DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

TULOBUTEROL TRANSDERMAL 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 a composition of bronchodilator transdermal patch.

The present invention also relates to a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients.

The present invention specifically relates to a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients for relieving obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and bronchitis with asthma.

The present invention more specifically relates to process for the preparation of Tulobuterol transdermal patch by hot-melt coating technique (HMC) comprising the steps of melting, adding, mixing, coating, laminating and cutting.

BACKGROUND OF INVENTION
Bronchodilators are a type of medication that makes breathing easier by relaxing the muscles in the lungs and widening the airways (bronchi). They're often used to treat long-term conditions where the airways may become narrow and inflamed, such as: (a) asthma, a common lung condition caused by inflammation of the airways, (b) chronic obstructive pulmonary disease (COPD), a group of lung conditions, usually caused by smoking, that make breathing difficult.

Bronchodilators may be either: (a) short-acting bronchodilators-used as short-term relief from sudden, unexpected attacks of breathlessness, (b) long-acting bronchodilators-used regularly to help control breathlessness in asthma and COPD, and increase the effectiveness of corticosteroids in asthma.

Tulobuterol is a ß2-adrenergic receptor agonist widely used in the treatment of acute bronchitis, chronic bronchitis, bronchial asthma, pulmonary emphysema, and like respiratory conditions to relieve dyspnea of patients suffering from bronchoconstriction. Tulobuterol is a recognized bronchodilator that acts selectively at a ß2-receptor of the sympathetic nervous system to relax the bronchial smooth muscles. The chemical name of Tulobuterol is (RS)-2-tert-butylamino-1-(2-chlorophenyl) ethanol. Tulobuterol has a chemical formula of C12H18ClNO and a molecular mass of 227.73 g/mol. It has a structural formula of:

Generally tulobuterol is administered in oral (tablets and syrups), inhalation (aerosol) and topical (ointment and cream) routes. The problems associated with oral route including difficult to administer to infants, steep increases of the drug concentration in the blood and a brief period of therapeutic efficacy. Aerosolized forms may lead to incorrect or excessive inhalation in case of misuse. When applied topically in ointment or cream form easily removed by clothing, making it difficult to control effecting the therapeutic dosage. Further, there would be dosing errors with ointments and creams. Hence, there is a requirement for the development of safe and easy to use formulation, which can provide sustained drug release.

US 5,254,348 A discloses transdermal therapeutic system with tulobuterol or one of the pharmaceutically acceptable salts thereof as active substance, comprising a backing layer which is substantially impermeable to active substances and at least one matrix layer which contains the active substance, which matrix layer comprises at least one styrene-1,3-diene-styrene block copolymer.

US 5,571,530 A discloses percutaneous preparation of tulobuterol comprising a support having thereon a base layer comprising a pressure-sensitive adhesive containing tulobuterol, the pressure-sensitive adhesive comprising polyisobutylene.

US 5,639,472 A discloses percutaneous absorption preparation comprising a support and, formed on one side thereof, a plaster layer comprising a pressure-sensitive adhesive and tulobuterol in an amount not lower than its saturation solubility in the pressure-sensitive adhesive.

US 5,866,157 A discloses matrix patch formulation which comprises an adhesive layer containing an organic acid, a physiological active substance comprising a basic drug which forms an ion pair with said organic acid, a hydrophobic high molecular weight material, a tackifying resin, a plasticizer and an absorption enhancer.

US 6,117,447 A discloses percutaneous absorption preparation comprising a support and a plaster layer laminated thereon, said plaster layer comprising tulobuterol in a proportion of not less than 5 wt % in a dissolution state and an adhesive, wherein the adhesive is an acrylic adhesive or a rubber adhesive.

US 7,056,528 B1 discloses a transdermal therapeutic system comprising a largely water vapor-impermeable backing layer, at least one active substance-containing matrix layer comprising the active substance tulobuterol, as well as a removable protective layer, is characterized in that said matrix is built-up on the basis of polyacrylate pressure-sensitive adhesives and contains tulobuterol in the form of its salt tulobuterol hydrochloride as active substance.

US 7,744,918 B2 discloses drug-containing patch which is very favourable in percutaneous absorbability and is excellent in sustainability of the drug efficacy, that is, the drug-containing patch having a sufficient percutaneous absorbability and effect sustainability in a degree to be actually used for therapy of patients. It discloses patch comprising tulobuterol, an adhesive base, at least one melting point lowering agent that lowers the melting point of the drug to increase skin permeation rate of the drug.

US 7,939,100 B2 discloses tulobuterol adhesive patch comprising (a) a support, (b) an acrylic pressure-sensitive adhesive layer containing the percutaneously absorbing drug tulobuterol and if necessary a lipophilic oily plasticizer, and (c) a release liner, laminated in that order, wherein the acrylic pressure-sensitive adhesive is a copolymer obtained by copolymerizing an acrylic monomer which is acetoacetoxyalkyl (meth)acrylate with one or more other vinyl monomers, to yield a tulobuterol adhesive patch with excellent release and skin permeability of tulobuterol from the pressure-sensitive adhesive layer, low skin irritation and excellent safety.

US 8,029,820 B2 discloses patches containing Tulobuterol in soluble form in adhesive matrix in the low concentration and having the stable release controllability, prepared by laminating an adhesive layer consisting of a rubber, an adhesive resin and plasticizer on a backing, wherein 1 to 4 % w/w of Tulobuterol in the lower concentration as an active ingredient and 0.1 to 3 % w/w of higher fatty acid as a drug releasing controlling agent are contained in the adhesive layer.

US 8,506,992 B2 percutaneous absorption-type pharmaceutical preparation, which comprises: a support comprising a plastic film and a nonwoven fabric; and a plaster layer containing tulobuterol, wherein the plastic film and the nonwoven fabric are laminated with an adhesive having a glass transition temperature of 40°C-90°C., and the plaster layer is laminated on opposite side of the plastic film surface that the nonwoven fabric is laminated with.

There are several Tulobuterol transdermal patches available in the market like Hokunalin, Tulobuterol Tape Sawai, Tulobuterol Tape Nichi-lko, Tulobuten Tape, Tulobuterol Tape HMT, Sekinarin Tape, Tulobuterol Tape Takata, Tulobuterol Tape Ohara, Tulobuterol Tape Teikoku, Tulobuterol Tape MED, Tulobuterol Tape SN, Tulobuterol Tape NP, Tuloplast, Bretol Patch etc.

All the prior art references discloses Tulobuterol transdermal patch comprising backing layer, matrix layer having styrene-1,3-diene-styrene block copolymer or polyisobutylene pressure-sensitive adhesive or organic acid, a hydrophobic high molecular weight material, a tackifying resin, a plasticizer and absorption enhancer or acrylic adhesive or a rubber adhesive. The inventors of present invention provide Tulobuterol transdermal patch comprising Tulobuterol as active ingredient, combination styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471 as hot melt adhesives and pharmaceutically acceptable excipients for relieving obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and bronchitis with asthma. The inventors of present invention also provide process for the preparation of Tulobuterol transdermal patch by hot-melt coating technique (HMC) comprising the steps of melting, adding, mixing, coating, laminating and cutting.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients for relieving obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and bronchitis with asthma.

Still another objective of the present invention is to provide a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and tackifying material, vehicle, antioxidant, optionally plasticizer as pharmaceutically acceptable excipients.

Still another objective of the present invention is to provide a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, combination of styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471 as hot melt adhesives, Arkon as tackifying resin, mineral oil as vehicle, butylated hydroxytoluene as antioxidant and optionally propylene glycol as plasticizer.

Still another objective of the present invention is to provide process for the preparation of Tulobuterol transdermal patch by hot-melt coating technique (HMC) comprising the steps of melting, adding, mixing, coating, laminating and cutting.

Still another objective of the present invention is to provide process for the preparation of Tulobuterol transdermal patch by hot-melt coating technique (HMC) comprising the steps of melting hot melt adhesives, adding tackifier and vehicle, adding active ingredient in powder form or adding dissolved active ingredient in vehicle and antioxidant into molten adhesive blend, coating, drying, laminating and cutting into desired size.

Still another objective of the present invention is to provide an improved/efficient manufacturing process for preparation of Tulobuterol transdermal patch by hot-melt coating technique, 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 obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and
bronchitis with asthma by application of Tulobuterol transdermal patch.

SUMMARY OF INVENTION
Accordingly, the present invention relates to a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients for relieving obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and bronchitis with asthma.

In another embodiment, the present invention provides a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, hot melt adhesives and tackifying material, vehicle, antioxidant, optionally plasticizer as pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a composition of bronchodilator transdermal patch comprising Tulobuterol as active ingredient, combination of styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471 as hot melt adhesives, Arkon as tackifying resin, mineral oil as vehicle, butylated hydroxytoluene as antioxidant and optionally propylene glycol as plasticizer

In another embodiment, the present invention provides process for the preparation of Tulobuterol transdermal patch by hot-melt coating technique (HMC) comprising the steps of melting, adding, mixing, coating, laminating and cutting.

In yet another embodiment, the present invention provides composition of bronchodilator transdermal patch comprising:
(a) 1% to 5% (w/w) of active ingredients,
(b) 1 to 95% (w/w) of hot melt adhesives,
(c) 1 to 18% (w/w) of tackifying material,
(d) 1 to 10% (w/w) of vehicle,
(e) 0.1 to 5% (w/w) of antioxidant, and
(f) optionally 0.5 to 4% (w/w) of plasticizer.

In yet another embodiment, the present invention provides composition of Tulobuterol transdermal patch comprising:
(a) 1% to 5% (w/w) of Tulobuterol,
(b) 1 to 95% (w/w) of combination of styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471,
(c) 1 to 18% (w/w) of Arkon,
(d) 1 to 10% (w/w) of mineral oil,
(e) 0.1 to 5% (w/w) of butylated hydroxytoluene, and
(f) optionally 0.5 to 4% (w/w) of propylene glycol.

In still another embodiment, the present invention is to provide an improved/efficient manufacturing process for preparation of Tulobuterol transdermal patch by hot-melt coating technique, 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 of the present invention provides a process for the preparation of bronchodilator transdermal patch, the process comprising steps of:
(a) melting hot melt adhesives under stirring at temperature in the range of 100ºC-180ºC,
(b) adding tackifier and mineral oil (50% of batch quantity) to molten adhesive base under stirring at temperature in the range of 100ºC -180ºC,
(c) adding active ingredient either directly in powder form or previously dissolved in a vehicle (50% of batch quantity) and antioxidant mixture or vehicle, antioxidant and plasticizer mixture to molten adhesive blend under stirring to obtain homogenous material at temperature 90ºC-110ºC,
(d) coating on to the polyethylene terephthalate release liner,
(e) laminating the obtained adhesive matrix, and
(f) cutting into desired size to get transdermal patch, pouching and labelling.

In yet another embodiment of the present invention provides a process for the preparation of Tulobuterol transdermal patch, the process comprising steps of:
(a) melting combination of styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471under stirring at temperature in the range of 100ºC-180ºC,
(b) adding Arkon and mineral oil (50% of batch quantity) to molten adhesive base under stirring at temperature in the range of 100ºC -180ºC,
(c) adding Tulobuterol either directly in powder form or previously dissolved in mineral oil (50% of batch quantity) and butylated hydroxytoluene mixture or mineral oil (50% of batch quantity), butylated hydroxytoluene and propylene glycol mixture to molten adhesive blend under stirring to obtain homogenous material at temperature 90ºC-110ºC,
(d) coating on to the polyethylene terephthalate release liner,
(e) laminating the obtained adhesive matrix, and
(f) cutting into desired size to get transdermal patch, pouching and labelling.

BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows comparison of in vitro drug release of Tulobuterol transdermal patch according to Example 1 with TuloplastTM.
Figure 2 shows comparison of in vitro drug release of Tulobuterol transdermal patch according to Example 2 with TuloplastTM.
Figure 3 shows comparison of in vitro drug release of Tulobuterol transdermal patch according to Example 5 with TuloplastTM.

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 bronchodilator transdermal patch comprising Tulobuterol as active ingredient and pharmaceutically acceptable excipients.

The term “active ingredient” of the present invention is used to relieve obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and bronchitis with asthma. Preferably used active ingredient is bronchodilator. Most preferably used active ingredient is Tulobuterol.

The concentration of active ingredient used in the bronchodilator transdermal patch is from 1% to 5% (w/w) and most preferably used concentration of active ingredient is from 1% to 3% (w/w).

Tulobuterol ((R, S)-2-tert-butylamino-1-(2-chlorophenyl) ethanol) transdermal tapes are used to cure bronchial asthma as a bronchodilator (ß2-blocker). TBR is one of the suitable compounds for systemic transdermal formulation because it has very high permeability into the keratin layer.

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”, a “dressing”, a “topical carrier system”.

The term “hot melt adhesives” of the present invention includes combination of one or more hot melt adhesives and includes at least two adhesives selected from the group of ethylene-vinyl acetate copolymer series (EVA hot melt adhesive), 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 hot melt adhesive is combination of styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471.

The concentration of hot melt adhesives used in the bronchodilator transdermal patch is from 1 to 95 % (w/w) and most preferably used concentration of hot melt adhesives is from 15 to 93% (w/w).

Tackifying material used in the composition of the present invention include, but are 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), aliphatic hydrocarbon resins (e.g., Quintone B170) terpene resins (e.g., Clearon P-125), maleic acid resins and the like. Preferably used tackifying material is Arkon.

The concentration of tackifying material used in the bronchodilator transdermal patch is from 1 to 18 % (w/w) and most preferably used concentration of tackifying material is from 1 to 15% (w/w).

Vehicle used herein refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art, i.e., any liquid gel, solvent, liquid diluent, adhesive, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner. Vehicle, which also may function as solvents in some instances, are used to provide the compositions of the invention in their preferred form. Examples include, but not limited to ethanol, propanol, isopropanol, mineral oil, silicone, polyethylene glycol, polypropylene glycol, waxes, petroleum jelly and a variety of other oils, aloe and polymeric materials along with polyacrylate, silicone, natural and synthetic rubbers or other adhesives. Preferably used vehicle is mineral oil.

The concentration of vehicle used in the bronchodilator transdermal patch is from 1 to 10 % (w/w) and most preferably used concentration of hot melt adhesives is from 3 to 6% (w/w).

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 hydroxytoluene.

The concentration of antioxidant used in the bronchodilator transdermal patch is from 0.1 to 5% (w/w) and most preferably used concentration of antioxidant 0.1 to 3% (w/w).

Plasticizer as used in the composition of present invention includes glycol derivatives such as propylene glycol, polyethylene glycol, glycerine, phthalate esters such as dibutyl phthalate, diethyl phthalate, phosphate esters, fatty acid esters such as Oleic acid etc,. Preferably, used plasticizer is propylene glycol.

The concentration of plasticizer used in the bronchodilator transdermal patch is from 0.5 to 4% (w/w) and most preferably used concentration of plasticizer is 0.5 to 2% (w/w).

The transdermal patch of the present invention has been prepared by hot melt coating technique. The advantage of this technique is simple and easy to manufacture, more economical and solvent free technique. Using HMC technique tuning drug release, adhesiveness (tack) and physical properties of patch is relatively good compared to solvent-based coating technique.

The transdermal patch preparation of present invention has been used by hot melt coating technique using polyethylene terephthalate release liner and coated layer is laminated using tan polyethylene and aluminum vapor coated polyester backing material.

The molten adhesive blend preparation comprising the SIS and Pressen 1471 or EVA and Pressen 1471 as hot melt adhesives. The physical & mechanical properties of matrix are achieved only with the combination of SIS and Pressen 1471 or EVA and Pressen 1471 to get the desired adhesion & flexibility to intact matrix.

The content of Pressen 1471 and SIS should contain 15% to 90% by mass with respect to total mass of adhesive layer. If the content falls within this range, the cohesive property and tack of adhesive layer can be maintained. Accordingly, favorable application properties can be obtained.

Various properties associated with each component of the transdermal patch compositions may affect the properties of the final product. Properties associated with the selection of raw materials, concentration and viscosity may influence the intact matrix formation, adhesion and therapeutic effect.

The invention disclosed herein is process for the preparation of bronchodilator transdermal patch useful in relieving obstructive disorders of airway, such as bronchial asthma, chronic bronchitis and bronchitis with asthma.

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 and prepared by the process of the present invention.

Example 1
S.No Ingredients Concentration (%) mg/patch
1. Tulobuterol 3 2
2. (Styrene Isoprene styrene thermoplastic elastomer) - SIS 5002 17 11.333
3. Pressen 1471 72 48
4. Arkon-P 100 4.5 3
5. Mineral oil 3 2
6. Butylated hydroxytoluene (BHT) 0.5 0.33

Manufacturing process
The hot melt adhesive blend was prepared by melting Pressen 1471 and SIS under stirring at 100ºC-180ºC temperature. Later, to the molten adhesive mineral oil (50% of batch quantity) and Arkon were added under stirring to obtain homogenous adhesive blend.

Tulobuterol was dissolved in mineral oil (50% of batch quantity) and BHT mixture and added to the molten adhesive blend at 110ºC. The hot melt adhesive blend was uniformly coated with desired thickness on to the polyethylene terephthalate release liner and laminated using PET backing. Then the resulting product cut into a desired size to produce transdermal patch and finally packed in triple laminated aluminum pouch.

Example 2
S.No Ingredients Concentration (%) mg/patch
1. Tulobuterol 3 2
2. (Styrene Isoprene styrene thermoplastic elastomer) - SIS 5002 17 11.333
3. Pressen 1471 70 46.66
4. Arkon-P 100 4.5 3
5. Mineral oil 3 2
6. Butylated hydroxytoluene (BHT) 0.5 0.33
7. Propylene Glycol 2 1.33

Manufacturing process
The hot melt adhesive blend was prepared by melting Pressen 1471 and SIS under stirring preferably at 100ºC-180ºC temperature. To the molten adhesive mineral oil, Arkon, propylene glycol and BHT were added under stirring to obtain homogenous adhesive blend. Later, Tulobuterol was directly added in powder form to blend under stirring to obtain homogenous mixture at 110ºC.

The hot melt adhesive blend was uniformly coated with desired thickness on to the polyethylene terephthalate release liner and laminated using PET backing. Then the resulting product cut into a desired size to produce transdermal patch and finally packed in triple laminated aluminum pouch.

Example 3
S.No Ingredients Concentration (%) mg/patch
1. Tulobuterol 3 2
2. Ethyl vinyl acetate 30 20
3. Pressen 1471 63.5 42.329
4. Mineral oil 3 2
5. Butylated hydroxytoluene (BHT) 0.5 0.33

Manufacturing process
The hot melt adhesive blend was prepared by melting of Pressen 1471 and EVA under stirring preferably at 100ºC-130ºC temperature.

Tulobuterol was dissolved in mineral oil and BHT mixture and added to the molten adhesive blend at 110ºC. The hot melt adhesive blend was uniformly coated with desired thickness on to the polyethylene terephthalate release liner and laminated using PET backing. Then the resulting product cut into a desired size to produce transdermal patch and finally packed in triple laminated aluminum pouch.

Example 4
S.No Ingredients Concentration (%) mg/patch
1. Tulobuterol 3 2
2. Ethyl vinyl acetate 30 20
3. Pressen 1471 63.5 42.329
4. Mineral oil 3 2
5. Butylated hydroxytoluene (BHT) 0.5 0.33

Manufacturing process
The hot melt adhesive blend is prepared by melting of Pressen 1471 and EVA under stirring preferably at 100ºC-130ºC temperature. To the molten adhesive mineral oil and BHT were added under stirring to obtain homogenous adhesive blend. Later, Tulobuterol was directly added in powder form to blend under stirring to obtain homogenous mixture at 110ºC.

The hot melt adhesive blend was uniformly coated with desired thickness on to the polyethylene terephthalate release liner and laminated using PET backing. Then the resulting product cut into a desired size to produce transdermal patch and finally packed in triple laminated aluminum pouch.

Example 5
S.No Ingredients Concentration (%) mg/patch
1. Tulobuterol 3 2
2. (Styrene Isoprene styrene thermoplastic elastomer) - SIS 5002 4 2.67
3. Pressen 1471 69.5 46.33
4. Arkon-P 100 15 10
5. Mineral oil 6 4
6. Propylene glycol 2 1.33
7. Butylated hydroxytoulene (BHT) 0.5 0.33

Manufacturing process
The hot melt adhesive blend was prepared by melting Pressen 1471 and SIS under stirring at 100ºC-180ºC temperature. Later, to the molten adhesive mineral oil (50% of batch quantity) and Arkon were added under stirring to obtain homogenous adhesive blend.

Tulobuterol was dissolved in mineral oil (50% of batch quantity), BHT & propylene glycol mixture and added to the molten adhesive blend at 90ºC. The hot melt adhesive blend was uniformly coated with desired thickness on to the polyethylene terephthalate release liner and laminated using PET backing. Then the resulting product cut into a desired size to produce transdermal patch and finally packed in triple laminated aluminum pouch.

In Vitro Drug Release study of In House Tulobuterol Transdermal Patch Vs TuloplastTM
In house Tulobuterol Transdermal Patch was compared with reference product TuloplastTM Tulobuterol Transdermal Patch (Manufacture by Teikoku seiyaku.co. Ltd., Japan)
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 skin side in direct contact with the receptor medium. Approx. 7 ml of the 0.9% Saline solution 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. Absorbance of the samples were read spectrophotometrically. The amount of Tulobuterol permeated per square centimeter at each time interval was calculated and plotted against time with the receptor medium as per Example 1 is shown in Figure 1, as per Example 2 is shown in Figure 2 and as per Example 5 is shown in Figure 3. Based on the results of in vitro-skin permeation study, the in house Tulobuterol Transdermal patch is bioequivalent with TuloplastTM Tulobuterol Transdermal Patch.
The matrix 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 in tables 1, 2 & 3;

Table 1
Stability Condition: 25°C/60% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 117.5% 109.4 % 106.2 % 102.1 %
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 10.2
10.4 10.9 11.5
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 Hr: 35.3%
4 Hrs: 78%
8 Hrs: 110.6%

1 Hr: 35.3%
4 Hrs: 73.4%
8 Hrs: 88.2% 1hr 34.5%
4hr 74.1%
8hr 90.3% 1hr 36.3%
4hr 73.1%
8hr 87.3%
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.31%
Total impurities : 0.81% Max unknown imp : 0.30%
Total impurities : 0.77% Max unknown imp : 1.55%
Total impurities : 2.2% Max unknown imp : 0.79%
Total impurities : 2.58%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 98.1% 101.7% 100.7% 101.9%
Tack Test NLT 2.0 N 4.2 N 4.2 N 4.1 N 3.9 N

Table 2
Stability Condition: 30°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 117.5% 111.3% 107.4% 101.2%
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 10.2 10.8 11.2 11.8
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1hr 35.3%
4hr 78.0%
8hr 110.6% 1hr 37.9%
4hr 75.8%
8hr 87.8% 1hr 35.6%
4hr 73.5%
8hr 89.1% 1hr 37.1%
4hr 74.5%
8hr 86.3%
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.31%
Total impurities : 0.81% Max unknown imp : 0.45%
Total impurities : 0.94% Max unknown imp : 1.48%
Total impurities : 2.28% Max unknown imp : 1.03%
Total impurities : 3.36%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 98.1% 97.3% 95.6 94.4 %
Tack Test NLT 2.0 N 4.2 N 4.1 N 4.0 N 3.7 N

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 colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 117.5% 107.3% 103.6% 97.5%
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 10.2 10.4 11.7 11.0
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1hr 35.3%
4hr 78.0%
8hr 110.6% 1hr 36.9%
4hr 73.5%
8hr 87.2% 1hr 35.0%
4hr 70.3%
8hr 85.1% 1hr 34.1%
4hr 68.4%
8hr 81.3%
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.31%
Total impurities : 0.81% Max unknown imp : 0.57%
Total impurities : 1.02% Max unknown imp : 1.18%
Total impurities : 2.27% Max unknown imp : 1.37%
Total impurities : 4.18%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 98.1% 95.8% 93.6 % 91.7%
Tack Test NLT 2.0 N 4.2 N 4.0 N 3.5 N 2.8 N

The matrix adhesive patch prepared as per the Example no. 2 of the present invention is evaluated for the stability at different conditions and the data is given below in tables 4, 5 & 6;

Table 4
Stability Condition: 25°C/60% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 117.5% 109.4 % 106.2 % 102.1 %
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 9.2 9.9 10.2 10.8
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 hr -50.4%
4 hr-87.6%
8 hr-96.6% 1 hr -48.7%
4 hr-86.9%
8 hr-94.9% 1 hr -51.6%
4 hr-87.8%
8 hr-94.5% 1 hr -49.6%
4 hr-83.7%
8 hr-91.5%
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.33%
Total impurities : 0.62% Max unknown imp : 0.34%
Total impurities : 0.71% Max unknown imp : 1.16%
Total impurities : 1.70% Max unknown imp : 0.53%
Total impurities : 1.75%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 109.9% 106.1% 108.9% 98.8 %
Tack Test NLT 2.0 N 4.0 N 3.8 N 3.7 N 3.3 N

Table 5
Stability Condition: 30°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 119.9% 110.6% 107.5% 100.1%
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 9.2 9.4 9.9 10.2
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 hr -50.4%
4 hr-87.6%
8 hr-96.6% 1 hr -55.6%
4 hr-88.9%
8 hr-92.6% 1 hr -51.6%
4 hr-85.2%
8 hr-90.3% 1 hr -49.8%
4 hr-81.3%
8 hr-89.1%
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.33%
Total impurities : 0.62% Max unknown imp : 0.37%
Total impurities : 0.81% Max unknown imp : 1.15%
Total impurities : 1.77% Max unknown imp : 0.84%
Total impurities : 2.90%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 109.9% 108.4% 105.3% 95.1 %
Tack Test NLT 2.0 N 4.0 N 3.7 N 3.5 N 3.2 N

Table 6
Stability Condition: 40°C/75% RH
Test Specification Initial 1 Month 3 Month 6 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 119.9% 108.4% 105.3% 98.9%
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 9.2 9.8 10.4 10.6
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 hr -50.4%
4 hr-87.6%
8 hr-96.6% 1 hr -44.3%
4 hr-84.6%
8 hr-92.6% 1 hr -42.4%
4 hr-74.4%
8 hr-81.8%
1 hr -28.2%
4 hr-68.5%
8 hr-76.3%
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.33%
Total impurities : 0.62% Max unknown imp : 0.40%
Total impurities : 0.84% Max unknown imp : 1.01%
Total impurities : 1.91% Max unknown imp : 0.83%
Total impurities : 3.29%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 109.9% 106.3% 101.9% 95.2 %
Tack Test NLT 2.0 N 4.0 N 3.6 N 3.1 N 2.7 N

The matrix adhesive patch prepared as per the Example no. 5 of the present invention is evaluated for the stability at different conditions and the data is given below in tables 7, 8 & 9;
Table 7
Stability Condition: 25°C/60% RH
Test Specification Initial 1 Month 3 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 112.2 % 109.4 % 108.8 %
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 9.5 10.1 10.8
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 hr -29 %
4 hr -57 %
8 hr -78 % 1 hr -29 %
4 hr -55 %
8 hr -77 % 1 hr -29 %
4 hr -56 %
8 hr -75 %
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.35%
Total impurities : 0.48% Max unknown imp : 0.76%
Total impurities : 1.45% Max unknown imp : 0.85%
Total impurities : 1.63%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 96.9 %
98.8 % 97.3
Tack Test NLT 2.0 N 4.31 N 4.72 N 4.15 N

Table 8
Stability Condition: 30°C/75% RH
Test Specification Initial 1 Month 3 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 112.2 % 101.7 % 99.8 %
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 9.5 10.4 11.2
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 hr -29 %
4 hr -57 %
8 hr -78 % 1 hr -27 %
4 hr -56 %
8 hr -74 % 1 hr -25 %
4 hr -54 %
8 hr -71 %
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.35%
Total impurities : 0.48% Max unknown imp : 0.77%
Total impurities : 1.47% Max unknown imp : 0.83%
Total impurities : 1.70%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 96.9 %
97.8 % 97.1
Tack Test NLT 2.0 N 4.31 N 4.12 N 3.51 N

Table 9
Stability Condition: 40°C/75% RH
Test Specification Initial 1 Month 3 Month
Description It is thin, transparent to pale yellow colour matrix type transdermal patch, that is square shape consisting of tan colour backing & release liner. Complies Complies Complies
Assay (%) Each patch contains 2.0 mg of Tulobuterol
Limit: (1.8 mg to 2.4 mg)
i.e 90 % to 120% of label claim 112.2 % 101.0 % 97.4 %
Uniformity of Dosage Units (by Content Uniformity) The acceptance value is L1 = 15 9.5 10.1 10.4
Dissolution NLT 15% of tulobuterol is released in 1 hr
NLT 45% of tulobuterol is released in 4 hr
NLT 65% of tulobuterol is released in 8 hr 1 hr -29 %
4 hr -57 %
8 hr -78 % 1 hr -26 %
4 hr -55 %
8 hr -72 % 1 hr -24 %
4 hr -53 %
8 hr -70 %
Related Substances Max unknown impurity :NMT 2.0%
Total impurities :NMT 5.0% Max unknown imp : 0.35%
Total impurities : 0.48% Max unknown imp : 0.97%
Total impurities : 1.82% Max unknown imp : 0.98%
Total impurities : 2.02%
BHT Content Each patch contains 0.333 mg of Tulobuterol
Limit: (0.266 mg to 0.366 mg)
i.e 80 % to 110% of label claim 96.9 % 95.2 % 94.6 %
Tack Test NLT 2.0 N 4.31 N 3.50 N 3.21 N

,CLAIMS:We Claim:
1. A bronchodilator transdermal patch composition comprising Tulobuterol as active ingredient, hot melt adhesives and pharmaceutically acceptable excipients.
2. The bronchodilator transdermal patch composition as claimed in claim 1 comprising:
(a) Tulobuterol,
(b) hot melt adhesives,
(c) tackifying material,
(d) vehicle,
(e) antioxidant, and
(f) optionally plasticizer.
3. The bronchodilator transdermal patch composition as claimed in claim 2, wherein the Tulobuterol is in the range of 1% to 5% (w/w), preferably in the range of 1% to 3% (w/w) of the total weight of the composition.
4. The bronchodilator transdermal patch composition as claimed in claim 1, wherein the hot melt adhesives includes at least two adhesives selected from the group of ethylene-vinyl acetate copolymer series (EVA hot melt adhesive), 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.
5. The bronchodilator transdermal patch composition as claimed in claim 4, wherein the hot melt adhesives is in the range of 1 to 95 % (w/w), preferably in the range of 15 to 93% (w/w) of the total weight of the composition.
6. The bronchodilator transdermal patch composition as claimed in claim 2, wherein the tackifying material is selected from petroleum resins such as aliphatic hydrocarbon resins, alicyclic hydrocarbon resins, and aromatic hydrocarbon resins; phenolic resins, xylene resins and coumarone indene resins rosin derivatives such as rosin, glycerin esters of rosin, hydrogenated rosins, glycerin esters of hydrogenated rosin, pentaerythritol esters of rosin; saturated alicyclic hydrocarbon resins such as ARKON; aliphatic hydrocarbon resins such as Quintone B170; terpene resins such as Clearon P-125, maleic acid resins and the like.
7. The bronchodilator transdermal patch composition as claimed in claim 6, wherein the tackifying material is in the range of 1 to 18% (w/w), preferably in the range of 1 to 15% (w/w) of the total weight of the composition.
8. The bronchodilator transdermal patch composition as claimed in claim 2, wherein the vehicle is selected from ethanol, propanol, isopropanol, mineral oil, silicone, polyethylene glycol, polypropylene glycol, waxes, petroleum jelly and a variety of other oils, aloe and polymeric materials along with polyacrylate, silicone, natural and synthetic rubbers or other adhesives.
9. The bronchodilator transdermal patch composition as claimed in claim 8, wherein the vehicle is in the range of 1 to 10 % (w/w), preferably in the range of 3 to 6% (w/w) of the total weight of the composition.
10. The bronchodilator transdermal patch composition as claimed in claim 2, wherein the antioxidant is selected from butylated hydroxy toluene, tocopherol and ester derivatives thereof, butylated hydroxy anisole, ascorbic acid, ascorbyl stearate, ascorbyl palmitate, nordihydroguaiaretic acid etc.
11. The bronchodilator transdermal patch composition as claimed in claim 10, wherein the antioxidant is in the range of 0.1 to 5% (w/w), preferably in the range of 0.1 to 3% (w/w) of the total weight of the composition.
12. The bronchodilator transdermal patch composition as claimed in claim 2, wherein the plasticizer is propylene glycol, polyethylene glycol, glycerine, phthalate esters such as dibutyl phthalate, diethyl phthalate, phosphate esters; fatty acid esters such as Oleic acid.
13. The bronchodilator transdermal patch composition as claimed in claim 12, wherein the plasticizer is in the range of 0.5 to 4% (w/w), preferably in the range of 0.5 to 2% (w/w) of the total weight of the composition.
14. A process for the preparation of bronchodilator transdermal patch claimed in claim 1, wherein the process comprising steps of:
(a) melting hot melt adhesives under stirring at temperature in the range of 100ºC-180ºC,
(b) adding tackifier and mineral oil (50% of batch quantity) to molten adhesive base under stirring at temperature in the range of 100ºC -180ºC,
(c) adding active ingredient either directly in powder form or previously dissolved in vehicle (50% of batch quantity) and antioxidant mixture or vehicle, antioxidant and plasticizer mixture to molten adhesive blend under stirring to obtain homogenous material at temperature 90ºC-110ºC,
(d) coating on to the polyethylene terephthalate release liner,
(e) laminating the obtained adhesive matrix, and
(f) cutting into desired size to get transdermal patch, pouching and labelling.
15. The process for the preparation of Tulobuterol transdermal patch claimed in claim 14, wherein the process comprising steps of:
(a) melting combination of styrene isoprene thermoplastic elastomer (SIS) and Pressen 1471 or Ethyl vinyl acetate (EVA) and Pressen 1471under stirring at temperature in the range of 100ºC-180ºC,
(b) adding Arkon and mineral oil (50% of batch quantity) to molten adhesive base under stirring at temperature in the range of 100ºC -180ºC,
(c) adding Tulobuterol either directly in powder form or previously dissolved in mineral oil (50% of batch quantity) and butylated hydroxytoluene mixture or mineral oil (50% of batch quantity), butylated hydroxytoluene and propylene glycol mixture to molten adhesive blend under stirring to obtain homogenous material at temperature 90ºC-110ºC,
(d) coating on to the polyethylene terephthalate release liner,
(e) laminating the obtained adhesive matrix, and
(f) cutting into desired size to get transdermal patch, pouching and labelling.

Dated this Twenty Ninth (29th) day of July, 2020

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