Suppository and composition comprising at least one polyethylene glycol

• US 6,740,333 B2
• Filed: 07/06/2001
• Issued: 05/25/2004
• Est. Priority Date: 07/07/2000
• Status: Expired due to Fees

• Current Assignee: Anestic APS
• Original Assignee: Anestic APS
• Inventors: Beckett, Christian Westy, Eliasen, Per Robert Topp
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/899,567
• Publication Number:
  US 20020048601A1
• Time in Patent Office: 1,054 Days
• Field of Search: 424/436, 424/DIG.15, 514/965, 514/966
• US Class Current: 424/436
• 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 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61K 9/025 characterised by shape or structure, e.g. hollow layered, coated
• CPC Class Codes: Y10S 424/05 Stick

Abstract

There is provided a suppository comprising at least one biocompatible polymer, wherein the biocompatible polymer is essentially non-biodegradable, and wherein the suppository essentially does not swell when contacted with an aqueous fluid. The suppository may further comprise a plurality of open cells at least partly separated from one another by an interpenetrating matrix comprising at least one biocompatible polymer in branched or crosslinked form. The plurality of interlinked, open cells are capable of containing an aqueous fluid, and the permeability of the suppository ensures that entry of body fluids into the open cells under practical circumstances occurs essentially without dehydration of mucousal membrane tissue contacting the suppository. The suppository furthermore preferably comprises a controlled release formulation.

Claims

1. Suppository for administration of at least one bioactive substance, said suppository comprising

i) a polymer composition comprising at least one biocompatible polymer, wherein the biocompatible polymer is essentially non-biodegradable;

and

ii) a controlled release formulation for controlled release of said at least one bioactive substance, said formulation comprising at least one biodegradable polymer; and

wherein the suppository essentially does not swell when contacted with an aqueous fluid.

2. The suppository according to claim 1, wherein the polymer compositions has a density of from about 100 gram per litre to about 250 gram per litre.

3. The suppository according to claim 1, wherein the compression modulus of the polymer composition at ambient temperature is from about 10 kPa to about 30 kPa.

4. The suppository according to claim 1, wherein the polymer composition further comprises a mixture of cells selected from the group consisting of open cells and closed cells.

5. The suppository according to claim 4, wherein the majority of the cells are open cells.

6. The suppository according to claim 5, wherein more than about 90% of the cells are open cells.

7. The suppository according to claim 6, wherein essentially all the cells are open cells.

8. The suppository according to claim 1, wherein the polymer composition further comprises a plurality of open cells at least partly separated from one another by an interpenetrating matrix comprising at least one biocompatible polymer in branched or crosslinked form.

9. The suppository according to claim 8, wherein at least part of the polymer composition comprises a plurality of interlinked, open cells capable of containing an aqueous fluid.

10. The suppository according to claim 9, wherein the contacting of the suppository with an aqueous fluid under practical circumstances results in essentially no fluid entering the open cells.

11. The suppository according to claim 10, wherein the permeability of the polymer composition results in entry of fluid into the open cells under practical circumstances essentially without dehydration of mucousal membrane tissue contacting the suppository.

12. The suppository according to claim 1, wherein the glass-rubber transition temperature of the polymer of the polymer composition is above about 15°

C. and preferably below 40°

C., such as a glass rubber transition temperature in the range of about 20°

C. to about 40°

C., for example about 35°

C., such as about 36°

C., for example in the range of about 25°

C. to about 35°

C., such as in the range of about 30°

C. to about 35°

C.

13. The suppository according to claim 1, wherein the biocompatible polymer is selected from the group consisting of polyurethanes, polyethylenes, and polypropylenes.

14. The suppository according to claim 1, wherein the biocompatible polymer is a polyurethane.

15. The suppository according to claim 14, wherein the polyurethane comprises at least one polyisocyanat that is at least partly polymerised with at least one polyol.

16. The suppository according to claim 15, wherein essentially all of the at least one polyisocyanat is polymerised with essentially all of the at least one polyol.

17. The suppository according to claim 15, wherein the at least one polyisocyanat is selected from the group consisting of aromatic polyisocyanates, aliphatic polyisocyanates, and heterocyclic polyisocyanates.

18. The suppository according to claim 15, wherein the at least one polyol is selected from the group consisting of aromatic polyols, aliphatic polyols, and heterocyclic polyols.

19. The suppository according to claim 15, wherein the at least one polyol is aliphatic and the at least one polyisocyanat is aliphatic.

20. The suppository according to claim 15, wherein the at least one polyol is aliphatic, such as a polymer comprising or essentially consisting of 2,2-dihydroxy-dipropylether, and the at least one polyisocyanat is aromatic, such as a polymer comprising or essentially consisting of diphenylmethandiisocyanat.

21. The suppository according to claim 15, wherein the at least one polyol is aromatic and the at least one polyisocyanat is aliphatic.

22. The suppository according to claim 15, wherein the at least one polyol is aromatic and the at least one polyisocyanat is aromatic.

23. The suppository according to claim 15, comprising two polyols.

24. The suppository according to claim 15, wherein the polyol is selected from the group consisting of diols and triols.

25. The suppository according to claim 23, wherein the average functionality of the at least one polyol is between 0.2 and 5, preferably between 0.5 and 2.

26. The suppository according to claim 15, wherein the ratio of i) NCO groups contained in the at least one polyisocyanate to ii) OH groups contained in the at least one polyol, respectively, is within the range of from about 0.5 to about 2.5, and preferably within the range of about 0.7 to about 1.3.

27. The suppository according to claim 1, wherein the controlled release formulation has a softening point between 15°

C. and 45°

C.

28. The suppository according to claim 1, wherein the controlled release formulation has a softening point between 25°

C. and 40°

C.

29. The suppository according to claim 1, wherein the controlled release formulation has a softening point between 30°

C. and 35°

C.

30. The suppository according to claim 1, wherein the controlled release formulation has a softening point such as the suppository is essentially rigid at room temperature, and the suppository is essentially soft at body temperature.

31. The suppository according to claim 1, wherein the controlled release formulation comprises two different biodegradable polymers.

32. The suppository according to claim 1, wherein the controlled release formulation comprises more than two different biodegradable polymers.

33. The suppository according to claim 1, wherein at least one polymer of the controlled release formulation is selected from the group consisting of polyethyleneglycols (PEG).

34. The suppository according to claim 33, wherein the PEG has an average molecular weight of between 100 and 1500.

35. The suppository according to claim 33, wherein the PEG has an average molecular weight of between 400 and 1000.

36. The suppository according to claim 33, wherein the PEG has an average molecular weight of around 400.

37. The suppository according to claim 33, wherein the PEG has an average molecular weight of around 1000.

38. The suppository according to claim 33, wherein the PEG has an average molecular weight of more than 1000.

39. The suppository according to claim 33, wherein the PEG has an average molecular weight between 1000 and 35,000.

40. The suppository according to claim 33, wherein the PEG has an average molecular weight between 1500 and 10,000.

41. The suppository according to claim 33, wherein the PEG has an average molecular weight around 2000.

42. The suppository according to claim 33, wherein the PEG has an average molecular weight around 4000.

43. The suppository according to claim 33, wherein the PEG has an average molecular weight 6000.

44. The suppository according to claim 31, wherein the controlled release formulation comprises (1) a polymer which is selected from the group consisting of PEG with an average molecular weight of between 200 and 1500 and (2) a polymer which is selected from the group consisting of PEG with an average molecular weight of between 1000 and 35,000.

45. The suppository according to claim 44, wherein the polymer (1) is PEG with an average molecular weight around 1000 and the polymer (2) is PEG with an average molecular weight around 4000.

46. The suppository according to claim 1, wherein the controlled release formulation furthermore comprises a surface active agent.

47. The suppository according to claim 1, wherein the surface active agent is a PEG monoester.

48. The suppository according to claim 1, wherein the surface active agent is a PEG monostearate.

49. The suppository according to claim 1, wherein the suppository comprises a central core comprising a first composition, and a surrounding part surrounding the central core and comprising a second composition.

50. The suppository according to claim 49, wherein the central core comprises the controlled release formulation and the surrounding part comprises the polymer composition.

51. The suppository according to claim 49, wherein the density of the central core, measured as mass per unit volume, is higher than the density of the surrounding part, measured as mass per unit volume.

52. The suppository according to claim 49, that further comprises a peripheral part comprising a third composition that is not identical to any of said first and second compositions, and wherein at least part of the third composition is in contact with the surrounding part comprising the second composition.

53. The suppository according to claim 52, wherein said peripheral part is a layer controlling the water permeability of the suppository by defining a barrier between the suppository and fluid present in an external environment that is in contact with the suppository under practical circumstances.

54. The suppository according to claim 1 and further comprising a coating composition, wherein the coating composition covers at least part of the surface area of said suppository, and wherein the coating composition is not identical to the polymer.

55. The suppository according to claim 1, wherein the bioactive substance is a medicament.

56. The suppository according to claim 55, wherein the medicament is selected from the group consisting of analgetics.

57. The suppository according to claim 56, wherein the analgetic is lidocain.

58. The suppository according to claim 1, wherein the controlled release formulation comprises the bioreactive substance comprised in capsules comprising at least one encapsulation agent.

59. The suppository according to claim 56, wherein the capsules comprise an encapsulation agent selected from the group of encapsulation agents consisting of PEG, proteins, lipids, and casein.

60. The suppository according to claim 56, wherein the capsules are adapted to disintegrate and release the medicament when contracting body tissue.

61. The suppository according to claim 56, wherein the capsules comprising the medicament are adapted to disintegrate and release the medicament when contacting a fluid, including moisture secreted by body tissue.

62. The suppository according to claim 56, wherein the capsules are adapted to dissolve and release the medicament when contacting body tissue.

63. The suppository according to claim 56, wherein the capsules comprising the medicament are adapted to dissolve and release the medicament when contacting a fluid.

64. The suppository according to claim 1, that further comprises an additive selected from the group of preservatives, adjuvants, stabilizers, lubricants, and disintegraters or any combinations thereof.

65. The suppository according to claim 1, wherein the suppository has an essentially oblong shape.

66. The suppository according to claim 1, wherein the suppository has an essentially cylindrical shape.

67. The suppository according to claim 1, wherein the suppository has a central portion, a first end portion and a second end portion, wherein at least one of said end portions is tapering, and preferably pointed.

68. The suppository according to claim 1, wherein the suppository has a central portion, a tapering, distal end portion, and a proximal end portion attached to a flange portion extending outwardly in the axial direction from said proximal end portion.

69. The suppository according to claim 67, wherein said flange portion has a recessed part in the axial direction.

70. The suppository according to claim 69, wherein the suppository has a shape that allows contact between parts of or essentially all of the outer surface of the suppository and parts of or essentially all of the mucosal membrane of the rectum below the caudal semilunary fold, when the suppository is situated in the rectum.

71. Method for preparation of a suppository according to claim 1, said method comprising the steps of

i) providing at least one monomeric reagent suitable for polymerization,

ii) polymerising said at least one monomeric reagent and obtaining a biocompatible polymer which is essentially non-biodegradable,

iii) providing a controlled release formulation for controlled release of at least one bioactive substance,

iv) mixing the controlled release formulation and the at least one bioactive substance, and

v) shaping the essentially non-biodegradable, biocompatible polymer and the mixture of the controlled release formulation and the at least one bioactive substance into a shape desirable for a suppository.

72. Method according to claim 71, wherein the suppository is shaped by injection moulding into a predetermined shape.

73. Method of claim 71, wherein the monomeric reagents used for obtaining the essentially non-biodegradable, biocompatible polymer comprise at least one polyisocyanate and at least one polyo.

74. Suppository obtainable by the method of claim 71.

75. Method for alleviating pain in an individual in need thereof, said method comprising the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises the bioactive substance in an amount effective to achieve said pain alleviation in said individual.

76. A method for diagnosing a clinical indication in an individual comprising the steps of bringing a suppository according to claim 1 into contact with body tissue of a body cavity an animal, wherein the suppository comprises a diagnostically active substance in an amount effective to achieve said diagnosis.

77. A cosmetic method comprising the steps of bringing a suppository according to claim 1 into contact with body tissue of a body cavity of an animal, wherein the suppository comprises a cosmetically active substance in an amount sufficient to achieve a desirable cosmetic effect.

78. The suppository of claim 33, where the controlled release formulation comprises

(a) a biodegradable polyethylene glycol with a molecular weight of between 100 and 1500, and

(b) a biodegradable polyethylene glycol with a molecular weight of between 1500 and 10,000.

79. The suppository of claim 33, where the controlled release formulation comprises

(a) a biodegradable polyethylene glycol with a molecular weight of between 400 and 1000, and

(b) a biodegradable polyethylene glycol with a molecular weight of more than 1000.

80. The suppository of claim 79 where PEG (b) has a molecular weight of not more than 35,000.

81. The suppository of claim 33 where at least two of the biodegradable polymers of said controlled release formulation differ in melting point from each other.

82. The suppository of claim 81 where the ratio of the lowest melting point biodegradable polymer to the highest melting point polymer of said controlled release formulation is about 3:

1.

83. Method of claim 75, wherein the bioactive substance is selected from the group consisting of analgesics, anaesthetics and antipyretics.

84. Method of claim 75, wherein the bioactive substance is selected from opioid analgesics, non-opioid analgesics, and lidocaine, and antiepileptics used to alleviate pain.

85. Method of claim 75, wherein the bioactive substance is selected from lidocaine, codeine, morphine, acetaminophen, aspirin, and ibuprofen.

86. Method of claim 75, wherein the body tissue is a rnucosal surface.

87. Method of claim 86, wherein the mucosal surface is a mucosal surface of the rectum.

88. Method of claim 87, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

89. Method of claim 75, wherein the individual is a human being.

90. In a method for surgical treatment of ruptured colon in an individual, the improvement comprising alleviating pain by performing the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an analgesic bioactive substance or an anaesthetic bioactive substance in an amount effective to achieve said pain alleviation in said individual.

91. Method of claim 90, wherein the body tissue is a mucosal surface.

92. Method of claim 91, wherein the mucosal surface is a mucosal surface of the rectum.

93. Method of claim 92, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

94. Method of claim 90, wherein the individual is a human being.

95. In a method for rectal surgery performed on an individual, the improvement comprising alleviating pain by performing the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an analgesic bioactive substance or an anaesthetic bioactive substance in an amount effective to achieve said pain alleviation in said individual.

96. Method of claim 95, wherein the body tissue is a mucosal surface.

97. Method of claim 96, wherein the mucosal surface is a mucosal surface of the rectum.

98. Method of claim 97, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

99. Method of claim 95, wherein the individual is a human being.

100. In a method for surgical treatment of haemorrhoids in an individual, the improvement comprising alleviating pain by performing the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an analgetic bioactive substance or an anaesthetic bioactive substance in an amount effective to achieve said pain alleviation in said individual.

101. Method of claim 100, wherein the body tissue is a mucosal surface.

102. Method of claim 101, wherein the mucosal surface is a mucosal surface of the rectum.

103. Method of claim 102, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

104. Method of claim 100, wherein the individual is a human being.

105. In a method for surgical treatment of ruptured vagina of a female mammal, the improvement comprising alleviating pain by performing the steps of contacting a mucosal surface of the vagina of the female mammal with the suppository of claim 1, wherein the suppository comprises an analgetic bioactive substance or an anaesthetic bioactive substance in an amount effective to achieve said pain alleviation in said female mammal.

106. Method of claim 105, wherein the mammal is a human being.

107. A method for treating an inflammatory condition in an individual, said method comprising the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an anti-inflammatory bioactive substance in an amount effective in treating said inflammatory condition.

108. Method of claim 107, wherein the body tissue is a mucosal surface.

109. Method of claim 108, wherein the mucosal surface is a mucosal surface of the rectum.

110. Method of claim 109, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

111. Method of claim 107, wherein the individual is a human being.

112. Method of claim 107, wherein the anti-inflammatory bioactive substance is selected from the group consisting of naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin, and sulindac.

113. Method of claim 107, wherein the anti-inflammatory bioactive substance is selected from the group consisting of hydrocortisone, triamcinolone, prednisone, cortisone acetate, prednisolone, methyl prednisolone and dexamethasone.

114. Method for treating an infection in an individual, said method comprising the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an anti-infective bioactive substance in an amount effective in treating said infection.

115. Method of claim 114, wherein the body tissue is a mucosal surface.

116. Method of claim 115, wherein the mucosal surface is a mucosal surface of the rectum.

117. Method of claim 116, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

118. Method of claim 114, wherein the individual is a human being.

119. Method of claim 114, wherein the anti-infective bioactive substance is selected from the group consisting of anti-biotics, anti-fungals, anti-virals, and anti-septics and anti-protozoans.

120. Method of claim 114, wherein the anti-biotic is selected from the group consisting of penicillins, cephalosporins, tetracyclines, ampicillin, aureothicin, bacitracin, chioramphenicol, cycloserine, erythromycin, gentamicin, gramacidin, kanamycin, neomycin, streptomycin, tobramycin, vancomycin, and metronidazole.

121. Method of claim 114, wherein the anti-biotic is a beta-lactam antibiotic selected from the group consisting of sulbenicillin, mecillinam, carbenicillin, piperacillin, ticarcillin, and thienamycin.

122. Method of claim 114, wherein the anti-biotic is a cephalosporin selected from the group consisting of cefotiam, cefsulodine, cefmenoxime, cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoxime and moxalactam.

123. Method of claim 114, wherein the anti-viral bioactive species is acyclovir.

124. A method for treating a cancer in an individual, said method comprising the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an anti-cancer bioactive substance in an amount effective in treating said cancer.

125. Method of claim 124, wherein the body tissue is a mucosal surface.

126. Method of claim 125, wherein the mucosal surface is a mucosal surface of the rectum.

127. Method of claim 126, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

128. Method of claim 124, wherein the individual is a human being.

129. Method of claim 124, wherein the anti-cancer bioactive substance is selected from the group consisting of antimetabolites, cytotoxic agents and immunomodulators.

130. Method of claim 129, wherein the antimetabolites are selected from methotrexate, 5-fluorouracil, cytosine arabinoside(ara-C), 5-azacytidine, 6-mercaptopurine, 6-thioguanine, and fludarabine phosphate.

131. Method of claim 129, wherein the cytotoxic agents are selected from taxol, epirubicin, esorubicin, doxorubicin, iodo-doxorubicin, daunorubicin, idarubicin, dactinomycin, bleomycin, mitomycin C, plicamycin, mitoxantrone, vincristine, vinblastine, vindesine, etoposide, and teniposide.

132. Method of claim 124, wherein the anti-cancer bioactive substance is selected from the group consisting of 5′

-fluorouracil, mitomycin, cisplatin, taxol, biteomycins, daunomycins, and methamycins.

133. Method for treating a hormone condition in an individual, said method comprising the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises a hormone bioactive substance in an amount effective in treating said deficiency.

134. Method of claim 133, wherein the body tissue is a mucosal surface.

135. Method of claim 134, wherein the mucosal surface is a mucosal surface of the rectum.

136. Method of claim 135, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

137. Method of claim 133, wherein the individual is a human being.

138. Method of claim 133, wherein the hormone is selected from growth hormone, tPA (tissue plasminogen activator), prolactin, adrenocorticotrophic hormone, melanocyte stimulating hormone, thyrotropin releasing hormone, thyroid stimulating hormone, thyroxine, luteinizing hormone, follicle stimulating hormone, vasopressin, oxytocin, calcitonin, parathyroid hormone, glucagon, gastrin, secretin, pancreozymin, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin, enkephalin, endorphin, insulin, alpha interferon, beta interferon, and gamma interferon.

139. Method of claim 133, wherein the hormone is selected from corticosteriods, estrogens, progestins, antiestrogens, aromastase inhibitors, androgens, antiandrogens, and endocrines for prostate cancer.

140. Method of claim 133, wherein the hormone is selected from cortisone acetate, hydrocortisone, prednisone, prednisolone, methyl prednisolone and dexamethasone, diethyistibesterol, estradiol, esterified estrogens, conjugated estrogen, chiorotiasnene, medroxyprogesterone acetate, hydroxy progesterone caproate, megestrol acetate, tamoxifen, aminoglutethimide, testosterone propionate, methyltestosterone, fluoxymesterone, testolactone, flutamide, leuprolide acetate, and ketoconazole.

141. A method for contraception comprising the steps of contacting body tissue of a body cavity of a female mammal with the suppository of claim 1, wherein the suppository comprises a contraceptive bioactive substance in an amount effective to achieve said contraception in said female mammal.

142. Method of claim 141, wherein the body tissue is a mucosal surface.

143. Method of claim 142, wherein the mucosal surface is a mucosal surface of the vagina.

144. Method of claim 141, wherein the mammal is a human being.

145. A surgical method performed on an individual, comprising modifying blood coagulation by performing the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises a coagulation modifying agent in an amount effective to achieve said blood coagulation modification.

146. Method of claim 145, wherein the body tissue is a mucosal surface.

147. Method of claim 146, wherein the mucosal surface is a mucosal surface of the rectum.

148. Method of claim 147, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

149. Method of claim 145, wherein the individual is a human being.

150. Method for immunising an individual, said method comprising the steps of contacting body tissue of a body cavity of the individual with the suppository of claim 1, wherein the suppository comprises an antigenic substance in an amount effective in achieving said immunisation.

151. Method of claim 150, wherein the body tissue is a mucosal surface.

152. Method of claim 151, wherein the mucosal surface is a mucosal surface of the rectum.

153. Method of claim 152, wherein the mucosal surface of the rectum is the surface located below the caudal semilunary fold.

154. Method of claim 150, wherein the individual is a human being.

155. Method of claim 150, wherein the suppository further comprises an adjuvant.