amount Lidocaine as topical anesthetic, adhesive material, low concentration of dissolving agent of organic acid and polyalcohol either individually or as a mixture and tackifying agent, plasticizer, penetration enhancers, antioxidants as pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a composition of low amount Lidocaine as topical anesthetic, low concentration of dissolving agent of oleic acid as organic acid and propylene glycol as polyalcohol, combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive Pressen 1471 as adhesive material, hydrogenated hydrocarbon as tackifying agent, mineral oil as plasticizer, isopropyl myristate or diethylene glycol monoethyl ether as penetration enhancers, butylated hydroxytoulene as antioxidant.

In another embodiment, the present invention provides process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.

In yet another embodiment, the present invention provides low amount Lidocaine non-aqueous matrix adhesive patch comprising:
1% to 5% (w/w) of lidocaine,
50% to 90% (w/w) of adhesive materials,
2% to 8% (w/w) of tackifying agent,
1% to 2% (w/w) of dissolving agent,
0.5% to 3% (w/w) of plasticizer,
1% to 3% (w/w) of penetration enhancer, and
0.1% to 0.5% (w/w) of antioxidant.

In yet another embodiment, the present invention provides low amount Lidocaine non-aqueous matrix adhesive patch comprising:
1% to 5% (w/w) of Lidocaine,
50% to 90% (w/w) of combination of adhesive materials,
2% to 8% (w/w) of tackifying hydrocarbon resins,
1% to 2% (w/w) of dissolving agent of organic acid and polyalcohol either individually or as a mixture,
0.5% to 3% (w/w) of plasticizer,
1% to 3% (w/w) of penetration enhancer, and
0.1% to 0.5% (w/w) of antioxidant.

In yet another embodiment, the present invention provides low amount Lidocaine non-aqueous matrix adhesive patch comprising:
1% to 5% (w/w) of Lidocaine,
50% to 90% (w/w) of combination of styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive Pressen 1471,
2% to 8% (w/w) of hydrogenated hydrocarbon,
1% to 2% (w/w) of dissolving agent of oleic acid and propylene glycol either individually or as a mixture,
0.5% to 3% (w/w) of mineral oil,
1% to 3% (w/w) of isopropyl myristate or diethylene glycol monoethyl ether, and
0.1% to 0.5% (w/w) of butylated hydroxytoulene.
In still another embodiment, the present invention provides process for the preparation of low amount Lidocaine non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) which is a solvent-free technique, faster and more economic coating process. In addition, HMC technique has several advantages including drug release, adhesiveness (tack) and physical properties of patch can be tuned relatively easy compared to solvent based coating technique.

In yet another embodiment, the present invention provides a process for preparing low amount Lidocaine non-aqueous matrix adhesive patch, the process comprising steps of:
a) melting combination of adhesive materials and tackyfying agent at 130ºC – 150ºC,
b) dissolving lidocaine in organic acid and polyalcohol solution either individually or as a mixture,
c) adding penetration enhancer, antioxidant, plasticizer to active ingredient solution and adding to obtained adhesive mixture of step (a) under continuous stirring,
d) coating the obtained adhesive base of step (c) on polyester nonwoven or woven fabric,
e) laminating the dried adhesive matrix by polyethylene terephthalate silicone coated release liner, and
f) cutting into desired size to get non-aqueous matrix adhesive patch, pouching and labelling.

In yet another embodiment of the present invention provides a process for preparing low amount lidocaine non-aqueous matrix adhesive patch, the process comprising steps of:
a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive Pressen 1471 and hydrogenated hydrocarbon resin at 130ºC – 150ºC,
b) dissolving Lidocaine in oleic acid and propylene glycol solution either individually or as a mixture,
c) adding isopropyl myristate or diethylene glycol monoethyl ether, butylated hydroxytoulene, mineral oil to Lidocaine solution and adding to obtained adhesive mixture of step (a) under continuous stirring at 100 to 120ºC,
d) coating the obtained adhesive base of step (c) on 100% polyester nonwoven or woven fabric,
e) laminating the dried adhesive matrix by 100% polyethylene terephthalate silicone coated release liner, and
f) cutting into desired size to get non-aqueous matrix adhesive patch, pouching and labelling.

BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 1 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 2 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 2 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 3 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 3 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 4 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 13 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 5 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 14 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 6 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 15 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 7 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 22 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.
Figure 8 shows comparison of in vitro-skin permeation of lidocaine patch 5% according to Example 23 with Salonpas® 4% Gel patch & ZTlidoTM Patch 1.8%.

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The present invention provides low amount local anesthetic non-aqueous matrix adhesive patch comprising Lidocaine as topical anesthetic and pharmaceutically acceptable excipients.

The concentration of active ingredient used in the non-aqueous matrix adhesive patch is 1% to 5% w/w. Preferably used concentration of active ingredient is 5% w/w.

Dermal patches are well known to administer local anesthetics topically to patients at wound sites and to treat skin ailments. Dermal pain patches have a number of benefits, not the least of which is convenience. Amide and ester group containing, for example, lidocaine of the amide type, exhibit, as a pharmacological active mechanism, an inhibition of the rapid sodium ion influx in nerve fibers. In this manner, the impulse conduction of the nerve path is blocked, which in principle involves all regional nerve fibers.

The term “patch” refers to a medicated patch, e.g., a patch, comprising a composition comprising at least one active ingredient that is placed on the skin to deliver a continuous dosage of the active ingredient through the skin and into the surrounding tissue. “Patch” may also be referred to herein as a “topical delivery system”, a “topical patch delivery system”, an “adhesive patch”, a “transdermal patch”, a “transdermal delivery system”, an “analgesic patch”, a “dressing”, a “topical carrier system”.

Aqueous based lidocaine containing preparation has poor adhesive property easy to fall off, and the availability of lidocaine is less. In addition, basic ingredients of lidocaine are easy to be dissolved in organic solvent such as methanol, ethanol, diethyl ether, and the like, and hardly to be dissolved in water.

The present invention provides a composition of non-aqueous matrix adhesive patch which can be used to relieve muscle pain, sprains, strain and post-herpetic neuralgic pain for long hours. The present invention composed of a small amount of lidocaine, NOT high amount of lidocaine, into plaster, and such small amount of lidocaine is long and stably transferred by transdermal absorption.

The present invention relates to non-aqueous matrix adhesive patch containing low amount of lidocaine but are bioequivalent to aqueous lidocaine patches. The non-aqueous patch is required have a low matrix weight for 14 x 10 cm size of patch, the plaster weight may be 0.72 gm to 3.6 gm. Because the lidocaine content of the matrix may be 1% to 5% w/w, the amount of lidocaine per patch can be kept as 36 mg.

In order to make Lidocaine present uniformly and stably in the plaster for effective use, lidocaine content of 1 to 5% w/w. When the lidocaine content is less than 1% w/w, the activity of relieving muscle pain is low, and the desire effectiveness cannot be achieved. In contrast, when the lidocaine content is more than 5% w/w, a large amount of dissolving agent is required to ensure the release of lidocaine. The adhesion of patch is thereby reduced, and the physical properties of the patch cannot be maintained, failing to cause the patch to be sufficiently attached to the affected part.

The non-aqueous matrix adhesive patch of the present invention requires small amount of lidocaine which is sufficiently dissolved, and thereby the lidocaine can be released stably and reliably over a long period of time.

Adhesive materials used in the composition of the present invention includes combination of one or more adhesive materials and includes at least two adhesives selected from the group of styrene isoprene styrene block copolymer, ethylene vinyl acetate, hot melt adhesive Pressen 1471, synthetic rubber-based hot melt adhesives, polyolefin based hot melt adhesive, polyamide based hot melt adhesive, polyester-based hot melt adhesives, polyurethane-based hot melt adhesives, styrene isoprene thermoplastic elastomer. Preferably used adhesive materials are styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive Pressen 1471.

The term “hot melt adhesive Pressen 1471” used in the present invention comprises polycyclopentadiene, poly-alpha-pinene and styrene isoprene styrene block copolymer.

The concentration of adhesive material used in the non-aqueous matrix adhesive patch is from 50% to 90% w/w and most preferably 70% to 90% w/w.

Tackifying agent used in the composition of the present invention include, but not limited to petroleum resins (e.g., aliphatic hydrocarbon resins, alicyclic hydrocarbon resins, and aromatic hydrocarbon resins), phenolic resins, xylene resins and coumarone indene resins rosin derivatives (e.g., rosin, glycerin esters of rosin, hydrogenated rosins, glycerin esters of hydrogenated rosin, pentaerythritol esters of rosin, etc.), saturated alicyclic hydrocarbon resins (e.g., ARKON P-100), aliphatic hydrocarbon resins (e.g., Quintone B170) terpene resins (e.g., Clearon P-125), maleic acid resins and the like. Preferably used tackyfying agent is hydrogenated hydrocarbon resin.

The concentration of tackyfying agent used in the non-aqueous matrix adhesive patch is from 2% to 8% w/w. Preferably used tackyfying agent is from 3% to 5% w/w.

Dissolving agent used in the composition of the present invention includes effective proportion of organic acid and polyalcohol either individually or as a mixture in the plaster that can efficiently dissolve lidocaine over a long period of time, revealing that dissolving agent composed of organic acid and polyalcohol allows continuous and reliable dissolution of lidocaine.

The term “organic acid” as used herein includes but not limited to oleic acid, short-chain fatty acids having 2 to 7 carbon atoms such as acetic acid, butyric acid and hexanoic acid; medium-chain fatty acids having 8 to 11 carbon atoms such as octanoic acid and decanoic acid; long-chain fatty acids having more than 12 carbon atoms such as myristic acid, stearic acid and isostearic acid; short-chain fatty acids substituted with a hydroxy group, an alkoxy group or an acyl group such as glycolic acid, lactic acid, methoxyacetic acid, mandelic acid, levulinic acid and 3-hydroxybutyric acid; benzene carboxylic acid such as benzoic acid, p-hydroxybenzoic acid, salicylic acid and acetylsalicylic acid; and organo sulfonic acid such as benzene sulfonic acid, toluenesulfonic acid, methyl sulfonic acid and dodecyl benzene sulfonic acid. Preferably used organic acid is oleic acid or isostearic acid.

The term “polyalcohol” as used herein includes but not limited to propylene glycol, di-propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerine etc. Preferably used polyalcohol is propylene glycol.

The most effective proportion of dissolving agent i.e. mixture of organic acid & polyalcohols to lidocaine is 1% to 2% w/w of dissolving agent 5% w/w of lidocaine.

The concentration of dissolving agent used in the composition of the present invention ranges from 1% to 2% w/w.

Plasticizer used in the composition of the present invention includes but not limited to mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, oleyl alcohol, liquid paraffins, hydrogenated oils, hydrogenated castor oil, higher alcohols such as octyldodecanol, castor oil, petroleum-based oil (for example, paraffinic process oil, naphthenic process oil, or aromatic process oil), vegetable based oils (for example, olive oil, camellia oil, tall oil or arachis oil), dibasic acid esters (for example, dibutyl phthalate, dioctyl phthalate, or the like), liquid rubbers (for example, polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, or diisopropyl sebacate), diethylene glycol, polyethylene glycol; glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamiton. Preferably used plasticizer is mineral oil.

The concentration of plasticizer used in the non-aqueous matrix adhesive patch is from 0.5 to 3% w/w and most preferably used plasticizer is from 0.5 to 2% w/w.

Penetration enhancer is added to increase the penetration of lidocaine from the plaster into the systemic circulation through the skin, which leads to increase the release & bioavailability of lidocaine. Penetration enhancer used in the composition of the present invention includes but not limited to isopropyl myristate, diethylene glycol monoethyl ether, dodecyl sulfoxide mono- or dimethyl acetamide, N-hydroxy ethyl lactide, higher fatty acid esters, salicylic acid, sorbitol, urea, glycerin, squalene, squalane, acetylated lanolin, cetyl laurate, olive oil, castor oil, lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, ethoxy stearyl alcohol, liquid paraffin, vaseline, camphor, glycerin fatty acid ester, fatty acid mono- (or di-) ethanol amide, ethylene glycol mono ethyl ether, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono(di)alkyl ester, propylene glycol monolaurate, polyoxyethylene lauryl ether, pyrrolidone derivatives. Preferably used penetration enhancers are isopropyl myristate and diethylene glycol monoethyl ether.

The concentration of penetration enhancer used in the non-aqueous matrix adhesive patch is from 1% to 3% w/w.
Antioxidant is added to non-aqueous base patch to prevent the degradation of preparation. Antioxidant used in the composition of the present invention includes but not limited to butylated hydroxy toulene, tocopherol and ester derivatives thereof, butylated hydroxy anisole, ascorbic acid, ascorbyl stearate, ascorbyl palmitate, nordihydroguaiaretic acid, etc. Preferably used antioxidant is butylated hydroxytoulene.

The concentration of antioxidant used in the non-aqueous matrix adhesive patch is from 0.1 to 0.5% w/w and most preferably used antioxidant is from 0.1 to 0.3% w/w.

The present invention is to provide process for the preparation of low amount local anesthetic non-aqueous matrix adhesive patch by hot-melt coating technique (HMC) comprising the steps of melting, dissolving, mixing, coating, laminating and cutting.

The plaster prepared by mixing these starting materials is held by a substrate comprising nonwoven fabric, woven fabric, or a combination thereof, which are generally used for patches. Since the drug may be adsorb to the substrate or release liner, polyester is generally used as their material.

The weight of the plaster is preferably in the range of 40 to 150 gms and more preferably 50 to 120 gms. When the plaster is less than 40 gms, in this case, lidocaine is not sufficiently dissolved and is crystallized; the crystallized lidocaine cannot be efficiently transferred to the skin. Additionally, it is difficult to control the adhesion of the patch and the plaster is not flexible against the skin and fails to maintain moderate adhesion. In contrast, when the plaster is more than 150 gm, the plaster is so heavy that plaster dripping easily occurs.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
EXAMPLES
Example 1
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 1
7. Propylene glycol 1
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol solution. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).
Example 2
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 2
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in oleic acid. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 3
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Propylene glycol 2
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 4
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 1
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in oleic acid. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 5
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Propylene glycol 1
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 6
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 0.5
7. Propylene glycol 0.5
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol solution. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 7
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.30
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 0.75
7. Propylene glycol 0.75
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol solution. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 8
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 1.5
7. Propylene glycol 0.5
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol solution. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 9
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 0.5
7. Propylene glycol 1.5
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol solution. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 10
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 1
7. Propylene glycol 1
8. Diethylene glycol monoethyl ether 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in mixture of oleic acid and propylene glycol solution. Lidocaine solution, diethylene glycol monoethyl ether, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 11
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Oleic acid 2
7. Diethylene glycol monoethyl ether 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in oleic acid. Lidocaine solution, diethylene glycol monoethyl ether, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 12
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Styrene isoprene styrene block copolymer 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoulene 0.2
6. Propylene glycol 2
7. Diethylene glycol monoethyl ether 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and styrene isoprene styrene block copolymer, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in propylene glycol. Lidocaine solution, diethylene glycol monoethyl ether, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 13
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 1
7. Propylene glycol 1
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 14
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 2
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in oleic acid. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 15
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Propylene glycol 2
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 16
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 1
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in oleic acid. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 17
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Propylene glycol 1
7. Iso-propyl myristate 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 18
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 0.5
7. Propylene glycol 0.5
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 19
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 74.30
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 0.75
7. Propylene glycol 0.75
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 20
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 1.5
7. Propylene glycol 0.5
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 21
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 0.5
7. Propylene glycol 1.5
8. Iso-propyl myristate 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol. Lidocaine solution, iso-propyl myristate, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 22
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 1
7. Propylene glycol 1
8. Diethylene glycol monoethyl ether 2
9. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in a mixture of oleic acid and propylene glycol. Lidocaine solution, diethylene glycol monoethyl ether, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 23
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Oleic acid 2
7. Diethylene glycol monoethyl ether 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in oleic acid. Lidocaine solution, diethylene glycol monoethyl ether, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

Example 24
S.No Ingredients Quantity (% w/w)
1. Lidocaine base 5
2. Hot melt adhesive Pressen 1471 73.80
3. Ethylene vinyl acetate 12
4. Hydrogenated hydrocarbon resin 4
5. Butylated hydroxytoluene 0.2
6. Propylene glycol 2
7. Diethylene glycol monoethyl ether 2
8. Mineral oil 1
Total weight of plaster: 40 to 150 gms
Backing type: non-woven fabric, 100% polyester (90 gms)
Release liner: Polyethylene terephthalate (75 micron)

Manufacturing process
The hot melt adhesive Pressen 1471 and ethylene vinyl acetate, hydrogenated hydrocarbon resin and mineral oil were placed in a dissolution mixer, melted and stirred continuously under heating at 130ºC-150ºC. The solution was cooled to 100oC to 120oC. Lidocaine was dissolved separately in propylene glycol. Lidocaine solution, diethylene glycol monoethyl ether, butylated hydroxytoulene and mineral oil were added to obtained adhesive mixture and stirred continuously at 100oC to 120oC until the mixture become homogenous, thereby obtaining a plaster solution. The plaster solution was coated on non-woven fabric 100% polyester and was then laminated with polyethylene terephthalate release liner. The resultant was then cut into a rectangle size (14 cm x 10 cm: 140 cm2).

The physical property of adhesive matrix i.e. Tack adhesion of in house patch was found to be more than Reference products, the value was between 4.0 newton to 7.0 newton tested by probe tack method using Universal Testing machine. With application of test product to human skin for 12 hrs, after removal of patch from skin, no residue was remained on the skin. The results are as follows.

The matrix adhesive patch prepared as per the Example no. 1 of the present invention is evaluated for the tack adhesion test.

Table No. 1: Tack adhesion test
S.No Example 1 Lidoderm® 5% ZtlidoTM 1.8% Salonpas® lidocaine 4% Gel patch
1 6.03 1.03 4.36 0.94
2 6.38 0.93 5.21 0.86
3 5.48 1.21 5.23 0.77
4 5.92 0.87 4.21 0.35
5 4.14 1.08 5.44 0.36
Average 5.59 1.02 4.89 0.65
In vitro drug release Test of In house lidocaine patch 5% Vs Salonpas® Lidocaine 4% Gel patch & ZTlidoTM Patch 1.8%
The patch containing 5% w/w lidocaine of the present invention was compared with reference product Salonpas® lidocaine 4% Gel patch (Manufactured by Hisamitsu Pharmaceutical Co. Inc.) & ZTlidoTM Patch 1.8% (Manufactured by Scilex Pharmaceuticals Inc.)

In vitro release test performed through human cadaver skin by using Franz diffusion cell. The 1.539 cm2 patch was attached on the human cadaver skin and then placed between the donor and receptor compartments of the cells, with the human cadaver skin side in direct contact with the receptor medium. Approx. 7 ml of the Phosphate buffer (pH 7.4) was placed in the receptor compartment. Its temperature was maintained at 32 ± 0.5°C using a water bath. This whole assembly was kept on a magnetic stirrer and solution in the receiver compartment was continuously stirred during the whole experiment using magnetic bead. The samples were withdrawn at different time intervals and an equal amount of phosphate buffer (pH 7.4) was replaced each time. Absorbances of the samples were read spectrophotometrically. The amount of lidocaine permeated per square centimetre at each time interval was calculated and plotted against time with the receptor medium shown in figures. Based on the results of in vitro-skin permeation study, the in house lidocaine patch 5% is bioequivalent with Salonpas® 4% Gel patch & ZTlidoTM patch 1.8%.

Adhesion performance
The In house non-aqueous lidocaine patch 5% is designed to equivalent to the Ztlido® 1.8%, Lidoderm® patch 5% and Salonpas® Lidocaine 4% Gel patch but with less lidocaine and superior adhesive properties. Because these properties are achieved by compounding the drug within the adhesive mixture layered onto the backing material, adhesion performance is very important property. Adhesion performance was measured 24 hours following application in 21 subjects who, sequentially by randomization, received In house non-aqueous lidocaine patch 5% and the comparator, ZtlidoTM patch 1.8%, Lidoderm® patch 5% and Salonpas® lidocaine 4% gel patch with a 3 day patch free resting period between products. The adhesion to the skin was scored as follows: 0-greater or equal to 90% adhered; 1-greater or equal to 75% adhered but less than 90% adhered; 2-greater or equal to 50% adhered but less than 75% adhered; 3-greater than 0% adhered but less than 50% adhered; and 4-0% adhered.

The matrix adhesive patch prepared as per the Example no. 1 of the present invention is evaluated for the adhesion performance study.

Table No. 2: Adhesion performance study
Score Example 1 Lidoderm® Patch 5% ZtlidoTM Patch 1.8% Salonpas® lidocaine 4% Gel patch
0 16 3 10 3
1 2 4 5 5
2 2 4 3 5
3 1 8 2 6
4 0 2 1 2
N* 21 21 21 21
N*: Total No. of subjects

After 24 Hr of adhesion study, 76.19% of the in house non-aqueous lidocaine patch 5% remained essentially adhered to the skin as compared with 14.28% of the Lidoderm® patch 5% & Salonpas® 4% gel patch and 47.61% of the ZtlidoTM patch 1.8%. In total only 4.76% of the in house non-aqueous lidocaine patch 5% had detached from the skin by 50% or more as compared to 47.61% of the Lidoderm® patch 5%, 38.09% of the Salonpas® 4% gel patch and 14.28% of the ZtlidoTM patch 1.8%.

From the above study, it is observed that the in house non-aqueous lidocaine patch 5% has better adhesion than Lidoderm® patch 5%, Salonpas® 4% Gel patch and ZtlidoTM patch 1.8%.

During adhesion study, skin sensitization and irritation study was conducted, who received in house non-aqueous lidocaine patch 5%, Lidoderm® patch 5%, Salonpas® 4% Gel patch and ZtlidoTM patch 1.8% every 24 hours for 21 days. Local tolerability was monitored throughout the study to assess dermal sensitization potential and irritability.

No skin sensitization and irritation was associated with either patch. The in house non-aqueous lidocaine patch 5%, Salonpas® 4% Gel patch & ZtlidoTM patch 1.8%, however, resulted in more skin reactions of greater severity than were observed with Lidoderm® patch 5% & Salonpas® 4% gel patch. Nevertheless, the in house non-aqueous patch 5% and ZtlidoTM patch 1.8% reactions were considered to be generally mild, acceptable to subjects and not clinically significant.

The matric adhesive patch prepared as per the Example no. 1 of the present invention is evaluated for the stability at different conditions and the data is given below tables;

Table 3
Stability Condition: 40°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow coloured matrix type transdermal patch that is rectangular shaped consisting of white backing, drug matrix & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 36 mg of Lidocaine Base
Limit: 32.4 mg to 39.6 mg
i.e 90% to 110% of label claim 106.6 102.4 101.9 103.8
Uniformity of Dosage Units (by Content Uniformity) L1 = 15 3.1

2.9 3.8 4.2
Dissolution 3 Hrs: NLT 40%
6 Hrs: NLT 60%
12 Hrs: NLT 75%

3 Hrs: 65.2%
6 Hrs: 79.3%
12 Hrs: 95.1 %

3 Hrs: 62.9%
6 Hrs: 77.5%
12 Hrs: 91.9 %
3 Hrs: 60.4%
6 Hrs: 75.8%
12 Hrs: 90.7 %
3 Hrs: 60.1%
6 Hrs: 73.1%
12 Hrs: 91.3 %

Related Substances Impurity H: NMT 0.1%
Impurity A: NMT 0.01%
Highest Unknown Imp: NMT 0.2%
Total Imp: NMT 1.0 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.06 %
Total Imp: 0.14 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.08 %
Total Imp: 0.12 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.07 % at 0.54 RRT
Total Imp: 0.10 % Impurity H:: BDL
Impurity A: 0.006 %
Highest Unknown Imp: 0.13 % at 0.81 RRT
Total Imp: 0.371 %
Butylated hydroxy toulene Content Each patch contains 1.44 mg of BHT
Limit: 1.29 mg to 1.58 mg
i.e 90% to 110% of label claim 109.8% 94.8% 93.9 % 97.8 %
Tack Test NLT 3.0 N 6.10 6.31 5.98 6.15
Peel Test NLT 6.0 N 9.71 9.43 9.21 9.52

Table 4

Stability Condition: 30°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow coloured matrix type transdermal patch that is rectangular shaped consisting of white backing, drug matrix & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 36 mg of Lidocaine Base
Limit: 32.4 mg to 39.6 mg
i.e 90% to 110% of label claim 106.6 % 103.5 % 104.0% 102.4%
Uniformity of Dosage Units (by Content Uniformity) L1 = 15 3.1

3.6 3.1 2.9
Dissolution 3 Hrs: NLT 40%
6 Hrs: NLT 60%
12 Hrs: NLT 75%

3 Hrs: 65.2%
6 Hrs: 79.3%
12 Hrs: 95.1 %

3 Hrs: 65.1%
6 Hrs: 80.2%
12 Hrs: 94.4%
3 Hrs: 63.8%
6 Hrs: 78.2%
12 Hrs: 93.1 %
3 Hrs: 62.1%
6 Hrs: 77.1%
12 Hrs: 92.3 %

Related Substances Impurity H: NMT 0.1%
Impurity A: NMT 0.01%
Highest Unknown Imp: NMT 0.2%
Total Imp: NMT 1.0 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.06 %
Total Imp: 0.14 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.05 %
Total Imp: 0.11 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.05 %
Total Imp: 0.05% Impurity H: BDL
Impurity A: 0.003%
Highest Unknown Imp: 0.073 %
Total Imp: 0.188 %
Butylated hydroxy toulene Content Each patch contains 1.44 mg of BHT
Limit: 1.29 mg to 1.58 mg
i.e 90% to 110% of label claim 109.8% 102.7% 104.8 % 99.9 %
Tack Test NLT 3.0 N 6.10 6.23 6.03 5.91
Peel Test NLT 6.0 N 9.7 9.2 9.1 9.0

Table 5

Stability Condition: 25°C/60% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow coloured matrix type transdermal patch that is rectangular shaped consisting of white backing, drug matrix & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 36 mg of Lidocaine Base
Limit: 32.4 mg to 39.6 mg
i.e 90% to 110% of label claim 106.6 % 104.4 % 103.1 % 102.8 %
Uniformity of Dosage Units (by Content Uniformity) L1 = 15 3.1

2.8 2.9 3.5
Dissolution 3 Hrs: NLT 40%
6 Hrs: NLT 60%
12 Hrs: NLT 75% 3 Hrs: 65.2%
6 Hrs: 79.3%
12 Hrs: 95.1 %
3 Hrs: 67.1%
6 Hrs: 82.4%
12 Hrs: 93.9% 3 Hrs: 64.1%
6 Hrs: 79.9%
12 Hrs: 94.7 % 3 Hrs: 63.7%
6 Hrs: 78.4%
12 Hrs: 93.8 %
Related Substances Impurity H: NMT 0.1%
Impurity A: NMT 0.01%
Highest Unknown Imp: NMT 0.2%
Total Imp: NMT 1.0 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.06 %
Total Imp: 0.14 % Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.07 %
Total Imp: 0.14% Impurity H: BDL
Impurity A: BDL
Highest Unknown Imp: 0.07 %
Total Imp: 0.08 % Impurity A: BDL
Impurity H: BDL
Highest Unknown Imp: 0.057 %
Total Imp: 0.151 %
BHT Content Each patch contains 1.44 mg of BHT
Limit: 1.29 mg to 1.58 mg
i.e 90% to 110% of label claim
109.8%
101.4% 97.1 % 99.8 %
Tack Test NLT 3.0 N 6.10 6.15 5.85 6.17
Peel Test NLT 6.0 N 9.7 9.0 9.8 9.3

,CLAIMS:
We Claim:
1. A low amount Lidocaine non-aqueous matrix adhesive patch comprising as active ingredient, low concentration of dissolving agent, adhesive material and pharmaceutically acceptable excipients.
2. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 1, wherein the Lidocaine is in the range of 1% to 5% (w/w), preferably 5% (w/w) of the total weight of the composition.
3. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 1, wherein the dissolving agent is organic acid and polyalcohol either individually or as a mixture.
4. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 3, wherein the organic acid is selected from oleic acid, short-chain fatty acids having 2 to 7 carbon atoms such as acetic acid, butyric acid and hexanoic acid; medium-chain fatty acids having 8 to 11 carbon atoms such as octanoic acid and decanoic acid; long-chain fatty acids having more than 12 carbon atoms such as myristic acid, stearic acid and isostearic acid; short-chain fatty acids substituted with a hydroxy group, an alkoxy group or an acyl group such as glycolic acid, lactic acid, methoxyacetic acid, mandelic acid, levulinic acid and 3-hydroxybutyric acid; benzene carboxylic acid such as benzoic acid, p-hydroxybenzoic acid, salicylic acid and acetylsalicylic acid; and organo sulfonic acid such as benzene sulfonic acid, toluenesulfonic acid, methyl sulfonic acid and dodecyl benzene sulfonic acid.
5. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 3, wherein the polyalcohol is selected from propylene glycol, di-propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerine etc.
6. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 3, wherein the mixture of organic acid and polyalcohols is in the range of 1% to 2% (w/w) to 5% (w/w) of lidocaine.
7. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 1, wherein the dissolving agent is in the range of 1% to 2% (w/w) of the total weight of the composition.
8. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 1, wherein the adhesive material is used in combination of one or more adhesive materials selected from styrene isoprene styrene block copolymer, ethylene vinyl acetate, hot melt adhesive Pressen 1471, synthetic rubber-based hot melt adhesives, polyolefin based hot melt adhesive, olyamide based hot melt adhesive, polyester-based hot melt adhesives, polyurethane-based hot melt adhesives, styrene isoprene thermoplastic elastomer, preferably styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive Pressen 1471.
9. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 8, wherein the adhesive material is in the range of 50% to 90% (w/w), preferably 70% to 90% (w/w) of the total weight of the composition.
10. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from tackifying agent, plasticizer, penetration enhancers and antioxidants.
11. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 10, wherein the tackifying agent is selected from petroleum resins (e.g., aliphatic hydrocarbon resins, alicyclic hydrocarbon resins, and aromatic hydrocarbon resins), phenolic resins, xylene resins and coumarone indene resins rosin derivatives (e.g., rosin, glycerin esters of rosin, hydrogenated rosins, glycerin esters of hydrogenated rosin, pentaerythritol esters of rosin, etc.), saturated alicyclic hydrocarbon resins (e.g., ARKON P-100), aliphatic hydrocarbon resins (e.g., Quintone B170) terpene resins (e.g., Clearon P-125), maleic acid resins and the like.
12. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 11, wherein the tackifying agent is in the range of 2% to 8% (w/w), preferably 3% to 5% (w/w) of the total weight of the composition.
13. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 10, wherein the plasticizer is selected from mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, oleyl alcohol, liquid paraffins, hydrogenated oils, hydrogenated castor oil, higher alcohols such as octyldodecanol, castor oil, petroleum-based oil (for example, paraffinic process oil, naphthenic process oil, or aromatic process oil), vegetable based oils (for example, olive oil, camellia oil, tall oil or arachis oil), dibasic acid esters (for example, dibutyl phthalate, dioctyl phthalate, or the like), liquid rubbers (for example, polybutene, liquid isoprene rubber), liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate, or diisopropyl sebacate), diethylene glycol, polyethylene glycol; glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate and crotamiton.
14. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 13, wherein the plasticizer is in the range of 0.5 to 3% (w/w), preferably 0.5 to 2% (w/w) of the total weight of the composition.
15. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 10, wherein the penetration enhancer is selected from isopropyl myristate, diethylene glycol monoethyl ether, dodecyl sulfoxide mono- or dimethyl acetamide, N-hydroxy ethyl lactide, higher fatty acid esters, salicylic acid, sorbitol, urea, glycerin, squalene, squalane, acetylated lanolin, cetyl laurate, olive oil, castor oil, lauric acid, oleic acid, lauryl alcohol, oleyl alcohol, ethoxy stearyl alcohol, liquid paraffin, vaseline, camphor, glycerin fatty acid ester, fatty acid mono- (or di-) ethanol amide, ethylene glycol mono ethyl ether, polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polyoxypropylene alkyl ether, propylene glycol mono(di)alkyl ester, propylene glycol monolaurate, polyoxyethylene lauryl ether and pyrrolidone derivatives.
16. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 15, wherein the penetration enhancer is in the range of 1% to 3% (w/w) of the total weight of the composition.
17. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 10, wherein the antioxidant is selected from butylated hydroxy toulene, tocopherol and ester derivatives thereof, butylated hydroxy anisole, ascorbic acid, ascorbyl stearate, ascorbyl palmitate, nordihydroguaiaretic acid, etc.
18. The low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 17, wherein the antioxidant is in the range of 0.1 to 0.5% (w/w), preferably 0.1 to 0.3% (w/w) of the total weight of the composition.
19. A process for preparing low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 1, wherein the process comprising steps of:
a) melting combination of adhesive materials and tackyfying agent at 130ºC – 150ºC,
b) dissolving Lidocaine in organic acid and polyalcohol solution either individually or as a mixture,
c) adding penetration enhancer, antioxidant, plasticizer to active ingredient solution and adding to obtained adhesive mixture of step (a) under continuous stirring,
d) coating the obtained adhesive base of step (c) on polyester nonwoven or woven fabric,
e) laminating the dried adhesive matrix by polyethylene terephthalate silicone coated release liner, and
f) cutting into desired size to get non-aqueous matrix adhesive patch, pouching and labelling.
20. The process for preparing low amount Lidocaine non-aqueous matrix adhesive patch as claimed in claim 19, wherein the process comprising steps of:
a) melting styrene isoprene styrene block copolymer or ethylene vinyl acetate & hot melt adhesive Pressen 1471 and hydrogenated hydrocarbon resin at 130ºC – 150ºC,
b) dissolving Lidocaine in oleic acid and propylene glycol solution either individually or as a mixture,
c) adding isopropyl myristate or diethylene glycol monoethyl ether, butylated hydroxytoulene, mineral oil to Lidocaine solution and adding to obtained adhesive mixture of step (a) under continuous stirring at 100 to 120ºC,
d) coating the obtained adhesive base of step (c) on 100% polyester nonwoven or woven fabric,
e) laminating the dried adhesive matrix by 100% polyethylene terephthalate silicone coated release liner, and
f) cutting into desired size to get non-aqueous matrix adhesive patch, pouching and labelling.

Dated this Tenth (10th) day of June, 2020

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883