FIELD OF THE INVENTION

The present invention relates to the taste masked orally dissolving strip formulations of amlodipine or pharmaceutically acceptable salts thereof, comprising amlodipine or pharmaceutically acceptable salts thereof as the active ingredient, surfactant, taste masking agent and least one water soluble polymeric component, and at least one pharmaceutically acceptable excipient. The invention further relates to the process for the preparation thereof.

BACKGROUND OF THE INVENTION

Calcium channel blockers are useful in treating a variety of cardiac conditions, primarily angina and hypertension.

EP 089167B1 discloses a class of substituted dihydro pyridine derivatives as being useful calcium channel blockers. This patent identify that one of the most preferred compounds is 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l,4dihydro pyridine, which is commonly known amlodipine (I)

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol.

Amlodipine itself does not behave satisfactory in photo-stability and preservation stability, and thus various salts are prepared to improve these characteristics. For example, EP '167 patent itself teaches that besylate salt and maleate salt are preferable among various salts of amlodipine. Thus, amlodipine currently commercially available with the trade name of Norvasc® is a besylate salt in the form of conventional tablets.

Moon, Young-Ho ; et al in US2004/0116478 discloses the another salt of amlodipine as camsylate salt with the improved the photo-stability and preservation stability along with the formulation of the same as solid oral tablet.

Tatsumi; Noboru et al in US 20110294860A1 discloses the stable aqueous oral preparation of amlodipine comprising amlodipine and an anionic surfactant having sulfuric acid group or sulfonic acid group and water. The preferred anionic surfactant disclosed in the patent application is sodium lauryl sulfate. US '860 Publication further states that the anionic surfactant is used to stabilize the amlodipine and also to mask the bitter taste of the amlodipine.

The form of preparing and dispensing of the conventional oral solid dosage forms of amlodipine and its pharmaceutically acceptable salts and the aqueous solutions disclosed in the US '860 publication has many disadvantages that includes a large proportion of adjuvants are added to the conventional oral solid and liquid dosage forms and further needs the additional storage space.

Despite disclosure of various formulations in liquid as well as solid dosage forms, however, still there exists a need for a convenient and patient friendly dosage form as well as to overcome the existing disadvantages of the stability, storage and difficulty in administration.

Inventors of the present application have provided here as an alternative to the conventional oral solid and liquid dosage forms as- taste masked orally dissolving strip formulation of amlodipine or pharmaceutically acceptable salts thereof, which not only addresses the existing disadvantages of the stability, storage and administration but also provide convenient and patient friendly dosage form.

SUMMARY OF THE INVENTION

In one aspect of the present invention, it relates to taste masked orally dissolving strips of amlodipine or pharmaceutically acceptable salts thereof comprising amlodipine or pharmaceutically acceptable salts, surfactant, taste masking agent and at least one water soluble polymeric component, and at least one pharmaceutically acceptable excipient.

In another aspect according to the present invention, it relates to taste masked orally dissolving strips of amlodipine or pharmaceutically acceptable salts thereof, comprising amlodipine or pharmaceutically acceptable salts thereof, surfactant, taste masking agent, flavoring agent and water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein the water soluble polymeric component comprises polyethylene oxide, hydrophilic cellulosic polymer and Maltodextrin.

In yet another aspect of the present application, it relates to a process for preparing amlodipine taste masked orally dissolving strip comprising the steps of-

a. preparing a taste masked orally dissolving strip composition of amlodipine or pharmaceutically acceptable salts thereof comprising amlodipine or pharmaceutically acceptable salts thereof, surfactant, taste masking agent, flavoring agent, water soluble polymeric component and at least one
pharmaceutically acceptable excipient

b. The composition prepared as per the step a.) is subjected to get layered on the heat stable polymer sheet

c. Layered composition on polymer sheet of step b) dried for a time ranging between 5 to 30 minutes at about 75-1059C

d. Collecting the dried and slitted orally dissolving unit strip of amlodipine or pharmaceutically acceptable salts

In a further aspect of the present application, it relates to taste masked oral amlodipine strip formulation, which has features as - Oral Strip thickness in the range of 0.13 to 0.20 mm, weight in the range of 45 to 130 mg, and surface area 450 to 1200mm, which is useful as in the treatment of cardiovascular diseases such as angina pectoris, hypertension, congestive cardiac paralysis and the like.

Further aspects of the present invention are demonstrated in detailed description section as well as examples.

DESCRIPTION OF THE INVENTION

As set forth herein, aspects of the present invention provides taste masked orally dissolving strips of amlodipine or pharmaceutically acceptable salts thereof comprising amlodipine or pharmaceutically acceptable salts, surfactant, taste masking agent and at least one water soluble polymeric component, and at least one pharmaceutically acceptable excipient.

Reference will now be made in detail to the presently preferred embodiments of the invention, which, together with the following examples, serve to explain the principles of the invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other embodiments may be utilized, and that various structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention.

In this embodiment of the present invention, it provides taste masked orally dissolving strips formulation of amlodipine or pharmaceutically acceptable salts thereof, comprising amlodipine or pharmaceutically acceptable salts thereof, surfactant, taste masking agent, flavoring agent and water soluble polymeric component and at least one pharmaceutically acceptable excipient, wherein the water soluble polymeric component comprises polyethylene oxide, hydrophilic cellulosic polymer and Maltodextrin.

The surfactants used in amlodipine strip formulation include, but are not limited to, sodium docusate, polyoxyethylene ether, poloxamer, polysorbates (Tween), polyoxyethylene stearates, cremophore, sodium lauryl sulfate, sorbitan esters and combinations thereof. In a particular embodiment of orally dissolving strips formulation of amlodipine or pharmaceutically acceptable salts, surfactant used is sodium lauryl sulphate. In accordance with the present invention, surfactant quantities may range from about 4 to 15 % w/w of the total dosage form.

The taste masking agents used in the stable orally dissolving strips of amlodipine or pharmaceutically acceptable salts thereof are preferably selected from Ion exchange resins.

Ion exchange resins preferred for use in the strips of the invention are water-insoluble and consist of a pharmacologically inert organic or inorganic matrix containing covalently bound functional groups that are ionic or capable of being ionized under the appropriate conditions of pH. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene), or partially synthetic (e.g., modified cellulose and dextrans). The inorganic matrix can also be, e.g., silica gel modified by the addition of ionic groups. The covalently bound ionic groups may be strongly acidic (e.g., sulfonic acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., quaternary ammonium), weakly basic (e.g., primary amine), or a combination of acidic and basic groups. :
In general, those types of ion exchangers suitable for use in ion exchange chromatography and for such applications as deionization of water are suitable for use in these controlled release drug preparations. Such ion exchangers are described by H. F. Walton in "Principles of Ion Exchange" (pp. 312 343). The resin is crosslinked with a crosslinking agent selected from difunctional compounds capable of crosslinking polystyrenes; these are commonly known in the art. Preferably, the crosslinking agent is a divinyl or polyvinyl compound. Most preferably the crosslinking agent is divinylbenzene. In a particular embodiment, taste masking agents used was Polacrillic Acid, Polacrillin Potassium and combination thereof.

As used the "water soluble polymeric component" refers to a polymeric component that comprises "water soluble polymer" that is at least partially soluble in water and fully or predominantly soluble in water or swellable in water.

The "water soluble polymer" may be partially water soluble polymer or predominantly water soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer. The polymers may include cellulose or cellulose derivatives. Suitable examples of water soluble polymer includes but are not limited to, polyethylene oxide, pullulan; hydroxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water-swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof. In accordance with the present invention "water soluble polymeric component" desirably ranges from about 20% to 50% w/w of the total weight of the dosage form. In a particular embodiment of the present invention, about 35% w/w of the water soluble polymeric component of the total weight of the dosage form.

The water soluble polymers utilized in the strip formulation are hydrophilic cellulosic polymer, maltodextrin and polyethylene oxide or combinations thereof. The Polyethylene oxide polymer, in combination with a hydrophilic cellulosic polymer and Maltodextrin achieves flexible, strong films. The cellulosic polymers used in combination with Polyethylene oxide and Maltodextrin are selected from but are not limited to HPC, and HPMC.

In accordance with the present invention polyethylene oxide desirably ranges from about 5% to 20% by weight of the water soluble polymeric component, preferably from about 5% to 15% by weight of the water soluble polymeric component by weight of the water soluble polymeric component. The stable rapid orally dissolving strips of amlodipine or pharmaceutically acceptable salts thereof with Polyethylene oxide of low viscosity.

In accordance with the present invention the cellulosic polymer preferably used is Hydroxypropy I methyl cellulose (HPMC). The low viscosity grade HPMC used is preferably in the range of about 5 to 15 cps. In one embodiment of the invention, the brand name (Methocel E15 Premium LV) was used.

Hydroxypropylmethyl ranges from about 30% to 100% by weight of the water soluble polymeric component, preferably from about 40% to 90% by weight of the water soluble polymeric component.

A further embodiment of the invention, another water soluble polymeric component comprises Maltodextrin. Maltodextrin polymer appears to increase the viscosity of the solution present in the formulation that apparently aids in providing the flexibility and tensile strength to the dried films of the amlodipine strip formulation of the present invention. The range of the water soluble polymeric component may vary from about 20% to 40% by weight of the water soluble polymeric component.

The composition of the amlodipine strip comprises plasticizer, which is utilized to impart flexibility, enhance elasticity and decrease brittleness. Preferred Plasticizers in the formulation of the present invention include triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol or combinations thereof.

Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, vanilla, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors.

Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin), combinations thereof and the like.
The sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-l-l-l,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.

Also color additives can be used in preparing the strips. A colouring agent, which may be provided in a dosage form of the present invention, includes pharmaceutically acceptable natural or artificially cynthesized dyes. A great variety of such pharmaceutically acceptable dyes have been known to be suitable for use in pharmaceutical compositions, for example natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin/CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, spinach, stinging nettle, titanium dioxide, turmeric, natural colors, aronia/redfruit, beet juice colors, paprika extract, paprika oleoresin; or artificial dyes such as allura red, Brilliant blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, and tartrazine.

The composition of the amlodipine strip comprises use of solvent, which may be selected from C2-C4 alcohols, purified water and combinations thereof. In one of the particular embodiment, isopropanol was used.

The diluents used in the amlodipine strip formulation are selected from but not limited to mannitol, macrocrystalline cellulose (MCC), lactose and combinations thereof. In one of the particular embodiment, mannitol was used.

In yet another aspect of the present application, it relates to a process for preparing amlodipine orally dissolving strip comprising the steps of-

a. preparing a taste masked orally dissolving strip composition of amlodipine or pharmaceutically acceptable salts thereof comprising amlodipine or pharmaceutically acceptable salts thereof, surfactant, taste masking agent, water soluble polymeric component and at least one pharmaceutically
acceptable excipient

b. The composition prepared as per the step a.) is subjected to get layered on the heat stable polymer sheet

c. Layered composition on polymer sheet of step b) dried for a time ranging between 5 to 30 minutes at about 75-1052C

d. Collecting the dried and slitted orally dissolving unit strip of amlodipine or pharmaceutically acceptable salts.

In a further aspect of the present application, it relates to taste masked oral amlodipine strip formulation, which has features as - Oral Strip thickness in the range of 0.13 to 0.20 mm, weight in the range of 45 to 130 mg, and surface area 450 to 1200mm, which is useful as in the treatment of cardiovascular diseases such as angina pectoris, hypertension, congestive cardiac paralysis and the like.

The oral strip according to the invention may have any shape but not limited to oblong, circular, square, rectangular, triangular or mutliangular. The shape may not be as important as the surface area and the compliance to the drug content required for therapeutic purpose as long as strip weight, tensile strength and other physical parameters are well in the acceptable ranges.

Certain specific aspects and embodiments of the present application relating to methods of preparing orally dissolving strips formulation of amlodipine or pharmaceutically acceptable salts shall be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXPERIMENTAL DETAILS

The process for preparation according to the present invention of a taste masked orally dissolving strip formulation of amlodipine besylate may be demonstrated by examples as given below.

Example-1: Amlodipine strip formulation (lOmg Unit)

The process for the preparation of the taste masked orally dissolving strip formulation of amlodipine besylate involves the following steps.

1. About 62 ml of Purified water was taken in a glass beaker, and then Polacrillin potassium (~28 gm) is added to it and stirred for 10 minutes.

2. Amlodipine besylate (~13.8 gm) was added to the contents of step 1 and stirred for about 5-10 minutes.

3. Sodium lauryl sulfate (lOgm), Sucralose (5gm), Mannitol (2 gm) flavoring agent (10 gm), Maltodextrin (12.5gm), Polyethylene oxide (3.25 gm), were added to the contents of step 2 gradually and stepwise and stirred the contents for about 5-20 minutes.

4. Hydroxy Propyl methyl cellulose solution (19.8gm in 105 gm water) was added to the contents of step 3 and stirred for 5-15 minutes.

5. Glycerol (10 gm), Color (0.08gm) and Isopropyl alcohol (58.5 ml) were added stepwise to the contents of step 4 and stirred for 10 minutes

6. The solution was subjected to deaeration.

7. The Step No. 6 composition is subjected to layering on the heat stable polyester sheet and allowed to dry for 10 to 25 minutes at 905C ± 15 ec.

8. Slit the above dried Amlodipine besylate strip of size equivalent to unit dose containing 10 mg of Amlodipine.

Slited Unit Strip physical parameters:
Example- 2: Amlodipine strip formulation (5 mg Strip Unit)

The process for the preparation of the taste masked orally dissolving strip formulation of amlodipine besylate containing 5 mg drug involves the steps similar to the steps as mentioned in the above example within the dose proportion quantities as per the example. The observed slit Unit Strip physical parameters were –

The composition obtained from the above formulation in the unit strip dose can be summarized as per the
table-3

Table-3: Composition for dosage strip unit

Present in traces

Example- 3: Amlodipine strip formulation (5 mg Strip Unit)
The process for the preparation of the taste masked orally dissolving strip formulation of amlodipine besylate containing 5 mg drug involves the steps similar to the steps as mentioned in the example-1.

Observed slit Unit Strip physical parameters obtained after analysis of the dried strip formulation were -

The composition of the above formulation in the unit strip dose can be summarized as per the table-4

Table-4: Composition for dosage strip unit

The aboVe-mentioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.

We claim:

1. A taste masked orally dissolving strip formulation of amlodipine or pharmaceutically acceptable salts thereof comprising amlodipine or pharmaceutically acceptable salts thereof, surfactant, taste masking agent, flavoring agent, water soluble polymeric component and at least one pharmaceutically acceptable excipient.

2. The orally dissolving strip formulation according to claim 1, wherein surfactant is selected from propylene glycol, polysorbate, sodium lauryl sulfate, or poloxamer.

3. The orally dissolving strip formulation according to claim 1, wherein taste masking agent is selected from Polyacrillic acid, potassium Polacrillin and combinations thereof.

4. The orally dissolving strips formulation according claim 1, wherein the water soluble polymeric component selected from polyethylene oxide, hydrophilic cellulosic polymer and Maltodextrin or mixtures thereof.

5. Amlodipine taste masked orally dissolving strip formulation according to claim-1, wherein weight of the strip range from 45 to 130 mg and thickness in the range of 0.13 to 0.20 mm.

6. Amlodipine taste masked orally dissolving strip formulation according to claim-5, wherein the surface area of the strip is in the range of 450 to 1200mm.

7. A process for preparing Amlodipine orally dissolving strip comprising the steps of-

a. preparing a taste masked orally dissolving strip composition of amlodipine or pharmaceutically acceptable salts thereof comprising amlodipine or pharmaceutically acceptable salts thereof, surfactant, taste masking agent, flavoring agent, water soluble polymeric component and at least one pharmaceutically acceptable excipient

b. the composition prepared as per the of the step a.) is subjected to layered on the heat stable polymer sheet

c. layered composition on polymer sheet of step b) dried for a time ranging between 5 to 30 minutes at about 75-1052C

d. collecting the dried and slitted orally dissolving unit strip of amlodipine or pharmaceutically acceptable salts.