Indian Patents. 224960:METHOD OF TREATMENT OF A PATIENT REQUIRING ANALGESIA

Title of Invention	METHOD OF TREATMENT OF A PATIENT REQUIRING ANALGESIA
Abstract	The invention provides a monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant selected from the group comprising alkyl suphosuccinates, alkyl sulphates or alkyl ammonium salts. The invention also proves uses of such compositions in the treatment of pain relief.

Full Text	MONOPHASIC PHARMACEUTICAL COMPOSITION CONTAINING DEVAZEPIDE This invention relates to a novel monophasic pharmaceutical composition containing devazepide. International Patent Application No. WO 99/18967 describes -pharmaceutical compositions for treating chronic and neuropathic pain which comprises an analgesic amount of an opioid and an opioid potentiating amount of a CCK antagonist WO 967 describes the use of both CCK-A (CCK-1) antagonists and CCK-B (CCK-2) antagonists, although it is described that, generally, CCK-B (CCK-2) antagonists are preferred Moreover, page 2, lines 6 to 8 of WO '967 describes (hat CCK-A (CCK-1) antagonists may be suitable, but only at relatively higher dosages. One specific CCK-A (CCK-1) antagonist which is mentioned in WO 99/18967 is devazepide (Devacade®), which is 3s-(-)-l,3-dihydro-3-(2-indolecarbonylammo)-l-methyl-5-phenyl-2H-l ,4-benzodiazepin-2-one. Devazepide is commonly administered alongside an opioid analgesic, e.g. such as morphine. However, in normal doses, the commonest side-effects of morphine and other opioid analgesics are nausea, vomiting, constipation, drowsiness, and -confusion; tolerance generally develops with long-term use, but not to constipation which is the most common undesirable side effect of morphine treatment International Patent Application No. WO 99/18967 specifically describes a pharmaceutical formulation comprising a CCK antagonist, such as devazepide, an opioid and a biphasic carder, comprising a glyceride derivative organic phase. This application suggests the possible use of a surfactant, especially when the formulation is in the form of an oil-m-water emulsion. We have now surprisingly found that a method of treatment of a patient requiring analgesia which comprises administering a monophasic form of devazepide which may be prepared .with a surfactant The use of a surfactant is advantageous in that, inter alia, it improves the powder flow and/or separation properties of solid devazepide and also reduces or mitigates the undesirable side effects of opioid administration, e.g. constipation. Thus, according to the invention there is provided a monophasic pharmaceutical composition for treatment of a patient requiring analgesia which composition, upon separate, simultaneous or sequential administration, provides a therapeutically effective amount of an opioid analgesic, devazepide and a pharmaceutically acceptable surfactant wherein the daily dosage of devazepide is up to 0.7 mg/kg/day. Accordingly, the present invention provides a monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant wherein the daily dosage of devazepide is up to 0.7 mg/kg/day, the surfactant being selected from the group consisting of alkyl sulphosuccinates, alkyl sulphates and alkyl ammonium salts. The devazepide and the pharmaceutically acceptable surfactant are in a monophasic form, e.g.- solid or liquid form. Preferably, the devazepide and the pharmaceutically acceptable surfactant are in a monophasic form, eg a liquid form or a solid dosage form. The phrase solid dosage form may mean, for example, in tablet form or,-preferably in the-form of a flowable powder in a capsule. We have found that the use of a surfactant in a solid dose devazepide composition as hereinbefore described has the advantage of mitigating constipation due to the concomitant administration of aa opioid analgesic, whilst also improving the physical properties of devazepide in a solid dose formulation, Any conventionally known pharmaceutically acceptable surfactants may be used in the method of the invention. Such surfactants include, but shall not be limited to, a lipophilic surfactant hydrophilic surfactant or a glyceride, or combinations thereof. When the surfactant is a hydrophilic surfactant, it may be an- ionic or a non-ionic surfactant. Examples of non-ionic hydrophilic surfactants include, inter alia, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyo3xyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid' esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fetty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction, mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; tocopherol polyethylene glycol succinates; sugar esters; sugar ethers; sucroglycerides; and mixtures thereof Examples of ionic hydrophilic surfactants include, inter alia, alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof, fatty acid derivatives of0 amino acids, carnitines, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-, diacetylated tartario acid esters of mono-, diglycerides; succinoylated monoglycerides; citric acid esters of mono-, diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulphates; salts of fatty acids; sodium docusate; and mixtures thereof Examples of lipophilic surfactants include, inter alia, alcohols; polyoxyethylene alkylethers; fatty acids; bile acids; glycerol fatty acid esters; acetylated glycerol tatty acid esters; lower alcohol fatty acids esters; polyethylene) glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic add derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof. Examples of glycerides include mono-, di- or tri-glyceiides. Such triglycerides include, inter alia, vegetable oils, fish, oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglyceride fractionated triglycerides, and mixtures thereof ln an especially preferred embodiment of the invention the surfactant will be capab of improving powder flow of devazepide and may be known to be a therapeutical effective laxative and/or stool softener. Such laxatives and/or stool softeners ma preferentially be ionic surfactants, especially alkyl sulphosucinates, alkyl sulphat or alkyl ammonium salts. Thus, in a preferred embodiment of the invention the surfactant may be selected fro: the group,' docusate sodium (dioctyl sodium sulphosuccinate), sodium dodec sulphate and tetradecyltrimethyl ammonium bromide. In a further embodiment of the invention the surfactant may also posse antimicrobial and/or antiseptic properties. Thus, for example, when the surfactant tetradecyltrimethylammonium bromide, it may, preferentially, be cetrimic (cetrimide is a mixture substantially comprising tetradecyltrimethyl ammonia bromide and -small amounts of dodecyltrimethylammonium bromide an cetrimonium bromide). In the most preferred embodiment of the invention the surfactant is docusate sodium The method of the invention may preferentially comprise the use of a compositic which comprises one or more fillers, Thus, such fillers may be selected from th group lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolysed starches, directly compressib starch, microcrystalline cellulose, cllulosics, sorbitol, sucrose, sucrose-base materials, icodextrin, calcium sulphate, dibasic calcium, phosphate and dextrose, . preferred filler is starch, e.g. com starch. When the method of the invention comprises the use of a composition which includes a filler, the size of the devazepide and filler particles may be title same c different However, in a preferred embodiment the sizes of the devazepide and filler particles will differ. Preferentially, the devazepide, surfactant and/or the filler may be of reduced particle size, e.g. by milling, The devazepide, surfactant and filler may be present as an intimate mixture. However, in a preferred embodiment the filler particles may be coated 'with the surfactant, the coated filler and devazepide then being formed into an intimate mixture. The method of the invention wherein the compositions, comprising devazepide, a filler and a surfactant are especially advantageous in that, inter alia, the surfactant acts to hinder or prevent separation of the devazepide and the filler. Furthermore, in one embodiment of the invention the surfactant may also have desirable laxative and/or stool softening properties. The amount of surfactant present in the composition used in the method of the invention may vary, depending upon, inter alia, the level of devazepide present, the level of concomitant opioid analgesic administered, etc. Generally, the ratio of devazepide:surfactant may be from 5:1 to 25:1 w/w, preferably from 10:1 to 15:1 w/w, most preferably 12.5:1 w/w. When the composition used in the method of the invention includes a filler, the composition may generally comprise devazepide and a surfactant, in the ratio as hereinbefore described, with the remainder of the composition being made up with a filler. A preferred embodiment of the invention comprises a method wherein a composition as hereinbefore described is filled into a capsule. Any conventionally known materials may be used for the capsule, however a preferred material is gelatin. Thus, for example, in one embodiment of the invention the composition as hereinbefore described may be made up into a capsule formulation, e.g. with a fill weight of 150 mg ± 5% by weight or 300 mg ± 5% by weight i the one preferred embodiment, the capsule formulation may comprise 1.25mg devazepide, 0.1 mg surfactant, e.g. docusate sodium, and 148.65 mg of a filler, e.g. com starch. In. a further preferred embodiment, the capsule formulation may comprise 2,5mg devazepide, 0.2 mg surfactant, e.g. docusate sodium, and 297,3 mg of a tiller, e.g. com starch-According to a further aspect of the invention we provide the use of devazepide in the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of devazepide and apharmaceutically acceptable surfactant The use of the invention is preferentially the use in the manufacture of a pharmaceutical composition wherein the composition comprises any of the aspects of the methods hereinbefore described. The use as hereinbefore described preferentially comprises the use in the manufacture of a pharmaceutical composition in monophasic form. By the term therapeutically effective amount of devazepide we generally mean an amount of devazepide effective in the enhancement of opioid analgesia. In the method of the invention a variety of opioids may be used. Thus, the opioid may be selected from those which are effective analgesics and particularly those which need to be administered at relatively high or increasing doses. Examples include morphine, or a salt thereof such as the sulphate, chloride or hydrochloride, or the other 1,4-hydroxymorphinan opioid analgesics such as naloxone, meperidine, butorphanol or pentazocine, or morphine-6-glucuronide, codeine, dihydrocodeine, diamorphine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprodine, buprenorphine, dextromoramide, diphenoxylate, dipipanone, heroin (diacetylmorphine), hydrocodone (dihydrocodeinone), hydromorphone (dihydromorphinone), levorphanol, meptazinol, methadone, metopon (methyldihydromorphine), nalbuphine, oxycodone (dihydrohydroxycodemone), oxymorphone (dihydrohydroxymorphinone), phenadoxone, phenazocine, remifentanil tramadol, or a salt of any of these. the opioid used in the method of the invention may comprise any combination of the aforementioned compounds. Naloxone is also included within the definition of am opioid. Especially preferred analgesics which may be mentioned are hydromorphone, oxycodone, morphine, e.g. morphine sulphate and fentanyl. In a preferred embodiment of the invention the analgesic is morphine or morphine sulphate. in a further preferred embodiment the opioid is fentanyl or a salt thereof. ln the method of the invention the devazepide and/or the opioid may be administered using any methods conventionally knownper se. Thus, such methods would include, but shall not be limited to, administration intravenously, intra-arterially, orally, intrathecally, intranasally, intrarectally, intramuscularly/subcutaneously, by inhalation and by transdermal patch. When the devazepide and/or opioid is administered intravenously, it may, for example, be as an intravenous bolus 0r a continuous intravenous infusion, Whea the devazepide and/or the opioid is administered subcutaneously, it may for example be by subcutaneous infusion. Preferably, tie opioid and/or devazepide are administered intravenously or orally. Oral administration is especially preferred. In a further preferred embodiment the opioid may be administered by a transdermal patch. When a transdermal patch is used, the preferred opioid is fentanyl or a salt thereof. Thus, in the method of the invention the daily dosage of devazepide may vary depending upon, inter alia, the weight of the patient, the method of administration, etc. In patients that are suffering serious disorders, such as cancer patients, the weight of the patient may be very low and therefore; the dosage of devazepide consequentially may be low. Preferably, the daily dosage of devazepide may be from 25 ug/kg/day to 0.7 mg/kg/day, more preferably from 50 ug/kg/day to 0.5 mg/kg/day. For oral administration the daily dosage of devazepide may be from 0.07 mg/kg/day to 0.7 mg/kg/day, preferably 0.07 mg/kg/day to 0.29 mg/kg/day. For intravenous administration the dosage of devazepide is preferably 50 ug/kg/day to 0.5 mg/kg/day. Thus, the expected daily dose of surfactant, which may optionally have laxative and/or stool softening properties, may be up to 0.056 mg/kg/day. Thus, dependant upon the patient, the daily dosage of surfactant may be from 0,4mg to 1.6mg, preferably 0.8mg. Most preferably, the surfactant will be one which, posses both laxative and stool softening properties, ln the method of the invention the dosage of the opioid analgesic administered may vary depending upon, inter alia, the nature of the opioid analgesic, the weight of the patient, the method of administration, etc. Thus, for example, the dosage of, e.g. an opioid, such as morphine, may be from 5 to 2000mg daily. A particular dosage which may be mentioned is from 10 to 240mg daily. A daily dosage of morphine may be from 5 to 100mg or occasionally up to 500mg. According to a yet further aspect of the invention we provide a monophasic pharmaceutical composition comprising an amount of devazepide effective in the enhancement of opioid analgesia and a pharmaceutically acceptable surfactant. Preferably, the devazepide and the pharmaceutically acceptable surfactant are in a solid dosage form. The phrase solid dosage form may mean, for example, in tablet form or, preferably in the form of a flowable powder in a capsule. The composition of this aspect of the invention is preferentially a composition which comprises any of the aspects of the methods hereinbefore descried. The devazepide used in the method and/or the composition of the invention, is the S enantiomer, preferentially, the S enantiomer wherein the level of R enantiomer, which may be present as an impurity, is not greater than 1.5% w/w. WE CLAIM: 1. A monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant wherein the daily dosage of devazepide is up to 0.7 mg/kg/day, the surfactant being selected from the group consisting of alkyl sulphosuccinates, alkyl sulphates and alkyl ammonium salts. 2. A monophasic pharmaceutical composition as claimed in claim 1, wherein the daily dosage of devazepide is from 25 ug/kg/day 0.7 mg/kg/day. 3. A monophasic pharmaceutical composition as claimed in claim 2, wherein the daily dosage of devazepide is from 50 ug/kg/day to 0.5 mg/kg/day. 4. A monophasic pharmaceutical composition as claimed in claim 1, which is in liquid form. 5. A monophasic pharmaceutical composition as claimed in claim 1, which is in a solid dosage form. 6. A monophasic pharmaceutical composition as claimed in claim 1, which is in the tablet form. 7. A monophasic pharmaceutical composition as claimed in claim 1, which is in the form of a flowable powder in a capsule. 8. A monophasic pharmaceutical composition as claimed in claim 1, which is adapted for the separate, simultaneous or sequential administration with a therapeutically effective amount of an opioid analgesic. 9. A monophasic pharmaceutical composition as claimed in claim 1, which is adapted to be administered intravenously, intra-arterially, orally, intrathecally, intranasally, intrarectally, intramuscularly/subcutaneously, by inhalation or by transdermal patch. 10. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide and/or the opioid is/are adapted to be administered intravenously. 11. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide and/or the opioid is/are adapted to be administered subcutaneously. 12. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide and/or the opioid is/are adapted to be administered orally. 13. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide is administered orally. 14. A monophasic pharmaceutical composition as claimed in claim 10, wherein the opioid is adapted to be administered intravenously and the devazepide is adapted to be to administered intravenously. 15. A monophasic pharmaceutical composition as claimed in claim 12, wherein the opioid is adapted to be administered orally and the devazepide is adapted to be to administered orally. 16. A monophasic pharmaceutical composition as claimed in claim 9, wherein the opioid is adapted to be administered intravenously or orally. 17. A monophasic pharmaceutical composition as claimed in claim 9, wherein the opioid is adapted to be administered by transdermal patch. 18. A monophasic pharmaceutical composition as claimed in claim 8, wherein the opioid is selected from the group consisting of morphine, or a salt thereof such as the sulphate, chloride or hydrochloride, or the other 1-4-hydroxymorphinan opioid analgesics such as naloxone, meperidine, butorphanol or pentazocine, or morphine-6-glucoronide, codeine, dihydrocodeine, diamorphine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprodine, buprenorphine, dextromoramide, diphenoxylate, dipipanone, heroin (diacetylmorphine), hydrocoodone (dihydrocodeinone), hydromorphone (dihydromorphinone), levorphanal, meptazinol, methadone, metopon (methyldihydromorphinone), nalbuphine, oxycodone (dihydrohydroxycodeinone), oxymorphone (dihydrohydroxymorphinone) phenadoxone, phenazocine, remifentanil, tramodol, or a salt of any of these, or any combination of the aforementioned compounds. 19. A monophasic pharmaceutical composition as claimed in claim 18, wherein the opioid is selected from the group consisting of hydromorphone, oxycodone,morphine and fentanyl, or a salt thereof. 20. A monophasic pharmaceutical composition as claimed in claim 19, wherein the opioid is morphine or morphine sulphate. 21. A monophasic pharmaceutical composition as claimed in claim 19, wherein the opioid is fentanyl, or a salt thereof. 22. A monophasic pharmaceutical composition as claimed in claim 1, wherein the daily dose of surfactant is up to 0.056 mg/kg/day. 23. A monophasic pharmaceutical composition as claimed in claim 1, wherein the daily dose of surfactant is from 0.4 mg/kg/day to 1.6 mg/kg/day. 24. A monophasic pharmaceutical composition as claimed in claim 8, wherein the dosage of and opioid is from 5 to 2000 mg daily. 25. A monophasic pharmaceutical composition as claimed in claim 24, wherein the dosage of and opioid is from 10 to 240mg daily. 26. A monophasic pharmaceutical composition as claimed in claim 25, wherein the daily dosage of and opioid is from 5 to 100mg daily. 27. A monophasic pharmaceutical composition as claimed in claim 1, wherein the devazepide is substantially the S enantiomer. 28. A monophasic pharmaceutical composition as claimed in claim 27, wherein the level of R enantiomer, which may be present as an impurity, is not greater than 1.5% w/w. 29. A monophasic pharmaceutical composition as claimed in claim 1, wherein the surfactant is selected from the group consisting of docusate sodium (dioctyl sodium sulphosuccinate), sodium dodecyl sulphate and tetradecyltrimethyl ammonium bromide. 30. A monophasic pharmaceutical composition as claimed in claim 1, wherein the surfactant also possesses antimicrobial and/or antiseptic properties. 31. A monophasic pharmaceutical composition as claimed in claim 30, wherein the surfactant is cetrimide. 32. A monophasic pharmaceutical composition as claimed in claim 29, wherein the surfactant is docusate sodium. 33. A monophasic pharmaceutical composition as claimed in claim 1, which contains one or more fillers, such as herein described. 34. A monophasic pharmaceutical composition as claimed in claim 33, wherein the filler particles are coated with the surfactant and the coated filler and devazepide are then formed into an intimate mixture. 35. A monophasic pharmaceutical composition as claimed in claim 33, wherein the filler is selected from the group consisting of lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolysed starches, starch, microcrystaline cellulose, cellulosics, sorbitol, sucrose, sucrose-based materials, icodextrin, calcium sulphate, dibasic calcium phosphate and dextrose and mixtures thereof. 36. A monophasic pharmaceutical composition as claimed in claim 35, wherein the filler is starch. 37. A monophasic pharmaceutical composition as claimed in claim 36, wherein the starch is corn starch. 38. A monophasic pharmaceutical composition as claimed in claim 33, wherein the sizes of the devazepide particles and the filler particles are different. 39. A monophasic pharmaceutical composition as claimed in claim 1, wherein the ratio of the devazepide: surfactant is from 5:1 to 25:1 w/w. 40. A monophasic pharmaceutical composition as claimed in claim 33, which comprises devazepide and the surfactant with the remainder of the composition being made up with the filler. 41. A monophasic pharmaceutical composition as claimed in claim 40, which comprises 1.25 mg of devazepide, 0.1 mg of the surfactant and 148.65 mg of the filler. 42. A monophasic pharmaceutical composition as claimed in claim 41, which comprises 1.25 mg of devazepide, 0.1 mg of the docusate sodium and 148.65 mg of corn starch. 43. A monophasic pharmaceutical composition as claimed in claim 40, which comprises 2.5 mg of devazepide, 0.2 mg of the surfactant and 297.3 mg of the filler. 44. A monophasic pharmaceutical composition as claimed in claim 43, which comprises 2.5 mg devazepide, 0.2 mg docusate sodium and 297.3 mg corn starch. 45. A monophasic pharmaceutical composition as claimed in claim 1, which is filled into a capsule. 46. A monophasic pharmaceutical composition as claimed in claim 45, wherein the capsule is a gelatin capsule. The invention provides a monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant selected from the group comprising alkyl suphosuccinates, alkyl sulphates or alkyl ammonium salts. The invention also proves uses of such compositions in the treatment of pain relief.

Full Text

MONOPHASIC PHARMACEUTICAL COMPOSITION CONTAINING DEVAZEPIDE
This invention relates to a novel monophasic pharmaceutical composition containing devazepide.
International Patent Application No. WO 99/18967 describes -pharmaceutical compositions for treating chronic and neuropathic pain which comprises an analgesic amount of an opioid and an opioid potentiating amount of a CCK antagonist WO 967 describes the use of both CCK-A (CCK-1) antagonists and CCK-B (CCK-2) antagonists, although it is described that, generally, CCK-B (CCK-2) antagonists are preferred Moreover, page 2, lines 6 to 8 of WO '967 describes (hat CCK-A (CCK-1) antagonists may be suitable, but only at relatively higher dosages.
One specific CCK-A (CCK-1) antagonist which is mentioned in WO 99/18967 is devazepide (Devacade®), which is 3s-(-)-l,3-dihydro-3-(2-indolecarbonylammo)-l-methyl-5-phenyl-2H-l ,4-benzodiazepin-2-one.
Devazepide is commonly administered alongside an opioid analgesic, e.g. such as morphine. However, in normal doses, the commonest side-effects of morphine and other opioid analgesics are nausea, vomiting, constipation, drowsiness, and -confusion; tolerance generally develops with long-term use, but not to constipation which is the most common undesirable side effect of morphine treatment
International Patent Application No. WO 99/18967 specifically describes a pharmaceutical formulation comprising a CCK antagonist, such as devazepide, an opioid and a biphasic carder, comprising a glyceride derivative organic phase. This application suggests the possible use of a surfactant, especially when the formulation is in the form of an oil-m-water emulsion.
We have now surprisingly found that a method of treatment of a patient requiring analgesia which comprises administering a monophasic form of devazepide which may be prepared .with a surfactant The use of a surfactant is advantageous in that,
inter alia, it improves the powder flow and/or separation properties of solid devazepide and also reduces or mitigates the undesirable side effects of opioid administration, e.g. constipation.
Thus, according to the invention there is provided a monophasic pharmaceutical composition for treatment of a patient requiring analgesia which composition, upon separate, simultaneous or sequential administration, provides a therapeutically effective amount of an opioid analgesic, devazepide and a pharmaceutically acceptable surfactant wherein the daily dosage of devazepide is up to 0.7 mg/kg/day.
Accordingly, the present invention provides a monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant wherein the daily dosage of devazepide is up to 0.7 mg/kg/day, the surfactant being selected from the group consisting of alkyl sulphosuccinates, alkyl sulphates and alkyl ammonium salts.
The devazepide and the pharmaceutically acceptable surfactant are in a monophasic form, e.g.- solid or liquid form. Preferably, the devazepide and the pharmaceutically acceptable surfactant are in a monophasic form, eg a liquid form or a solid dosage form. The phrase solid dosage form may mean, for example, in tablet form or,-preferably in the-form of a flowable powder in a capsule. We have found that the use of a surfactant in a solid dose devazepide composition as hereinbefore described has the advantage of mitigating constipation due to the concomitant administration of aa opioid analgesic, whilst also improving the physical properties of devazepide in a solid dose formulation,
Any conventionally known pharmaceutically acceptable surfactants may be used in the method of the invention. Such surfactants include, but shall not be limited to, a lipophilic surfactant hydrophilic surfactant or a glyceride, or combinations thereof.
When the surfactant is a hydrophilic surfactant, it may be an- ionic or a non-ionic surfactant. Examples of non-ionic hydrophilic surfactants include, inter alia, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyo3xyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid' esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fetty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols,
derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction, mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; tocopherol polyethylene glycol succinates; sugar esters; sugar ethers; sucroglycerides; and mixtures thereof
Examples of ionic hydrophilic surfactants include, inter alia, alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof, fatty acid derivatives of0 amino acids, carnitines, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-, diacetylated tartario acid esters of mono-, diglycerides; succinoylated monoglycerides; citric acid esters of mono-, diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulphates; salts of fatty acids; sodium docusate; and mixtures thereof
Examples of lipophilic surfactants include, inter alia, alcohols; polyoxyethylene alkylethers; fatty acids; bile acids; glycerol fatty acid esters; acetylated glycerol tatty acid esters; lower alcohol fatty acids esters; polyethylene) glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic add derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
Examples of glycerides include mono-, di- or tri-glyceiides. Such triglycerides include, inter alia, vegetable oils, fish, oils, animal fats, hydrogenated vegetable oils,
partially hydrogenated vegetable oils, synthetic triglycerides, modified triglyceride
fractionated triglycerides, and mixtures thereof
ln an especially preferred embodiment of the invention the surfactant will be capab of improving powder flow of devazepide and may be known to be a therapeutical effective laxative and/or stool softener. Such laxatives and/or stool softeners ma preferentially be ionic surfactants, especially alkyl sulphosucinates, alkyl sulphat or alkyl ammonium salts.
Thus, in a preferred embodiment of the invention the surfactant may be selected fro: the group,' docusate sodium (dioctyl sodium sulphosuccinate), sodium dodec sulphate and tetradecyltrimethyl ammonium bromide.
In a further embodiment of the invention the surfactant may also posse antimicrobial and/or antiseptic properties. Thus, for example, when the surfactant tetradecyltrimethylammonium bromide, it may, preferentially, be cetrimic (cetrimide is a mixture substantially comprising tetradecyltrimethyl ammonia bromide and -small amounts of dodecyltrimethylammonium bromide an cetrimonium bromide).
In the most preferred embodiment of the invention the surfactant is docusate sodium
The method of the invention may preferentially comprise the use of a compositic which comprises one or more fillers, Thus, such fillers may be selected from th group lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolysed starches, directly compressib starch, microcrystalline cellulose, cllulosics, sorbitol, sucrose, sucrose-base materials, icodextrin, calcium sulphate, dibasic calcium, phosphate and dextrose, . preferred filler is starch, e.g. com starch.
When the method of the invention comprises the use of a composition which includes a filler, the size of the devazepide and filler particles may be title same c
different However, in a preferred embodiment the sizes of the devazepide and filler particles will differ. Preferentially, the devazepide, surfactant and/or the filler may be of reduced particle size, e.g. by milling,
The devazepide, surfactant and filler may be present as an intimate mixture. However, in a preferred embodiment the filler particles may be coated 'with the surfactant, the coated filler and devazepide then being formed into an intimate mixture.
The method of the invention wherein the compositions, comprising devazepide, a filler and a surfactant are especially advantageous in that, inter alia, the surfactant acts to hinder or prevent separation of the devazepide and the filler. Furthermore, in one embodiment of the invention the surfactant may also have desirable laxative and/or stool softening properties.
The amount of surfactant present in the composition used in the method of the invention may vary, depending upon, inter alia, the level of devazepide present, the level of concomitant opioid analgesic administered, etc. Generally, the ratio of devazepide:surfactant may be from 5:1 to 25:1 w/w, preferably from 10:1 to 15:1 w/w, most preferably 12.5:1 w/w.
When the composition used in the method of the invention includes a filler, the composition may generally comprise devazepide and a surfactant, in the ratio as hereinbefore described, with the remainder of the composition being made up with a filler.
A preferred embodiment of the invention comprises a method wherein a composition as hereinbefore described is filled into a capsule. Any conventionally known materials may be used for the capsule, however a preferred material is gelatin.
Thus, for example, in one embodiment of the invention the composition as hereinbefore described may be made up into a capsule formulation, e.g. with a fill
weight of 150 mg ± 5% by weight or 300 mg ± 5% by weight i the one preferred embodiment, the capsule formulation may comprise 1.25mg devazepide, 0.1 mg surfactant, e.g. docusate sodium, and 148.65 mg of a filler, e.g. com starch. In. a further preferred embodiment, the capsule formulation may comprise 2,5mg devazepide, 0.2 mg surfactant, e.g. docusate sodium, and 297,3 mg of a tiller, e.g. com starch-According to a further aspect of the invention we provide the use of devazepide in the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of devazepide and apharmaceutically acceptable surfactant

The use of the invention is preferentially the use in the manufacture of a pharmaceutical composition wherein the composition comprises any of the aspects of the methods hereinbefore described. The use as hereinbefore described preferentially comprises the use in the manufacture of a pharmaceutical composition in monophasic form.
By the term therapeutically effective amount of devazepide we generally mean an amount of devazepide effective in the enhancement of opioid analgesia.
In the method of the invention a variety of opioids may be used. Thus, the opioid may be selected from those which are effective analgesics and particularly those which need to be administered at relatively high or increasing doses. Examples include morphine, or a salt thereof such as the sulphate, chloride or hydrochloride, or the other 1,4-hydroxymorphinan opioid analgesics such as naloxone, meperidine, butorphanol or pentazocine, or morphine-6-glucuronide, codeine, dihydrocodeine, diamorphine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprodine, buprenorphine, dextromoramide, diphenoxylate, dipipanone, heroin (diacetylmorphine), hydrocodone (dihydrocodeinone), hydromorphone (dihydromorphinone), levorphanol, meptazinol, methadone, metopon (methyldihydromorphine), nalbuphine, oxycodone (dihydrohydroxycodemone), oxymorphone (dihydrohydroxymorphinone), phenadoxone, phenazocine,
remifentanil tramadol, or a salt of any of these. the opioid used in the method of the invention may comprise any combination of the aforementioned compounds. Naloxone is also included within the definition of am opioid. Especially preferred analgesics which may be mentioned are hydromorphone, oxycodone, morphine, e.g. morphine sulphate and fentanyl. In a preferred embodiment of the invention the analgesic is morphine or morphine sulphate. in a further preferred embodiment the opioid is fentanyl or a salt thereof.
ln the method of the invention the devazepide and/or the opioid may be administered using any methods conventionally knownper se. Thus, such methods would include, but shall not be limited to, administration intravenously, intra-arterially, orally, intrathecally, intranasally, intrarectally, intramuscularly/subcutaneously, by inhalation and by transdermal patch. When the devazepide and/or opioid is administered intravenously, it may, for example, be as an intravenous bolus 0r a continuous intravenous infusion, Whea the devazepide and/or the opioid is administered subcutaneously, it may for example be by subcutaneous infusion. Preferably, tie opioid and/or devazepide are administered intravenously or orally. Oral administration is especially preferred. In a further preferred embodiment the opioid may be administered by a transdermal patch. When a transdermal patch is used, the preferred opioid is fentanyl or a salt thereof.
Thus, in the method of the invention the daily dosage of devazepide may vary depending upon, inter alia, the weight of the patient, the method of administration, etc. In patients that are suffering serious disorders, such as cancer patients, the weight of the patient may be very low and therefore; the dosage of devazepide consequentially may be low. Preferably, the daily dosage of devazepide may be from 25 ug/kg/day to 0.7 mg/kg/day, more preferably from 50 ug/kg/day to 0.5 mg/kg/day. For oral administration the daily dosage of devazepide may be from 0.07 mg/kg/day to 0.7 mg/kg/day, preferably 0.07 mg/kg/day to 0.29 mg/kg/day. For intravenous administration the dosage of devazepide is preferably 50 ug/kg/day to 0.5 mg/kg/day.
Thus, the expected daily dose of surfactant, which may optionally have laxative and/or stool softening properties, may be up to 0.056 mg/kg/day. Thus, dependant upon the patient, the daily dosage of surfactant may be from 0,4mg to 1.6mg, preferably 0.8mg. Most preferably, the surfactant will be one which, posses both laxative and stool softening properties,
ln the method of the invention the dosage of the opioid analgesic administered may vary depending upon, inter alia, the nature of the opioid analgesic, the weight of the patient, the method of administration, etc. Thus, for example, the dosage of, e.g. an opioid, such as morphine, may be from 5 to 2000mg daily. A particular dosage which may be mentioned is from 10 to 240mg daily. A daily dosage of morphine may be from 5 to 100mg or occasionally up to 500mg.
According to a yet further aspect of the invention we provide a monophasic pharmaceutical composition comprising an amount of devazepide effective in the enhancement of opioid analgesia and a pharmaceutically acceptable surfactant.
Preferably, the devazepide and the pharmaceutically acceptable surfactant are in a solid dosage form. The phrase solid dosage form may mean, for example, in tablet form or, preferably in the form of a flowable powder in a capsule.
The composition of this aspect of the invention is preferentially a composition which comprises any of the aspects of the methods hereinbefore descried.
The devazepide used in the method and/or the composition of the invention, is the S enantiomer, preferentially, the S enantiomer wherein the level of R enantiomer, which may be present as an impurity, is not greater than 1.5% w/w.
WE CLAIM:
1. A monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant wherein the daily dosage of devazepide is up to 0.7 mg/kg/day, the surfactant being selected from the group consisting of alkyl sulphosuccinates, alkyl sulphates and alkyl ammonium salts.
2. A monophasic pharmaceutical composition as claimed in claim 1, wherein the daily dosage of devazepide is from 25 ug/kg/day 0.7 mg/kg/day.
3. A monophasic pharmaceutical composition as claimed in claim 2, wherein the daily dosage of devazepide is from 50 ug/kg/day to 0.5 mg/kg/day.
4. A monophasic pharmaceutical composition as claimed in claim 1, which is in liquid form.
5. A monophasic pharmaceutical composition as claimed in claim 1, which is in a solid dosage form.
6. A monophasic pharmaceutical composition as claimed in claim 1, which is in the tablet form.
7. A monophasic pharmaceutical composition as claimed in claim 1, which is in the form of a flowable powder in a capsule.
8. A monophasic pharmaceutical composition as claimed in claim 1, which is adapted for the separate, simultaneous or sequential administration with a therapeutically effective amount of an opioid analgesic.
9. A monophasic pharmaceutical composition as claimed in claim 1, which is adapted to be administered intravenously, intra-arterially, orally, intrathecally, intranasally, intrarectally, intramuscularly/subcutaneously, by inhalation or by transdermal patch.
10. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide and/or the opioid is/are adapted to be administered intravenously.
11. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide and/or the opioid is/are adapted to be administered subcutaneously.
12. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide and/or the opioid is/are adapted to be administered orally.
13. A monophasic pharmaceutical composition as claimed in claim 9, wherein the devazepide is administered orally.
14. A monophasic pharmaceutical composition as claimed in claim 10, wherein the opioid is adapted to be administered intravenously and the devazepide is adapted to be to administered intravenously.
15. A monophasic pharmaceutical composition as claimed in claim 12, wherein the opioid is adapted to be administered orally and the devazepide is adapted to be to administered orally.
16. A monophasic pharmaceutical composition as claimed in claim 9, wherein the opioid is adapted to be administered intravenously or orally.
17. A monophasic pharmaceutical composition as claimed in claim 9, wherein the opioid is adapted to be administered by transdermal patch.
18. A monophasic pharmaceutical composition as claimed in claim 8, wherein the opioid is selected from the group consisting of morphine, or a salt thereof such as the sulphate, chloride or hydrochloride, or the other 1-4-hydroxymorphinan opioid analgesics such as naloxone, meperidine, butorphanol or pentazocine, or morphine-6-glucoronide, codeine, dihydrocodeine, diamorphine, dextropropoxyphene, pethidine, fentanyl, alfentanil, alphaprodine, buprenorphine, dextromoramide, diphenoxylate, dipipanone, heroin
(diacetylmorphine), hydrocoodone (dihydrocodeinone), hydromorphone
(dihydromorphinone), levorphanal, meptazinol, methadone, metopon (methyldihydromorphinone), nalbuphine, oxycodone (dihydrohydroxycodeinone), oxymorphone (dihydrohydroxymorphinone) phenadoxone, phenazocine, remifentanil, tramodol, or a salt of any of these, or any combination of the aforementioned compounds.
19. A monophasic pharmaceutical composition as claimed in claim 18, wherein the opioid is selected from the group consisting of hydromorphone, oxycodone,morphine and fentanyl, or a salt thereof.
20. A monophasic pharmaceutical composition as claimed in claim 19, wherein the opioid is morphine or morphine sulphate.
21. A monophasic pharmaceutical composition as claimed in claim 19, wherein the opioid is fentanyl, or a salt thereof.
22. A monophasic pharmaceutical composition as claimed in claim 1, wherein the daily dose of surfactant is up to 0.056 mg/kg/day.
23. A monophasic pharmaceutical composition as claimed in claim 1, wherein the daily dose of surfactant is from 0.4 mg/kg/day to 1.6 mg/kg/day.
24. A monophasic pharmaceutical composition as claimed in claim 8, wherein the dosage of and opioid is from 5 to 2000 mg daily.
25. A monophasic pharmaceutical composition as claimed in claim 24, wherein the dosage of and opioid is from 10 to 240mg daily.
26. A monophasic pharmaceutical composition as claimed in claim 25, wherein the daily dosage of and opioid is from 5 to 100mg daily.
27. A monophasic pharmaceutical composition as claimed in claim 1, wherein the devazepide is substantially the S enantiomer.
28. A monophasic pharmaceutical composition as claimed in claim 27, wherein the level of R enantiomer, which may be present as an impurity, is not greater than 1.5% w/w.
29. A monophasic pharmaceutical composition as claimed in claim 1, wherein the surfactant is selected from the group consisting of docusate sodium (dioctyl sodium sulphosuccinate), sodium dodecyl sulphate and tetradecyltrimethyl ammonium bromide.
30. A monophasic pharmaceutical composition as claimed in claim 1, wherein the surfactant also possesses antimicrobial and/or antiseptic properties.
31. A monophasic pharmaceutical composition as claimed in claim 30, wherein the surfactant is cetrimide.
32. A monophasic pharmaceutical composition as claimed in claim 29, wherein the surfactant is docusate sodium.
33. A monophasic pharmaceutical composition as claimed in claim 1, which contains one or more fillers, such as herein described.
34. A monophasic pharmaceutical composition as claimed in claim 33, wherein the filler particles are coated with the surfactant and the coated filler and devazepide are then formed into an intimate mixture.
35. A monophasic pharmaceutical composition as claimed in claim 33, wherein the filler is selected from the group consisting of lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolysed starches, starch, microcrystaline cellulose, cellulosics, sorbitol, sucrose, sucrose-based materials, icodextrin, calcium sulphate, dibasic calcium phosphate and dextrose and mixtures thereof.
36. A monophasic pharmaceutical composition as claimed in claim 35, wherein the filler is starch.
37. A monophasic pharmaceutical composition as claimed in claim 36, wherein the starch is corn starch.
38. A monophasic pharmaceutical composition as claimed in claim 33, wherein the sizes of the devazepide particles and the filler particles are different.
39. A monophasic pharmaceutical composition as claimed in claim 1, wherein the ratio of the devazepide: surfactant is from 5:1 to 25:1 w/w.
40. A monophasic pharmaceutical composition as claimed in claim 33, which comprises devazepide and the surfactant with the remainder of the composition being made up with the filler.
41. A monophasic pharmaceutical composition as claimed in claim 40, which comprises 1.25 mg of devazepide, 0.1 mg of the surfactant and 148.65 mg of the filler.
42. A monophasic pharmaceutical composition as claimed in claim 41, which comprises 1.25 mg of devazepide, 0.1 mg of the docusate sodium and 148.65 mg of corn starch.
43. A monophasic pharmaceutical composition as claimed in claim 40, which comprises 2.5 mg of devazepide, 0.2 mg of the surfactant and 297.3 mg of the filler.
44. A monophasic pharmaceutical composition as claimed in claim 43, which comprises 2.5 mg devazepide, 0.2 mg docusate sodium and 297.3 mg corn starch.
45. A monophasic pharmaceutical composition as claimed in claim 1, which is filled into a capsule.
46. A monophasic pharmaceutical composition as claimed in claim 45, wherein the capsule is a gelatin capsule.
The invention provides a monophasic pharmaceutical composition comprising a therapeutically effective amount of devazepide and a pharmaceutically acceptable surfactant selected from the group comprising alkyl suphosuccinates, alkyl sulphates or alkyl ammonium salts. The invention also proves uses of such compositions in the treatment of pain relief.

Documents:

« Previous Patent

Next Patent »

Patent Number

224960

Indian Patent Application Number

00923/KOLNP/2004

PG Journal Number

44/2008

Publication Date

31-Oct-2008

Grant Date

29-Oct-2008

Date of Filing

02-Jul-2004

Name of Patentee

PANOS THERAPEUTICS LIMITED

Applicant Address

THE DOCTORS HOUSE, HIGH STREET, LITTLE MILTON, OXFORD OX44 7PU

Inventors:

#	Inventor's Name	Inventor's Address
1	JACKSON KAREN	11 ROOKERY DELL, DEEPCAR SHEFFIELD S35 2ND

PCT International Classification Number

A61K 9/48

PCT International Application Number

PCT/GB03/00221

PCT International Filing date

2003-01-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0201367.0	2002-01-22	U.K.