Antidepressive therapy

• US 5,688,518 A
• Filed: 07/27/1995
• Issued: 11/18/1997
• Est. Priority Date: 02/27/1992
• Status: Expired due to Term

• Current Assignee: Encinal Pharmaceutical Investments, LLC
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Ridzon, Dana, Ayer, Atul Devdatt
• Primary Examiner(s): Reamer, James H.
• Application Number:
  US08/507,890
• Time in Patent Office: 845 Days
• Field of Search: 514/252, 514/255, 474/422, 474/457, 474/468, 474/473
• US Class Current: 424/422
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

A dosage form is provided for administering a drug of the formula ##STR1## to a patient to produce an anxiolytic benefit in the patient.

Claims

1. A therapeutic composition of matter comprising:

(a) less than 45% by weight of a drug of the following formula;

##STR9## in either exo or endo form and the base and pharmaceutically acceptable salts thereof;

wherein A is selected from the group consisting of an oxygen atom, a methylene group and an ethylene group, the full line embracing a broken line (------) designates either a single bond or a double bond, R is a phenyl group optionally substituted with a member selected from the group consisting of halogen, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, a trifluoromethyl group, a 2-pyridyl group and a 2-pyrimidinyl group;

(b) 30% to 60% by weight of a polymeric composition comprising;

(i) a first polymer selected from the group consisting of the repeating molecular unit --(--O--CH₂ CH₂ --)--_n wherein n is in the range of 4000 to 5500, or a second polymer having the same repeating molecular unit wherein n is in the range of 5700 to 7500; and

,

(c)

(ii) 0-3% by weight of a lubricant;

(iii) 0-20% by weight of an osmagent;

(iv) 0-4% by weight of an antioxidant and

(v) 0-10% by weight of a binder.

2. The composition of claim 1 wherein the polymer (i) must be the above 45% by weight.

3. The composition of claim 1 or 2 wherein said drug is selected from the group consisting of tandospirone, its base and pharmaceutically acceptable salts.

4. The composition of claim 3 wherein said drug is tandospirone citrate.

5. The composition of claim 3 comprising 38.7% by weight tandospirone citrate, 58.3% by weight of polymer (i) wherein n is in the range of 4500-5500, 2% by weight polyvinyl pyrrolidone, 0.05% by weight of butyl hydroxytoluene and 0.95% by weight of magnesium stearate.

6. The composition of claim 3 comprising 38.7% by weight of tandospirone citrate, 58.3% by weight of a polymer (i) wherein n is in the range of 5700 to 7500, 2% by weight of polyvinyl pyrrolidone, 0.05% by weight of a butyl hydroxytoluene and 0.95% by weight of magnesium stearate.

7. The composition of any preceding claim wherein said composition contains from 1 to 750 mg of the drug.

8. An osmotic dosage form comprising:

(a) the therapeutic composition of any preceding claim contained within a compartment formed at least in part by a semipermeable material;

(b) a passageway providing communication between said composition and the exterior of said compartment;

(c) a push composition is said compartment which swells when said semipermeable material is contacted by water to push said therapeutic composition through said passageway at a substantially constant rate over a period of up to 30 hours.

9. The dosage form of claim 8 wherein said push composition comprises:

(a) 50%-75% by weight of a polymer consisting of the repeating molecular unit --(--O--CH₂ CH₂ --)--_n wherein n is in the range of 90,000 to 230,000

(i) 15%-35% by weight of an osmagent;

(ii) 0.1%-20% by weight of a cellulose ether;

(iii) 0%-5% by weight of a lubricant;

(iv) 0%-4% by weight of an antioxidant; and

(v) 0%-10% by weight of an inert pigment.

10. The dosage form of claim 9 wherein at least 0.03% by weight of said antioxidant is present in said push layer.

11. The dosage form of claim 9 or 10 wherein said semipermeable material is a composition comprising 70%-100% by weight of a material selected from the group consisting of cellulose acylate, cellulose diacylate and cellulose triacylate, 0%-25% by weight of a cellulose ether and 0%-15% by weight of polyethylene glycol.

20. The composition of any of claims 1 or 12 wherein the average molecular weight of said first polymer is 200,000 and the average molecular weight of said second polymer is 300,000.

21. The dosage form of any of claims 1-7 or 12-14 wherein the average molecular weight of said first polymer is 200,000 and the average molecular weight of said second polymer is 300,000.

30. The dosage form of claim 1 or 12 wherein the push composition comprises the product of claim 26.

12. A therapeutic composition of matter comprising:

(a) tandospirone citrate;

(b) a polymeric composition comprising;

(i) a polymer selected from the group consisting of the repeating molecular unit --(--O--CH₂ CH₂ --)--_n wherein n is in the range of 4000 to 5500, and a polymer having the same repeating molecular unit wherein n is in the range of 5700 to 7500; and

,

(c)

(ii) 0-3% by weight of a lubricant;

(iii) 0-20% by weight of an osmagent;

(iv) 0-4% by weight of an antioxidant and

(v) 0-10% by weight of polyvinyl a binder.

13. The composition of claim 12 wherein component (i) must be the mixture of polymers at a tandospirone citrate concentrations above 45% by weight.

14. The composition of claim 12 containing from 1-750 mg tandospirone citrate.

15. An osmotic dosage form comprising:

(a) the therapeutic composition of claim 12 contained within a compartment formed at least in part by a semipermeable material;

(b) a passageway providing communication between said composition and the exterior of said compartment;

(c) a push composition is said compartment which swells when said semipermeable material is contacted by water to push said therapeutic composition through said passageway at a substantially constant rate over a period of up to 30 hours.

16. The dosage form of claim 15 wherein said push composition comprises:

(a) 50%-75% by weight of a polymer consisting of the repeating molecular unit --(--O--CH₂ CH₂ --)--_n wherein n is in the range of 90,000 to 230,000

(i) 15%-35% by weight of an osmagent;

(ii) 0.1%-20% by weight of a cellulose ether;

(iii) 0%-5% by weight of a lubricant;

(iv) 0%-4% by weight of an antioxidant; and

(v) 0%-10% by weight of an inert pigment.

17. The dosage form of claim 16 wherein at least 0.03% by weight of said antioxidant is present in said push layer.

18. The dosage form of claim 16 or 17 wherein said semi permeable material is a composition comprising 70%-100% by weight of a material selected from the group consisting of cellulose acylate, cellulose diacylate and cellulose triacylate, 0%-25% by weight of a cellulose ether and 0%-15% by weight of polyethylene glycol.

19. The dosage form of claim 12 wherein said antioxidant is butyl hydroxytoluene.

22. A dosage form comprising 1 mg to 750 mg of a tandospirone salt that is released at a continuous rate of 1 mg/hr to 20 mg/hr by the dosage form.

23. The dosage form according to claim 22 wherein the tandospirone salt is tandospirone citrate and is released continuously up to 24 hrs.

24. The dosage form according to claim 23 wherein the tandospirone is blended with a poly(ethylene oxide) of 200,000 average molecular weight.

25. The dosage form according to claim 23 wherein the tandospirone is blended with a poly(ethylene oxide) of 300,000 average molecular weight.

26. A process for preparing a drug-free push formulation for use in an osmotic dosage form, said formulation comprising:

(a) 50%-75% by weight of a polymer consisting of the repeating molecular unit --(--O--CH₂ CH₂ --)--_n wherein n is in the range of 90,000 to 230,000;

(b) 15%-35% by weight of an osmagent;

(c) 0.1%-20% by weight of a cellulose ether;

(d) 0%-5% of a lubricant;

(e) 0%-10% by weight of an inert pigment; and

(f) 0.03%-4% by weight of butyl hydroxytoluene;

said process comprising the steps of;

(1) thoroughly mixing components (a), (b), (e) and a portion of (c) in an air suspended fluid bed;

(2) forming an aqueous solution of the remainder of component (c);

(3) forming an ethanolic solution of component (e);

(4) thoroughly mixing the aqueous and ethanolic solutions to form a coating solution;

(5) spraying said coating solution into the fluid bed to coat the suspended solids;

(6) drying the coated particulate product so produced to a moisture content no greater than 0.29%; and

(7) mixing component (d) into the coated particulate product.

27. The process of claim 26 further comprising the step of compressing the product of step (7) in a tablet press.

28. The product produced by claim 26.

29. The product of claim 26 wherein said push composition contains at least 0.03% by weight of butyl hydroxytoluene.