SLEEP AID TRANSDERMAL PATCH AND ITS PROCESS OF PREPARATION

Abstract

The present invention relates to composition of sleep aid transdermal patch comprising natural herbal ingredient as active ingredient, synergistic additives and pharmaceutically acceptable excipients. The present invention relates to composition of transdermal patch comprising valerian as natural herbal ingredient, skullcap, licorice, passionflower as synergistic additives and pharmaceutically acceptable excipients to aid sleep in insomnia conditions. The present invention also relates to an efficient process for the preparation of sleep aid transdermal patch by using hot-melt coating technique (HMC), comprising the steps of melting, mixing, coating, laminating and cutting.

Claims

1. A sleep aid transdermal patch composition comprising Valerian as herbal active ingredient, synergistic additives and pharmaceutically acceptable excipients.

2. The sleep aid transdermal patch composition as claimed in claim 1 comprising: (a) Valerian, (b) synergistic additives, (c) permeation enhancer, (d) hot melt adhesives, (e) tackifier, and (f) vehicle.

3. The sleep aid transdermal patch composition as claimed in claim 2, wherein the Valerian is in the range of 0.1 to 5% (w/w), more preferably 0.75 to 1.875% (w/w) of the total weight of the composition.

4. The sleep aid transdermal patch composition as claimed in claim 1, wherein the synergistic additives are skullcap, licorice and passionflower used individually or in combination.

5. The sleep aid transdermal patch composition as claimed in claim 4, wherein the individual synergistic additive is in the range of 0.1 to 10% (w/w), preferably used concentration of synergistic additives individually is from 0.125 to 0.75% (w/w) of the total weight of the composition.

6. The sleep aid transdermal patch composition as claimed in claim 4, wherein the combination synergistic additives are in the range of 0.1 to 3% (w/w) of the total weight of the composition.

7. The sleep aid transdermal patch composition as claimed in claim 2, wherein the permeation enhancer is selected from azones, isopropylmyristate, fatty acids, menthol, essential oils, terpenes, terpenoids, N-methyl-2-pyrrolidone, 1-dodecyl-azacycloheptan-2-one, oleic acid, oleyl alcohol, linoleic acid, isopropyl linoleate, butanediol, lauryl alcohol, lauryl acetate, lauryl lactate, ethyl acetate, dimethyl isosorbide and isostearic acid.

8. The sleep aid transdermal patch composition as claimed in claim 7, wherein the permeation enhancer is in the range of 0.1 to 3% (w/w), more preferably in the range of 0.1 to 2% of the total weight of the composition.

9. The sleep aid transdermal patch composition as claimed in claim 2, wherein the hot melt adhesives includes at least two adhesives selected from 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 and styrene isoprene thermoplastic elastomer.

10. The sleep aid transdermal patch composition as claimed in claim 9, wherein the hot melt adhesives is a combination of (styrene isoprene thermoplastic elastomer)-SIS 5002 and pressen 1471.

11. The sleep aid transdermal patch composition as claimed in claim 9, wherein the hot melt adhesives are in the range of 20 to 90% (w/w), preferably used concentration of hot melt adhesives individually is from 23 to 60% (w/w), preferably used in combination in the range of 70 to 90% (w/w), more preferably used combination in the range of 82 to 83.125% (w/w) of the total weight of the composition.

12. The sleep aid transdermal patch composition as claimed in claim 2, wherein the tackifier 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) and maleic acid resins.

13. The sleep aid transdermal patch composition as claimed in claim 12, wherein the tackifier is in the range of 1 to 10% (w/w), more preferably in the range of 3 to 6% (w/w) of the total weight of the composition.

14. The sleep aid transdermal patch composition as claimed in claim 2, wherein the vehicle is selected from water, ethanol, propanol, isopropanol, mineral oil, silicone, polyethylene glycol, polypropylene glycol, liquid sugars, waxes, petroleum jelly, variety of other oils, aloe, polymeric materials along with polyacrylate, silicone, natural and synthetic rubbers or other adhesives.

15. The sleep aid transdermal patch composition as claimed in claim 14, wherein the vehicle is in the range of 0.5 to 20% (w/w), more preferably in the range of 5 to 15% (w/w) of the total weight of the composition.

16. A process for preparing sleep aid transdermal patch claimed in claim 1, wherein the process comprising steps of: (a) melting hot melt adhesives under stirring at 100-180° C., (b) adding vehicle and tackifier to molten adhesive under stirring at 100-180° C., (c) adding active ingredient and synergistic additives along with permeation enhancer to molten adhesive blend under stirring to obtain homogenous material, (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.

17. The process for preparing sleep aid transdermal patch as claimed in claim 16, wherein the process comprising steps of: (a) melting SIS 5002 and Pressen 1471 under stirring at 100-180° C., (b) adding mineral oil and arkon-P 100 to molten adhesive under stirring at 100-180° C., (c) adding Valerian and passionflower, skullcap, licorice along with oleic acid to molten adhesive blend under stirring to obtain homogenous material, (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.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0077] 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.

[0078] The present invention provides sleep aid transdermal patch composition of sleep aid transdermal patch comprising natural herbal as active ingredient, synergistic additives and pharmaceutically acceptable excipients.

[0079] The present invention provides composition of sleep aid transdermal patch comprising valerian as natural herbal, skullcap, licorice, passionflower as synergistic additives and permeation enhancer, hot melt adhesives, tackifier, vehicle as pharmaceutically acceptable excipients.

[0080] The present invention provides composition of sleep aid transdermal patch comprising valerian as active ingredient and skullcap, licorice, passionflower as synergistic additives, oleic acid as permeation enhancer, (styrene isoprene thermoplastic elastomer)-SIS 5002 and pressen 1471 as hot melt adhesives, arkon-P 100 as tackifier and mineral oil as vehicle.

[0081] The term “active ingredients” of the present invention is used to relieve a person in need from insomnia conditions. Preferably used active ingredient is valerian.

[0082] Valerian has been used in sleeplessness with anxiety, spasms with mental tension, pain with muscle tension, anti convulsive for tremors, spasms, palpitations, menstrual cramps, eclectic use in cases of depression, nervous debility, as a stimulating nervine, headaches, palpitations, irritable or spastic bowel, high blood pressure, epilepsy and childhood behavior problems and learning.

[0083] The extract of the root of valerian (Valeriana officinalis), a flowering plant, has been widely used to treat sleeping disorders. Valerian is an effective treatment for insomnia, it may be an important treatment alternative because it is relatively inexpensive and without known side effects.

[0084] The valerenic acid in valerian root has been shown to inhibit breakdown of GABA, resulting in greater calm and relaxation. Provides sedative and sleep-enhancing properties. Restores circadian rhythm and maintains daytime freshness. Safe choice in case of stress-related conditions that result in sleeplessness, anxiety and irritability.

[0085] The concentration of valerian used in the sleep aid transdermal patch is in the range of 0.1 to 5% (w/w), more preferably 0.75 to 1.875% (w/w) of the total weight of the composition.

[0086] Valerian when used in combination with synergistic additives including passion flower, licorice and skullcap can provide synergistic additive effect in providing better sleep in insomnia conditions.

[0087] The concentration of synergistic additives used in the sleep aid transdermal patch is in the range of 0.1 to 10% (w/w). Preferably used concentration of synergistic additives individually is from 0.125 to 0.75% (w/w). The concentration of synergistic additives used in combination in the sleep aid transdermal patch of the present invention is from 0.1 to 3% (w/w).

[0088] 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, hot melt adhesives are (styrene isoprene thermoplastic elastomer)-SIS 5002 and pressen 1471.

[0089] Hot melt adhesives used in the sleep aid transdermal patch is in the range of 20 to 90% (w/w). Preferably used concentration of hot melt adhesives individually is from 23 to 60% (w/w). The concentration of hot melt adhesives used in combination in the sleep aid transdermal patch of the present invention is from 70 to 90% (w/w), more preferably in the range of 82 to 83.125% (w/w) of the total weight of the composition.

[0090] Permeation enhancer used in the composition of the present invention include, but are not limited to azones, isopropylmyristate, fatty acids, menthol, essential oils, terpenes, terpenoids, N-methyl-2-pyrrolidone, 1-dodecyl-azacycloheptan-2-one, oleic acid, oleyl alcohol, linoleic acid, isopropyl linoleate, butanediol, lauryl alcohol, lauryl acetate, lauryl lactate, ethyl acetate, dimethyl isosorbide, isostearic acid. Preferably, the permeation enhancer is oleic acid.

[0091] Permeation enhancer used in the sleep aid transdermal patch is in the range of 0.1 to 3% (w/w), more preferably in the range of 0.1 to 2% of the total weight of the composition.

[0092] Tackifier 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 P-100), aliphatic hydrocarbon resins (e.g., Quintone B170) terpene resins (e.g., Clearon P-125), maleic acid resins and the like. Preferably, the tackifier is arkon-P 100.

[0093] Tackifier used in the sleep aid transdermal patch is in the range of 1 to 10% (w/w), more preferably in the range of 3 to 6% (w/w) of the total weight of the composition.

[0094] “Vehicle” as 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, water, ethanol, propanol, isopropanol, mineral oil, silicone, polyethylene glycol, polypropylene glycol, liquid sugars, 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, the vehicle is mineral oil.

[0095] Vehicle used in the sleep aid transdermal patch is in the range of 0.5 to 20% (w/w), more preferably in the range of 5 to 15% (w/w) of the total weight of the composition.

[0096] 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.

[0097] The transdermal patch of the present invention has been prepared by hot melt coating technique using polyethylene terephthalate release liner and coated layer is laminated using nonwoven or woven fabric backing material.

[0098] The molten adhesive blend preparation comprising the SIS and pressen 1471 as hot melt adhesives. The physical & mechanical properties of adhesive matrix are achieved only with the combination of SIS 5002 and Pressen 1471 to get the desired adhesion & flexibility to adhesive matrix.

[0099] The content of SIS and pressen 1471 should contain 20% to 90% by mass with respect to total mass of transdermal patch. 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.

[0100] For the transdermal patch preparation of present invention, it is preferred that the permeation enhancer used to enhance the permeation of active ingredient and synergistic additives through the skin to provide better and fast therapeutic action. The concentration of permeation enhancer should be in the range of 0.1-3% by mass with respect to total mass of the adhesive matrix.

[0101] For the transdermal patch preparation of present invention, it is preferred that the tackifier play a key role to maintain optimum sticking to skin. The physical and mechanical properties of transdermal patch are achieved only with the optimized concentration of tackifier to get the desired tackiness & flexibility. The concentration of tackifier should be in the range of 1-10% by mass with respect to total mass of adhesive matrix.

[0102] 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, molecular weight, concentration and viscosity may influence the adhesive matrix formation, adhesion and therapeutic effect.

[0103] The invention disclosed herein is process for the preparation of transdermal patch useful in facilitating sleep.

Manufacturing Process for Sleep Aid Transdermal Patch:

1. Preparation of Hot Melt Adhesive Blend

[0104] The hot melt adhesive blend is prepared by melting of SIS and pressen 1471 under stirring preferably at 100° C.-180° C. temperature. Later, add mineral oil and arkon-P 100 to the molten adhesive under stirring to obtain homogenous adhesive blend. Preferably, the concentration of SIS should be in the range of 5-30% (w/w) and pressen 1471 should be in the range of 20-80% (w/w), preferably, mineral oil should be in the range of 0.5-20% (w/w), preferably, arkon-P 100 should be in the range of 1-10% (w/w).

2. Addition of Active and Synergistic Additives

[0105] Add valerian, passionflower, skullcap and licorice along with oleic acid to the molten adhesive blend under stirring to obtain homogenous material. Preferably, the concentration of valerian should be in the range of 0.1-5% (w/w), preferably, the concentration of passionflower should be in the range of 0.1-2% (w/w), preferably, the concentration of skullcap should be in the range of 0.1-2% (w/w), preferably, the concentration of licorice should be in the range of 0.05-2% (w/w), preferably, the concentration of oleic acid should be in the range of 0.1-3% (w/w).

3. Coating

[0106] The hot melt adhesive blend was uniformly coated with desired thickness on to the polyethylene terephthalate release liner.

4. Lamination and Cutting and Packaging

[0107] Then coated adhesive matrix was laminated using Nonwoven fabric.

5. Cutting and Packaging

[0108] Then the resulting product cut into a desired size to produce transdermal patch and finally packed in triple laminated aluminum pouch.

[0109] Formulations were developed using different concentrations of oleic acid, SIS, pressen 1471 and arkon-P 100. The formulations prepared with different variations were evaluated for their description, adhesion (tack), peel test, assay.

[0110] 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 bench scale.

Example 1

[0111]

TABLE-US-00001 Concentration mg/ S.No. Ingredients (%) patch 1. Valerian (Valeriana officinalis) 0.75 3 2. Passionflower (Passiflora incarnata) 0.75 3 3. Skullcap (Scutellaria baicalensis) 0.25 1 4. Licorice (Glycyrrhiza glabra) 0.125 0.5 5. Oleic acid 1 4 6. (Styrene Isoprene thermoplastic 23.125 92.5 elastomer)-SIS 5002 7. Pressen 1471 60 240 8. (Alicyclic saturated hydrocarbon 5 20 resin)-Arkon-P 100 9. Mineral oil 9 36

Example 2

[0112]

TABLE-US-00002 Concentration mg/ S.No. Ingredients (%) patch 1. Valerian (Valeriana officinalis) 1.125 4.5 2. Passionflower (Passiflora incarnata) 0.75 3 3. Skullcap (Scutellaria baicalensis) 0.25 1 4. Licorice (Glycyrrhiza glabra) 0.125 0.5 5. Oleic acid 1 4 6. (Styrene Isoprene thermoplastic 23 92 elastomer)-SIS 5002 7. Pressen 1471 59.75 239 8. (Alicyclic saturated hydrocarbon 5 20 resin)-Arkon-P 100 9. Mineral oil 9 36

Example 3

[0113]

TABLE-US-00003 Concentration mg/ S.No. Ingredients (%) patch 1. Valerian (Valeriana officinalis) 1.5 6 2. Passionflower (Passiflora incarnata) 0.75 3 3. Skullcap (Scutellaria baicalensis) 0.25 1 4. Licorice (Glycyrrhiza glabra) 0.125 0.5 5. Oleic acid 1 4 6. (Styrene Isoprene thermoplastic 23 92 elastomer)-SIS 5002 7. Pressen 1471 59.375 237.5 8. Alicyclic saturated hydrocarbon 5 20 resin)-Arkon-P 100 9. Mineral oil 9 36

Example 4

[0114]

TABLE-US-00004 Concentration mg/ S.No. Ingredients (%) patch 1. Valerian (Valeriana officinalis) 1.875 7.5 2. Passionflower (Passiflora incarnata) 0.75 3 3. Skullcap (Scutellaria baicalensis) 0.25 1 4. Licorice (Glycyrrhiza glabra) 0.125 0.5 5. Oleic acid 1 4 6. (Styrene Isoprene thermoplastic 23 92 elastomer)-SIS 5002 7. Pressen 1471 59 236 8. Alicyclic saturated hydrocarbon 5 20 resin)-Arkon-P 100 9. Mineral oil 9 36

Manufacturing Process:

[0115] Required quantity of pressen 1471 and SIS, were molten in hot vessel at 100° C.-180° C. under stirring.

[0116] Required quantity of arkon and mineral oil were added to molten adhesive blend under stirring at 100° C.-180° C. temperature to obtain homogenous blend.

[0117] Required quantity of all herbal extracts, valerian, skullcap, licorice and passion flower along with oleic acid were added to above molten adhesive base under stirring to obtain homogenous mixture of active ingredient and synergistic additives in blend for coating.

[0118] Sleep aid transdermal patch prepared as per the present invention is evaluated at different stability conditions and the data is given as below:

TABLE-US-00005 TABLE 1 Stability Condition: 40° C./75% RH for transdermal patch of Example 3 Test Specification Initial 3 Month 6 Month Description Brown to dark brown Complies Complies Complies coloured matrix type transdermal patch that is square shape patch Assay Each patch 100.1 100.2 99.5 (Total contains 6 mg of Valerenic Valerenic acids. acid) Limit: (5.4 mg to 6.6 mg) i.e 90% to 110% of label claim Uniformity of L1 ≤ 15 3.1 3.8 4.2 Dosage Units (by Content Uniformity) Tack Test (N) 2.5-6.0 4.2 4.0 3.8 Peel Test 1.5-4.0 2.7 2.4 2.2 Microbial Enumeration Limit @ Total Aerobic Not more than 100 Absent NA Absent Microbial Count (cfu/gm) Total yeasts Not more than 10 Absent NA Absent and molds count (cfu/gm) Pseudomonas Absent Absent NA Absent aeruginosa (gm) Staphylococcus Absent Absent NA Absent aureus (gm)

TABLE-US-00006 TABLE 2 Stability Condition: 30° C./75% RH for transdermal patch of Example 3 Test Specification Initial 3 Month 6 Month Description Brown to dark brown Complies Complies Complies coloured matrix type transdermal patch that is square shape patch Assay Each patch 100.1 99.8 99.7 (Total contains 6 mg of Valerenic Valerenic acids. acid) Limit: (5.4 mg to 6.6 mg) i.e 90% to 110% of label claim Uniformity of L1 ≤ 15 3.1 3.6 3.8 Dosage Units (by Content Uniformity) Tack Test 2.5-6.0 4.2 3.8 3.7 Peel Test 1.5-4.0 2.7 2.3 2.2 Microbial Enumeration Limit @ Total Aerobic Not more than 100 Absent NA Absent Microbial Count (cfu/gm) Total yeasts Not more than 10 Absent NA Absent and molds count (cfu/gm) Pseudomonas Absent Absent NA Absent aeruginosa (gm) Staphylococcus Absent Absent NA Absent aureus (gm)

TABLE-US-00007 TABLE 3 Stability Condition: 25° C./60% RH for transdermal patch of Example 3 Test Specification Initial 3 Month 6 Month Description Brown to dark brown Complies Complies Complies coloured matrix type transdermal patch that is square shape patch Assay Each patch 100.1 100 100.2 (Total contains 6 mg of Valerenic Valerenic acids. acid) Limit: (5.4 mg to 6.6 mg) i.e 90% to 110% of label claim Uniformity of L1 ≤ 15 3.1 3.2 3.5 Dosage Units (by Content Uniformity) Tack Test 2.5-6.0 4.2 4.1 3.9 Peel Test 1.5-4.0 2.7 2.6 2.4 Microbial Enumeration Limit @ Total Aerobic Not more than 100 Absent NA Absent Microbial Count (cfu/gm) Total yeasts Not more than 10 Absent NA Absent and molds count (cfu/gm) Pseudomonas Absent Absent NA Absent aeruginosa (gm) Staphylococcus Absent Absent NA Absent aureus (gm)