US3676557A - Long-acting narcotic antagonist formulations - Google Patents
Long-acting narcotic antagonist formulations Download PDFInfo
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- US3676557A US3676557A US120336A US3676557DA US3676557A US 3676557 A US3676557 A US 3676557A US 120336 A US120336 A US 120336A US 3676557D A US3676557D A US 3676557DA US 3676557 A US3676557 A US 3676557A
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- This invention relates to the known narcotic antagonists, N- allyl-7,8-dihydro-l4-hydroxynormorphinone and N- (cyclopropylmethyl)-7,8-dihydro-l4-hydroxynormorphinone.
- the former compound will sometimes be referred to hereinafter by its generic name, naloxone.
- Naloxone and certain of its salts are disclosed in US. Pat. No. 3,254,088 as potent narcotic antagonists.
- a report by Fink et al., Naloxone in Heroin Dependence," Clinical Pharmacology and Therapeutics, Vol. 9, No. 5, pp. 568-577 (1968) confirms that naloxone is a highly potent antagonist which is relatively free of adverse side, effects. Fink et al. note however that the antagonist action of naloxone is quite brief, and conclude:
- naloxone is the best drug available for such studies, but pharmaceutical ingenuity may create compounds with longer durations of action and equal potency and safety.
- N-(cyclopropylmethyl)-7,8-dihydro-l4-hydroxynormorphinone and certain of its salts are disclosed in U.S. Pat. No. 3,332,950.
- This compound is also a potent narcotic antagonist but, like naloxone it suffers the disadvantage of relatively short duration of action.
- Di-naloxone pamoate is an odorless, light yellowish-tan powder with the empirical formula (C,,,H ,NO,,) -C H ,O,
- Di-naloxone pamoate is prepared by mixing naloxone hydrochloride with disodium pamoate in a 2:1 molar ratio in aqueous solution.
- the relatively insoluble di-naloxone pamoate precipitates, is removed by filtration, purified by recrystallization from ethanol or other suitable solvent, and dried.
- the product need not be anhydrous. it will ordinarily contain at least 1 mole of water and may contain up to about 10 percent by weight of combined or uncombined water and/or combined or uncombined solvent.
- a specific procedure which can be used to produce di-naloxone pamoate is as follows:
- Di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone] pamoate is an odorless, buff-colored powder with the empirical formula (C ,,H ',NO,,) -C.,, -,H ,0 and the structural formula: I
- Di-[N-(cyclopropylmethyl)-7,S-dihydro-14-hydroxynormorphinone] pamoate is prepared in a manner similar to that used for preparing di-naloxone pamoate, and like di-naloxone pamoate it may contain up to about 10 percent by weight of combined or uncombined water and/or solvent.
- a specific procedure which can be used to produce this salt is as follows:
- Recrystallization from ethanol yields 6.1 g. in two crops, which are combined and dried for 3 hours at 100 C. in a vacuum oven to give material which decomposes at 200-207 C.
- the oil medium for suspensions of this invention can be any vegetable oil which is suitable for parenteral use.
- the vegetable oil for example, may be peanut oil, corn oil, sesame oil, or cottonseed oil.
- a viscosity-increasing agent is incorporated into the vegetable oil.
- Suitable viscosityincreasing agents are the fatty acid salts of aluminum, especially those containing about seven to 25 carbon atoms.
- Aluminum monostearate is particularly preferred.
- the aluminum monostearate or other viscosity-increasing agent will ordinarily be used in an amount in the range of from 01-50 percent (w/v), based on the oil. The preferred range is 1.0-4.0 percent (w/v).
- the viscosity-increasing agent is incorporated into the vegetable oil with agitation and heating as necessary to produce a stable vegetable oil gel.
- an aluminum monostearate gel can be prepared by suspending an amount of aluminum monostearate in a suitable vegetable oil. Under constant agitation, heat is applied until a temperature of 85-90 C. is attained. A heating rate of 5 C. per minute is applied until this temperature is reached. This temperature is maintained for 30-45 minutes to eliminate water from the system. Heating is continued, but retarded to 23 C. per minute until a temperature of C. is attained. 15 minutes stirring at this temperature will stabilize the gel that is formed. Using this technique, vegetable oil gels can be made at temperatures between 125C. and C.
- a preservative can be added to the vegetable oil gel, if desired, in an amount ordinarily used in injectable dosage forms, i.e. about 0.05 percent to 0.5 percent (w/v) based on oil.
- the parabens, in combinations ordinarily used in parenterals, are preferred, but other preservatives recognized for use in parenterals (e.g. phenol, cresol, chlorobutanol) can also be used.
- Antioxidants commonly used in pharmaceutical products may also be incorporated. These include, for example, ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated hydroxy toluene, butylated hydroxy anisole, a-tocopherol and its esters, phenyl anaphthylamine, lecithin, and mixtures of these.
- the amount of antioxidant, when used, will ordinarily be in the range from about 0.005 to 0.2 percent (w/v) based on the oil.
- the suspensions of the invention can also contain other therapeutically active compounds, in amounts sufficient to enhance the utility of the formulation for its intended purpose.
- These adjuvants can be formulated so as to be released immediately or over an extended period of time.
- examples of other types of therapeutically active ingredients which can be included in the suspensions, either as the compounds themselves or their pharmaceutically acceptable salts, are:
- major tranquilizers such as chlorpromazine or molindone
- minor tranquilizers such as chlordiazepoxide, glutethimide or pentobarbital, for the symptomatic relief of narcotic withdrawal symptoms
- analeptics such as picrotoxin or pentamethylenetetrazole, or central nervous system stimulants such as methylphenidate, for antagonism of acute respiratory depression caused by agents other than narcotics; and
- narcotics or other narcotic antagonists such as methadone, meperidine or cyclazocine, in dosage ratios which provide retention of analgesia or appropriate withdrawal therapy, while simultaneously minimizing side effects.
- the di-naloxone pamoate or di-[N-(cyclopropylmethyl)-7,8-dihydro-l4- hydroxynormorphinone] pamoate is added to the vegetable oil gel in amounts equivalent to naloxone hydrochloride or N- cycloproylmethyl-7,8-dihydro-l4-hydroxynormorphinone hydrochloride (anhydrous basis) in the range from about 1 to about 500 mg./ml. of suspension, preferably 2 to 200 mg./ml., more preferably to 100 mg./ml.
- the mixture is then mechanically worked to reduce the particle size of the suspended materials and thoroughly disperse them in the gel.
- the average particle size of the suspended materials should be sufficiently small that the suspension is syringeable through a 20 gauge needle. It is preferred that the average particle size be between 5 and 50 microns, and that essentially all of the particles be less than about 100 microns. Particle size reduction and dispersion of the suspended materials can be accomplished with the use of a laboratory blender, colloid mill, sonic mill, or other comparable equipment.
- Aseptic techniques may be used throughout the preparation, or other suitable techniques for making sterile parenterals can be used.
- a suspension of the invention containing an amount of dinaloxone pamoate equivalent to mg. of naloxone hydrochloride per ml. in 2 percent aluminum monostearate in peanut oil, was tested for duration of Numorphan-antagonist effect in mice.
- the test used was the subcutaneous counteraction of the Numorphan HCl induced Straub tail in mice. Two tests, each using three mice, were made. Each mouse received one injection of the above formulation (5 cc./kg.) and was challenged with a Numorphan HCl injection (2 mg./kg.) at various time intervals thereafter. Results, expressed as the number of mice protected out of three, were as follows:
- the same formulation was also tested for duration of effect in rats.
- the test was subcutaneous injection for prevention of Numorphan induced loss of righting reflex.
- Each rat received one subcutaneous injection of the above formulation (1 cc./kg.) and was challenged with a subcutaneous Numorphan injection (l mg./kg.) at various time intervals thereafter.
- the rats were considered protected if they did not lose their righting reflex in 30 minutes after the Numorphan subcutaneous challenge. Results, expressed as the number of rats protected out of four. were as follows:
- results showed that a dosage of 0.2 cc./kg. gives almost complete protection against Numorphan after 17 days.
- a suspension of the invention containing an amount of di- [N-(cyclopropylmethyl)-7,8-dihydrol 4-hydroxynormorphinone] pamoate equivalent to 10 mg. of N-cyclopropylmethyl- 7,8-dihydro-l4-hydroxynormorphinone hydrochloride per ml., in a peanut oil gel containing 2 percent aluminum monostearate, was compared with an aqueous control solution containing 10 mg./ml. of the N-(cyclopropylmethyl)-7,8- dihydro-l4-hydroxynormorphinone hydrochloride for duration of Numorphan antagonist effect in mice.
- the same formulations, as well as the di-naloxone pamoate formulation described above in the rat test were also compared for duration of Numorphan antagonist effect in rats.
- mice The protocol was the same as that described above for the test of the di-naloxone pamoate suspension in mice, except that each individual animal was challenged only once with a subcutaneous injection of Numorphan (different groups of mice being challenged at the various time intervals), and groups of animals were used for each point. Results, expressed as the number of mice protected out of 10, are shown in the following table; column D shows the results for mice injected with the suspension of the invention, and column C shows the results for the mice injected with the control solution.
- Time of Challenge D minutes 10/ 10 10/10 2 hours 10/10 6 hours 6/10 24 hours 0/10 9/10 48 hours 2/10 72 hours 0/10
- the protocol was the same as that described above for the test of the di-naloxone pamoate suspension in rats, except that each individual animal was challenged only once with a subcutaneous injection of Numorphan (different groups of rats being challenged at the various time intervals), the dosage of the test or control solution was 10 mg./kg., and groups of 10 animals were used for each point, except that a group of only five animals was used for the 92 hour period.
- Results expressed as the number of rats protected out of 10 (or five) are shown in the following table; column D shows the results for rats injected with the di-[N-(cyclopropylmethyl)- 7,8-dihydrol 4-hydroxynormorphinone] pamoate suspension, column C shows the results for rats injected with the control solution and column E shows the results for rats injected with the di-naloxone pamoate suspension.
- An injectable, long-acting narcotic antagonist formulation, syringeable through a 20 gauge needle which comprises:
- a salt selected from the group consisting of di-(N-allyl-7,8-dihydro-14-hydroxynormorphinone) pamoate and di-[N-(cyclopropyl-methyl)-7,8-dihydro-14 -hydroxynormorphinone] pamoate, the average particle size of the salt being between 5 and 50 microns, and essentially all of the particles being less than microns, thoroughly dispersed and suspended in B.
- a gel composed of a vegetable oil which is suitable for subcutaneous or intramuscular administration, gelled with about 0.1 to 5 percent w/v of aluminum monostearate, the concentration of the pamoate salt in the gel being equivalent to a concentration of the corresponding hydrochloride salt in the range of about 1 to about 500 mg./ml.
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Abstract
The pamoate salts of N-(cyclopropylmethyl)-7,8-dihydro-14hydroxynormorphinone and N-allyl-7,8-dihydro-14hydroxynormorphinone, in oil suspension, are injectable, longacting forms of these narcotic antagonists.
Description
United States Patent Lachman et al.
[ 51 July 11,1972
[54] LONG-ACTING NARCOTIC ANTAGONIST FORMULATIONS Hempstead; Walter Specter, Valley Stream, all of NY.
[73] Assignee: Endo Laboratories, Inc., Garden City,
[22] Filed: March 2, 1971 [21] Appl.No.: 120,336
Related U.S. Application Data [63] Continuation-impart of Ser. No. 56,975, July 21,
1970, abandoned.
[$2] U.S. Cl. ..424/260 [5 1] Int. Cl. ..A6lk 27/12 [58] Field of Search ..424/244, 260
[56] References Cited UNITED STATES PATENTS 3,254,088 5/1966 Lowenstein ..260/285 3,332,950 7/ l 967 3,326,896 6/1967 2,964,448 12/1960 2,507,193 5/ 1950 Buckwalter ..424/271 FOREIGN PATIEN'I'S OR APPLICATIONS 1,461,407 12/1966 France 6,706,464 6/1968 South Africa OTHER PUBLICATIONS Thompson, Am. J. Trop. Med. Hyg. 12, 481 (1963) McGregor, Brit. Med. .1. 695, Mar. 19, 1966 Coatney, Am. J. Trop. Med. Hyg. 12, 504 1963) Waltz, Science, 141 723, Aug. 1963 Blumberg et al ..260/285 Primary ExaminerShep K. Rose AuomeyDon M. Kerr [57] ABSTRACT The pamoate salts of N-(cyclopropylmethyl)-7,8-dihydro-14- hydroxynormorphinone and N-allyl-7,8-dihydro-l4-hydroxynormorphinone, in oil suspension, are injectable, long-acting forms of these narcotic antagonists.
3 Claims, No Drawings LONG-ACTING NARCOTIC ANTAGONIST FORMULATIONS RELATED APPLICATIONS This application is a continuation-in-part of application Ser. No. 56,975, filed July 21, 1970 now abandoned.
BACKGROUND OF THE INVENTION This invention relates to the known narcotic antagonists, N- allyl-7,8-dihydro-l4-hydroxynormorphinone and N- (cyclopropylmethyl)-7,8-dihydro-l4-hydroxynormorphinone. The former compound will sometimes be referred to hereinafter by its generic name, naloxone.
Naloxone and certain of its salts are disclosed in US. Pat. No. 3,254,088 as potent narcotic antagonists. A report by Fink et al., Naloxone in Heroin Dependence," Clinical Pharmacology and Therapeutics, Vol. 9, No. 5, pp. 568-577 (1968) confirms that naloxone is a highly potent antagonist which is relatively free of adverse side, effects. Fink et al. note however that the antagonist action of naloxone is quite brief, and conclude:
The short duration of action may be a serious limitation. Further trials of the narcotic antagonist treatment model are necessary, and naloxone is the best drug available for such studies, but pharmaceutical ingenuity may create compounds with longer durations of action and equal potency and safety.
N-(cyclopropylmethyl)-7,8-dihydro-l4-hydroxynormorphinone and certain of its salts are disclosed in U.S. Pat. No. 3,332,950. This compound is also a potent narcotic antagonist but, like naloxone it suffers the disadvantage of relatively short duration of action.
SUMMARY OF THE INVENTlON DESCRIPTION OF THE INVENTION Di-naloxone pamoate is an odorless, light yellowish-tan powder with the empirical formula (C,,,H ,NO,,) -C H ,O,
and the structural fonnula:
. C OOH CH -CH=CH: I l OH HO I H2 OH H!) 2 COOH Di-naloxone pamoate is prepared by mixing naloxone hydrochloride with disodium pamoate in a 2:1 molar ratio in aqueous solution. The relatively insoluble di-naloxone pamoate precipitates, is removed by filtration, purified by recrystallization from ethanol or other suitable solvent, and dried. The product need not be anhydrous. it will ordinarily contain at least 1 mole of water and may contain up to about 10 percent by weight of combined or uncombined water and/or combined or uncombined solvent. A specific procedure which can be used to produce di-naloxone pamoate is as follows:
To a solution of 9.6 g. (0.024 mol) of naloxone hydrochloride monohydrate in approximately l00.ml. water a solution of 5.4 g. (0.012 mol) of disodium pamoate monohydrate in a similar volume of water is slowly added, with stirring. The precipitate, which forms almost instantaneously, is stirred for about 1 hour, the solvent is filtered off, and the residue washed with water and then dried. Yield: 12 g'.
Recrystallization from 300 ml. of boiling ethanol yields 8 g. of product, which, after drying for 3 hours at in a vacuum oven, decomposes at l98225 C.
Di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone] pamoate is an odorless, buff-colored powder with the empirical formula (C ,,H ',NO,,) -C.,, -,H ,0 and the structural formula: I
: coon r l N OH OH: HO I Hi) 0 2 COOH Di-[N-(cyclopropylmethyl)-7,S-dihydro-14-hydroxynormorphinone] pamoate is prepared in a manner similar to that used for preparing di-naloxone pamoate, and like di-naloxone pamoate it may contain up to about 10 percent by weight of combined or uncombined water and/or solvent. A specific procedure which can be used to produce this salt is as follows:
To a solution of 5.7 g. (0.015 mol) of N-(cyclopropylmethyl )-7,8-dihydro- 1 4hydroxynormorphinone hydrochloride in approximately 100 ml. water a solution of 3.4 g. (0.0075 mol) of disodium pamoate monohydrate in a similar volume of water is slowly added, with stirring. The precipitate which fonns is stirred for about an hour, filtered, and the residue washed with water and dried. Yield: 7.2 g.
Recrystallization from ethanol yields 6.1 g. in two crops, which are combined and dried for 3 hours at 100 C. in a vacuum oven to give material which decomposes at 200-207 C.
The oil medium for suspensions of this invention can be any vegetable oil which is suitable for parenteral use. The vegetable oil, for example, may be peanut oil, corn oil, sesame oil, or cottonseed oil.
ln order to provide stable suspensions, a viscosity-increasing agent is incorporated into the vegetable oil. Suitable viscosityincreasing agents are the fatty acid salts of aluminum, especially those containing about seven to 25 carbon atoms. Aluminum monostearate is particularly preferred. The aluminum monostearate or other viscosity-increasing agent will ordinarily be used in an amount in the range of from 01-50 percent (w/v), based on the oil. The preferred range is 1.0-4.0 percent (w/v).
The viscosity-increasing agent is incorporated into the vegetable oil with agitation and heating as necessary to produce a stable vegetable oil gel. For example, an aluminum monostearate gel can be prepared by suspending an amount of aluminum monostearate in a suitable vegetable oil. Under constant agitation, heat is applied until a temperature of 85-90 C. is attained. A heating rate of 5 C. per minute is applied until this temperature is reached. This temperature is maintained for 30-45 minutes to eliminate water from the system. Heating is continued, but retarded to 23 C. per minute until a temperature of C. is attained. 15 minutes stirring at this temperature will stabilize the gel that is formed. Using this technique, vegetable oil gels can be made at temperatures between 125C. and C.
A preservative can be added to the vegetable oil gel, if desired, in an amount ordinarily used in injectable dosage forms, i.e. about 0.05 percent to 0.5 percent (w/v) based on oil. The parabens, in combinations ordinarily used in parenterals, are preferred, but other preservatives recognized for use in parenterals (e.g. phenol, cresol, chlorobutanol) can also be used.
Antioxidants commonly used in pharmaceutical products may also be incorporated. These include, for example, ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated hydroxy toluene, butylated hydroxy anisole, a-tocopherol and its esters, phenyl anaphthylamine, lecithin, and mixtures of these. The amount of antioxidant, when used, will ordinarily be in the range from about 0.005 to 0.2 percent (w/v) based on the oil.
The suspensions of the invention can also contain other therapeutically active compounds, in amounts sufficient to enhance the utility of the formulation for its intended purpose. These adjuvants can be formulated so as to be released immediately or over an extended period of time. Examples of other types of therapeutically active ingredients which can be included in the suspensions, either as the compounds themselves or their pharmaceutically acceptable salts, are:
a. major tranquilizers, such as chlorpromazine or molindone, or minor tranquilizers, such as chlordiazepoxide, glutethimide or pentobarbital, for the symptomatic relief of narcotic withdrawal symptoms;
b. analeptics, such as picrotoxin or pentamethylenetetrazole, or central nervous system stimulants such as methylphenidate, for antagonism of acute respiratory depression caused by agents other than narcotics; and
0. various narcotics or other narcotic antagonists such as methadone, meperidine or cyclazocine, in dosage ratios which provide retention of analgesia or appropriate withdrawal therapy, while simultaneously minimizing side effects.
ln preparing the suspensions of the invention the di-naloxone pamoate or di-[N-(cyclopropylmethyl)-7,8-dihydro-l4- hydroxynormorphinone] pamoate is added to the vegetable oil gel in amounts equivalent to naloxone hydrochloride or N- cycloproylmethyl-7,8-dihydro-l4-hydroxynormorphinone hydrochloride (anhydrous basis) in the range from about 1 to about 500 mg./ml. of suspension, preferably 2 to 200 mg./ml., more preferably to 100 mg./ml. The mixture is then mechanically worked to reduce the particle size of the suspended materials and thoroughly disperse them in the gel. The average particle size of the suspended materials should be sufficiently small that the suspension is syringeable through a 20 gauge needle. It is preferred that the average particle size be between 5 and 50 microns, and that essentially all of the particles be less than about 100 microns. Particle size reduction and dispersion of the suspended materials can be accomplished with the use of a laboratory blender, colloid mill, sonic mill, or other comparable equipment.
Aseptic techniques may be used throughout the preparation, or other suitable techniques for making sterile parenterals can be used.
A suspension of the invention, containing an amount of dinaloxone pamoate equivalent to mg. of naloxone hydrochloride per ml. in 2 percent aluminum monostearate in peanut oil, was tested for duration of Numorphan-antagonist effect in mice. The test used was the subcutaneous counteraction of the Numorphan HCl induced Straub tail in mice. Two tests, each using three mice, were made. Each mouse received one injection of the above formulation (5 cc./kg.) and was challenged with a Numorphan HCl injection (2 mg./kg.) at various time intervals thereafter. Results, expressed as the number of mice protected out of three, were as follows:
Time ofChallengc Test 1 Test 2 minutes 3/3 3/3 24 minutes 3/3 3/3 48 hours 2/3 2/3 72 hours 0/3 The fact that all of the mice were protected at 15 minutes shows that the suspension of the invention provides quick onset of action. At the same time the suspension provided protection to all of the mice for 24 hours and for two thirds of the mice for 48 hours. In contrast, an aqueous solution of naloxone hydrochloride protects mice for only about 5 hours.
The same formulation was also tested for duration of effect in rats. The test was subcutaneous injection for prevention of Numorphan induced loss of righting reflex. Two tests, each using four rats, were made. Each rat received one subcutaneous injection of the above formulation (1 cc./kg.) and was challenged with a subcutaneous Numorphan injection (l mg./kg.) at various time intervals thereafter. The rats were considered protected if they did not lose their righting reflex in 30 minutes after the Numorphan subcutaneous challenge. Results, expressed as the number of rats protected out of four. were as follows:
Time of Challenge Test l Test 2 15 minutes 4/4 4/4 24 hours 3/4 3/4 48 hours 2/4 3/4 72 hours l/4 25 Another suspension of the invention, containing an amount of di-naloxone pamoate equivalent to 50 mg. of naloxone hydrochloride per ml. in 2 percent aluminum monostearate in peanut oil, was tested for duration of effect in dogs. Six dogs were used. Each dog received one I.M. injection of the di- 3 naloxone pamoate suspension. The dosage was 0.1 cc./kg. for two dogs and 0.2 cc./kg. for the other four. Numorphan HCl was given at various time intervals thereafter; the dosage was 0.5 mg./kg. l.V., a prostrating dose. The following is the score system used:
0 Prostration, head drop no protection I Head weakness slight protection 2 Hind and front leg weakness moderate protection 3 Hind leg weakness only almost complete protection 4 Normal, no effect complete protection.
Results were as follows:
Antagonist Time Intervals Dog Dosage 24 48 72 96 7 l0 l4 2| NoJSex (co/kg.) hrs. hrs. hrs. hrs. days days days days l/M 0.l 4 3 0 (i/M 0.2 3 l O In a similar test on two dogs, using a suspension of the invention containing an amount of di-naloxone pamoate equivalent to 50 mg. of naloxone hydrochloride per ml. of 2 percent aluminum monostearate in sesame oil, results showed that a dosage of 0.2 cc./kg. gives almost complete protection against Numorphan after 17 days.
A suspension of the invention, containing an amount of di- [N-(cyclopropylmethyl)-7,8-dihydrol 4-hydroxynormorphinone] pamoate equivalent to 10 mg. of N-cyclopropylmethyl- 7,8-dihydro-l4-hydroxynormorphinone hydrochloride per ml., in a peanut oil gel containing 2 percent aluminum monostearate, was compared with an aqueous control solution containing 10 mg./ml. of the N-(cyclopropylmethyl)-7,8- dihydro-l4-hydroxynormorphinone hydrochloride for duration of Numorphan antagonist effect in mice. The same formulations, as well as the di-naloxone pamoate formulation described above in the rat test, were also compared for duration of Numorphan antagonist effect in rats.
In the mouse: The protocol was the same as that described above for the test of the di-naloxone pamoate suspension in mice, except that each individual animal was challenged only once with a subcutaneous injection of Numorphan (different groups of mice being challenged at the various time intervals), and groups of animals were used for each point. Results, expressed as the number of mice protected out of 10, are shown in the following table; column D shows the results for mice injected with the suspension of the invention, and column C shows the results for the mice injected with the control solution.
Time of Challenge C D minutes 10/ 10 10/10 2 hours 10/10 6 hours 6/10 24 hours 0/10 9/10 48 hours 2/10 72 hours 0/10 In the rat: The protocol was the same as that described above for the test of the di-naloxone pamoate suspension in rats, except that each individual animal was challenged only once with a subcutaneous injection of Numorphan (different groups of rats being challenged at the various time intervals), the dosage of the test or control solution was 10 mg./kg., and groups of 10 animals were used for each point, except that a group of only five animals was used for the 92 hour period. Results, expressed as the number of rats protected out of 10 (or five) are shown in the following table; column D shows the results for rats injected with the di-[N-(cyclopropylmethyl)- 7,8-dihydrol 4-hydroxynormorphinone] pamoate suspension, column C shows the results for rats injected with the control solution and column E shows the results for rats injected with the di-naloxone pamoate suspension.
Time of Challenge C D E 30 minutes 10/10 10/10 l0/l0 1 hour 10/10 6 hours 8/10 24hours0/l0 10/10 10/10 41hours- 9/10 4/10 48 hours 6/10 2/10 65 hours 1/10 0/l0 72 hours- 1/10 0/10 92 hours 0/5 What is claimed is:
1. An injectable, long-acting narcotic antagonist formulation, syringeable through a 20 gauge needle, which comprises:
A. particles of a salt selected from the group consisting of di-(N-allyl-7,8-dihydro-14-hydroxynormorphinone) pamoate and di-[N-(cyclopropyl-methyl)-7,8-dihydro-14 -hydroxynormorphinone] pamoate, the average particle size of the salt being between 5 and 50 microns, and essentially all of the particles being less than microns, thoroughly dispersed and suspended in B. a gel composed of a vegetable oil which is suitable for subcutaneous or intramuscular administration, gelled with about 0.1 to 5 percent w/v of aluminum monostearate, the concentration of the pamoate salt in the gel being equivalent to a concentration of the corresponding hydrochloride salt in the range of about 1 to about 500 mg./ml.
2. Formulation of claim 1 wherein the vegetable oil is selected from the group consisting of peanut oil, corn oil, sesame oil, and cottonseed oil.
3. Formulation of claim 2 wherein the concentration of the pamoate salt in the gel is equivalent to a concentration of the corresponding hydrochloride salt in the range of about 2 to 200 mg./ml., and the concentration of aluminum monostearate in the vegetable oil is in the range of about 1.0 to 4.0 percent w/v.
Claims (2)
- 2. Formulation of claim 1 wherein the vegetable oil is selected from the group consisting of peanut oil, corn oil, sesame oil, and cottonseed oil.
- 3. Formulation of claim 2 wherein the concentration of the pamoate salt in the gel is equivalent to a concentration of the corresponding hydrochloride salt in the range of about 2 to 200 mg./ml., and the concentration of aluminum monostearate in the vegetable oil is in the range of about 1.0 to 4.0 percent w/v.
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Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4218454A (en) * | 1977-07-08 | 1980-08-19 | Sri International | N-αMethylcyclopropylmethyl derivatives of normorphine and noroodeine, and analgesic compositions and methods employing the normorphine derivatives |
US4269843A (en) * | 1978-05-24 | 1981-05-26 | Sri International | N-Sec-alkyl analogs of norcodeine and normorphine and analgesic compositions and methods employing the normorphine derivatives |
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US8846090B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2507193A (en) * | 1949-05-17 | 1950-05-09 | Bristol Lab Inc | Penicillin product |
US2964448A (en) * | 1959-01-27 | 1960-12-13 | Anschel Joachim | Relaxin composition and process for preparing same |
FR1461407A (en) * | 1965-06-09 | 1966-02-25 | Sobio Lab | New amine pamoates and processes for their preparation |
US3254088A (en) * | 1961-03-14 | 1966-05-31 | Lewenstein | Morphine derivative |
US3326896A (en) * | 1964-01-24 | 1967-06-20 | Geigy Chem Corp | Embonic acid addition salts of 10, 11-dihydro-5h-dibenz[b, f]azepines |
US3332950A (en) * | 1963-03-23 | 1967-07-25 | Endo Lab | 14-hydroxydihydronormorphinone derivatives |
-
1971
- 1971-03-02 US US120336A patent/US3676557A/en not_active Expired - Lifetime
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2507193A (en) * | 1949-05-17 | 1950-05-09 | Bristol Lab Inc | Penicillin product |
US2964448A (en) * | 1959-01-27 | 1960-12-13 | Anschel Joachim | Relaxin composition and process for preparing same |
US3254088A (en) * | 1961-03-14 | 1966-05-31 | Lewenstein | Morphine derivative |
US3332950A (en) * | 1963-03-23 | 1967-07-25 | Endo Lab | 14-hydroxydihydronormorphinone derivatives |
US3326896A (en) * | 1964-01-24 | 1967-06-20 | Geigy Chem Corp | Embonic acid addition salts of 10, 11-dihydro-5h-dibenz[b, f]azepines |
FR1461407A (en) * | 1965-06-09 | 1966-02-25 | Sobio Lab | New amine pamoates and processes for their preparation |
Non-Patent Citations (4)
Title |
---|
Coatney, Am. J. Trop. Med. Hyg. 12, 504 (1963) * |
McGregor, Brit. Med. J. 695, Mar. 19, 1966 * |
Thompson, Am. J. Trop. Med. Hyg. 12, 481 (1963) * |
Waltz, Science, 141, 723, Aug. 1963 * |
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