Spill resistant pharmaceutical compositions in semi-solid form

• US 6,399,079 B1
• Filed: 04/13/2000
• Issued: 06/04/2002
• Est. Priority Date: 06/03/1998
• Status: Expired due to Term

• Current Assignee: Taro Pharmaceutical Industries Limited (Sun Pharmaceutical Industries Limited)
• Original Assignee: Taro Pharmaceutical Industries Limited (Sun Pharmaceutical Industries Limited)
• Inventors: Mehta, Rakesh, Moros, Dan
• Primary Examiner(s): Page, Thurman K.
• Application Number:
  US09/549,148
• Time in Patent Office: 782 Days
• Field of Search: 414/401, 414/400, 222/192, 222/212, 222/153.06, 141/18, 141/114, 141/115
• US Class Current: 424/400
• CPC Class Codes: A61J 7/0015 Devices specially adapted for taking medicines
• CPC Class Codes: A61J 7/0023 Spoons
• CPC Class Codes: A61J 7/0053 Syringes, pipettes or oral dispensers
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/10 Expectorants
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

A spill-resistant pharmaceutical formulation for oral administration from a squeezable container comprises a pharmaceutical agent in a suitable vehicle comprising a liquid base and a thickening agent, the formulation consisting of mutually compatible components and having the following properties: a viscosity within the range of about 7500 to about 12,500 cps using a Brookfield Viscometer with a ‘C’ spindle with Helipath movement at a spindle speed of 10 rpm and 20-25° C., a viscometric yield value of a semi-solid, a spill-resistant consistency permitting the composition to be squeezed by light manual pressure through a channel, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling on spoon inversion, tilting at 90 degrees, and vibration, homogeneity such that the components do not separate under conditions of use, and a storage stability such that the foregoing properties are retained for at least two years shelf life. A method for producing a formulation for a spill-resistant pharmaceutical composition comprises combining a per-unit dose effective amount of a pharmaceutical agent with suitable vehicle components comprising a liquid base and a thickening agent, and testing the formulation for acceptance criteria.

Claims

1. A pharmaceutical formulation for oral administration from a squeezable container, comprising a pharmaceutical agent in a vehicle comprising a liquid base and a thickening agent, the formulation consisting of mutually compatible components, wherein said thickening agent comprises components selected from the group consisting of cellulose derivatives in an amount of less than about 2 weight % by volume, and water-soluble carboxyvinyl polymer in an amount less than 1 weight % by volume, the formulation having the following properties:

an initial viscosity within the range of about 5,000 cps to about 12,500 cps;

a viscometric yield value of a semi-solid;

a spill resistant consistency permitting the formulation to be squeezed by light manual pressure through a channel of about 1 to about 5 mm, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling for at least about one second and less than about 20 seconds on spoon tilting, and for at least about 30 seconds upon spoon vibration;

homogeneity wherein the components do not separate under conditions of use; and

storage stability.

2. The formulation of claim 1, wherein the formulation has a viscosity between about 7500 and about 25,000 cps after storage for three months at a temperature of 40 degrees C. and 75% humidity.

3. The formulation of claim 2, wherein the formulation has a viscosity between about 7500 and about 12,500 cps after storage.

4. The formulation of claim 1, wherein the formulation comprises from about 0.25 to less than 1 weight % water-soluble carboxyvinyl polymer.

5. The formulation of claim 1, wherein the liquid base comprises glycerin and sorbitol.

6. The formulation of claim 1, wherein the thickening agent comprises sodium carboxymethylcellulose in an amount of about 0.9% and microcrystalline cellulose in an amount of about 0.9%.

7. The formulation of claim 1, wherein the thickening agent comprises cellulosed derivatives in an amount of less than about 2 weight % by volume, and the formulation further comprises glycerin and sorbitol as a solution of about 70% in water, the combined concentration of glycerin and sorbitol solution being about 40%.

8. The formulation of claim 1, wherein the thickening agent comprises water-soluble carboxyvinyl polymer in an amount of from about 0.25 to about 0.5 weight % by volume.

9. The formulation of claim 1, having a spill-resistant consistency permitting the composition to remain in the spoon bowl without spilling for from about 1 second to about 4 seconds on spoon tilting.

10. The formulation of claim 1, wherein the thickening agent comprises cellulose derivatives in an amount of less than about 2 weight % by volume, and the liquid base comprises propylene glycol in an amount of from about 10 to about 85 weight % by volume.

11. The formulation of claim 1, wherein the pharmaceutical agent is selected from the group consisting of an analgesic, non-steroidal anti-inflammatory, antihistamine, cough suppressant, expectorant, bronchodilator, anti-infective, CNS active drug, cardiovascular drug, antineoplastic, cholesterol-lowering drug, anti-emetic, vitamin, mineral supplement and fecal softener.

12. The formulation of claim 1, wherein the pharmaceutical agent is selected from the group consisting of acetaminophen, aspirin, ibuprofen, diphenhydramine, dextromethorphan, guafenesin, pseudoephedrine, carbidopa, levodopa, terfenadine, ranitidine, ciprofloxacin, triazolam, fluconazole, propranolol, acyclovir, fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically acceptable salt or ester thereof.

13. The formulation of claim 1, wherein the liquid base comprises from about 30% to about 50% glycerin.

14. The formulation of claim 13, wherein the liquid base further comprises propylene glycol in an amount up to about 25 weight % by volume.

15. The formulation of claim 1, wherein the liquid base comprises propylene glycol.

16. The formulation of claim 1, wherein the liquid base comprises glycerin.

17. The formulation of claim 1, the formulation spreading as quickly as honey, and having spill resistance greater than honey.

18. The formulation of claim 1, the formulation spreading to the edge of a spoon within about five seconds.

19. The formulation of claim 1, wherein the formulation remains in a spoon bowl without spilling for 20-30 seconds on spoon inversion.

20. The formulation of claim 1, wherein the formulation is readily consumed from a spoon bowl.

21. The formulation of claim 1, having a spill-resistant consistency permitting the composition to remain in the spoon bowl without spilling for from about 1 second to about 4 seconds on spoon inversion.

22. The formulation of claim 1, wherein the storage stability extrapolates to at least two years shelf life at room temperature.

23. The formulation of claim 1, wherein the viscosity is at least about 7,000 cps.

24. The formulation of claim 1, wherein the viscosity is at least about 7,500 cps.

25. The formulation of claim 1, wherein after storage for three months at elevated temperature, the viscosity remains within a range of 50% less to 100% more than the initial viscosity.

26. A pharmaceutical formulation for oral administration from a squeezable container, comprising a pharmaceutical agent in a vehicle comprising a liquid base comprising from about 30% to about 50% glycerin, and a thickening agent, the formulation consisting of mutually compatible components and having the following properties:

an initial viscosity within the range of about 5,000 cps to about 12,500 cps;

a viscometric yield value of a semi-solid;

a spill-resistant consistency permitting the formulation to be squeezed by light manual pressure through a channel of about one to about five mm, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling for at least about 1 second but less than twenty seconds on spoon tilting, and for at least about 30 seconds upon spoon vibration;

homogeneity wherein the components do not separate under conditions of use; and

storage stability for at least three months of storage at elevated temperature, with viscosity remaining within a range of 50% less to 100% more than the initial viscosity.

27. The formulation of claim 26, wherein said thickening agent comprises components selected from the group consisting of cellulose derivatives in an amount of from about 0.9 to 2.5 weight %, and water-soluble carboxyvinyl polymer in an amount less than 1 weight % by volume.

28. The formulation of claim 26, wherein the liquid base comprises about 50% glycerin and the thickening agent comprises water-soluble carboxyvinyl polymer in an amount of from about 0.25 to about 1 weight % by volume.

29. The formulation of claim 26, wherein the liquid base further comprises propylene glycol.

33. The formulation of claim 26, wherein the viscosity is at least about 7,000 cps.

34. The formulation of claim 26, wherein the viscosity is at least about 7,500 cps.

30. A pharmaceutical composition comprising:

a water-soluble carboxyvinyl polymer in an amount of from about 0.25% to about 0.5% by weight;

a liquid base comprising glycerin and/or propylene glycol; and

a pharmaceutical agent,

the composition being a homogeneous semi-solid and dispensable from a squeezable container into a spoon, the composition spilling from the spoon within 20 seconds after tilting the spoon.

31. The composition of claim 30, wherein the pharmaceutical agent is selected from the group consisting of guafenesin, dextromethorphan, pseudoephedrine, acetaminophen, and combinations.

35. The formulation of claim 30, wherein the viscosity is within the range of about 7,000 cps to about 12,500 cps.

36. The formulation of claim 35, wherein the viscosity is at least about 7,500 cps.

32. A pharmaceutical composition comprising:

a water-soluble carboxyvinyl polymer in an amount of 1.0% by weight or less;

a liquid base comprising glycerin in an amount greater than 15% and propylene glycol; and

a pharmaceutical agent,

the composition being a homogeneous semi-solid and dispensable from a squeezable container, and having a viscosity of less than about 12,000 cps.

37. The formulation of claim 32, wherein the viscosity is at least about 5,000 cps.

38. The formulation of claim 32, wherein the viscosity is at least about 7,000 cps.

39. The formulation of claim 32, wherein the viscosity is at least about 7,500 cps.