US2770569A - Analgesic compositions - Google Patents
Analgesic compositions Download PDFInfo
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- US2770569A US2770569A US314954A US31495452A US2770569A US 2770569 A US2770569 A US 2770569A US 314954 A US314954 A US 314954A US 31495452 A US31495452 A US 31495452A US 2770569 A US2770569 A US 2770569A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
Definitions
- This invention relates to compositions of matter useful in therapy to produce analgesia. It relates especially to such compositions wherein undesired side effects common to analgesics, particularly respiratory depression, are diminished or suppressed by incorporation of material which antagonizes the tendency of the analgesic material to produce such side effects.
- Morphine-type analgesics have found extensive medical application because of their fi"1cacy even in cases of very severe pain. However, overdoses of such analgesics often are attended by very serious side reactions. In addition, many people react even to minimal therapeutic doses by exhibiting similar side reactions, which are mainly evidenced in the form of respiratory depression, nausea, and vomiting. In the management of labor, analgesic medication administered to the mother often results in respiratory depression of the newborn infant.
- the present invention rests upon the discovery that levo-3-hydroxy-N-allyl-rnorphinan, either in the form of the free base or in the form of its acid addition salts, has the characteristic of suppressing or eliminating undesired side reactions of morphine-type analgesics.
- this antagonistic effect of 3-hydroxy-N-allyl-morphinan is limited to the levo enantiomorph thereof; the dextro form having little or no antagonistic effect; and the racemic form having the activity only of its levo content.
- the antagonistic effect of levo-3-hydroxy-N-allylmorphinan extends not only to the undesired side reactions of morphine-type analgesics but also extends to the analgesic activity itself. Accordingly, the dosage of the antagonist, levo-3-hydroxy-N-allylmorphinan, must be carefully proportioned with respect to the dosage of the analgesic material so as to diminish or suppress the side reactions without significantly influencing the desired analgesic action.
- compositions wherein the proportion of analgesic material and antagonist material differs slightly from the range indicated above, but which exhibit the desirable qualities indicated in this disclosure, are equivalent to the compositions described in detail herein and are comprehended within the scope of the invention disclosed in this specification.
- the present invention provides compositions of matter containing as essential therapeutic ingredients morphine-type analgesic material and antagonist maicrial selected from the group consisting of levo-3-hydroxy-N-allyl-morphinan and its acid addition salts, the effective content of levo-3-hydroxy-N-allyl-morphinan in said compositions being from about 0.5 percent to about 10 percent by weight of said analgesic material.
- Morphine-type analgesics includes morphine itself and analgesically active derivatives and synthetic substitutes therefor, as discussed in parts II and III of a paper by Bergel and Morrison in Quarterly Reviews of the Chemical Society, vol. II, pages 349-382 (194-8), and in a paper by Eddy in Journal of the American Pharmaceutical Association (Scientific Edition) vol. 39, pages 245251 (1950).
- Illustrative morphine-type analgesics include morphine and its derivatives, 3-hydroxy-N-methyl-morphinan, 1-methyl-4-phenyl-piperidine-4carboxylic acid ethyl ester, 1,3-dimethyl-4-phenyl-4-propionoxypiperidine, 1-methyl-4- (m-hydroxyphenyl) -piperidine-4- ethyl ketone, 4,4-diphenyl-6-dimethylamino-heptan-3-one and acid addition salts thereof. It will be understood by those skilled in the art that these analgesic materials can be used either as the free bases or in the form of their acid addition salts, and can be used individually or in combination with each other when desirable.
- optically active or racemic forms possessing significant analgesic activity can be used in practicing the invention.
- Mixtures of free bases and salts, or of racemic and optically active forms, or of analgesics having different chemical constitutional formuias, or any combination of tl foregoing materials, can be employed.
- racemic 3-hydroxy-Nallyl-1norphinan exhibits the antagonistic effect discussed. above, in consequence of its content of the levo enantiomorph, it should be understood that the levo content of the compositions of the invention may be present in whole or in part as a constituent of racemic 3-hydroxy-N-allyl-rnorphinan.
- the antagonist may be used either in the form of the free base 3-hydroxy-N-allyl-morphinan, or in the form of an acid addition salt of 3-hydroxy-N allyl-mon phinan, or as a mixture of the base and acid addition salts thereof, either levo or racemic.
- compositions of matter according to the invention should provide from about 0.5 percent by weight to about 10 percent by Weight of the free base levo-3-hydroxy-N allyl'morphinan, based upon the total weight of analgesic material in the composition.
- compositions of matter according to the invention may also be formulated to contain pharmaceutical adjuvant material of various sorts, e. g. carriers, buffers, antiseptics, flavoring agents, stabilizers, diluents and the like.
- a preferred aspect of the invention relates to compositions of matter containing as essential therapeutic ingredients: analgesic material selected from the group consisting of morphine, dihydrodesoxymorphine, 3-hydroxy- N--methyl-morphinan, 1-methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester, l,3-dimethyl-4-phenyl-4-propionoxy-riperidine, 1-methyl-4-(m-hydroxyphenyl -piperidinetethyl ketone, 4,4-diphenyl-6-dimethylaminoheptan-3- one and acid addition salts thereof; and antagonist maerial selected from the group consisting of levo-3-hydroxyl-sllyl-morphinan and its acid addition salts; the effective cor out of levo-3-hydroxy-N-ally1-morphinan in said composit. .n being from about 0.5 percent to about 19 percent by weight of said analgesic material.
- analgesic material selected from the group consisting of
- a particularly preferred embodiment of the invention relates to compositions of matter in dosage unit form consisting essentially of an acid addition salt of levo-3- hydroxy-Nanethyl-morphinan, an acid addition salt of 3 lave-3-hydroxy-N-allyl-morphinan, and pharmaceutical adjuvant material, the proportion of said levo-3-hydroxy- N-allyl-morphinan to said levo-3-hydroxy-N-methylmorphinan being from about 0.5 percent to about 10 percent by weight.
- a second particularly preferred embodiment of the in vention relates to compositions of matter in dosage unit form consisting essentially of an acid addition salt of racemic-3-hydroxy-N-methyl-morphinan, an acid addition salt of levo-3-hydroxy-N-allyl-rnorphinan, and pharmaceutical adjuvant material, the proportion of said levo-3-hydroxy-N-allyhmorphinan to said racemic-3-hydroxy-N- methyl-morphinan being from about 0.5 percent to about 10 percent by weight.
- Example 1 To a paste prepared from 54 g. of cornstarch, were added 1.5 g. of levo-3-hydroxy-N-methyl-morphinan tartrate, 0.1 g. of levo-3-hydroxy-N-allyl-morphinan tartrate, 90 g. of milk sugar, 4.2 g. of talc, and 0.2 g. stearin. The ingredients were mixed homogeneously, the whole granulated through a sieve, dried, and made up into tablets, each weighing 150 mg. and each containing 1.5 mg. of levo-3-hydroxy-N-methyl-morphinan tartrate and 0.1 mg. levo-3-hydroxy-N-allyl-morphinan tartrate.
- Example 2 3 g. of dihydrodesoxymorphine hydrobromide, and 0.1 g. of levo-3-hydroxy-IJ-allyl-rnorphinan hydrobromide were dissolved in a mixture of cc. of water and 30 cc. of ethanol, and mixed with 2000 g. of cocoa butter and 100 g. of white wax to form a homogeneous mass. From the latter were prepared suppositories each containing 3 mg. of dihydrodesoxymorphine hydrobromide and 0.1 mg. of levo-3-hydroXy-N-allyl-morphinan hydrobromide.
- Example 3 A solution was prepared from double distilled water containing in each cc. 4 mg. of dihydrodesoxymorphine hydrobromide, and 0.1 mg. of levo-3-hydroxy-N-allylmorphinan hydrobromide. The solution was filled into ampuls and heated for minutes at 95 C. in order to sterilize the same.
- Example 4 In 900 cc. of double distilled water were dissolved 0.8 g. of p-hydroxy-benzoic acid methyl ester 0.1 g. of p-hydroxy-benzoic acid propyl ester 3.0 g. of levo-3-hydroxy-N-methyl-morphinan tartrate 0.15 g. of levo-3-hydroxy-N-allyl-morphinan tartrate.
- the solution was set to pH 6.0 by adding approximately 7.4 cc. of normal NaOH, adjusted to 1000 cc. with double distilled water and filled into 1 cc. ampuls.
- a composition of matter in a form for administration by injection containing as essential therapeutic ingredients: analgesic material selected from the class consisting of morphine, dihydrodesoxymorphine, 3-hydroxy-N-methylmorphinan, 1-methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester, l,3dimethyl-4-phenyl-4-propionoxy-piperidine, l-methyl-4-(m-hydroxyphenyl) piperidine4-ethyl ketone, 4,4-diphenyl-6-dimethylamino-heptan-3-one and acid addition salts thereof; and antagonist material selected from the group consisting of levo-3-hydroxy-N-allylmorphinan and its acid addition salts; the effective content of levo-3-hydroxy-N-allyl-morphinan in said composition being from about 0.5 percent to about 10 percent by Weight of said analgesic material.
- analgesic material selected from the class consisting of morphine, dihydrodesoxymorphine,
- composition of matter in dosage unit form for administration by in ection consisting essentially of an acid addition salt of 1evo-3-hydroxy-N-methyl-morphinan, an acid addition salt of levo-3-hydroxy-N-allyl-morphinan, and pharmaceutical adjuvant material, the proportion of said levo3-hydroxy-N-allyl-morphinan to said levo-3-hydroxy-N-methyl-morphinan being from about 0.5 percent to about 10 percent by weight.
- a composition of matter in dosage unit form for administration by injection consisting essentially of an acid addition salt of racemic-3-hydroxy-N-methyl-morphinan, an acid addition salt of levo-3-hydroxy-N-allyl-morphinan, and pharmaceutical adjuvant material, the proportion of said levo-3-hydroxy-N-allyl-morphinan to said racemic-3 hydroxy-N-methyl-morphinan being from about 0.5 percent to about 10 percent by weight.
- a composition of matter in a form for administration by injection containing as essential therapeutic ingredients morphine-type analgesic material and antagonist material selected from the group consisting of levo-3-hydroxy-N-allyl-rnorphinan and its acid addition salts, the effective content of levo-3-hydroxy-N-allyl-morphinan in said composition being from about 0.5 percent to about 10 percent by weight of said analgesic material.
- composition according to claim 4 wherein said morphine-type analgesic material comprises a substantial 1 proportion of levo-3-hydroxy-N-methyl-morphinan.
- composition according to claim 4 wherein said morphine-type analgesic material comprises a substantial proportion of an acid addition salt of levo-3-hydroxy-N- methyl-morphinan.
Description
Patented Nov. 135,
ANALGESHI (IOMPOSITIONS Konrad Fromlierz, Andre Grnessner, Bela Pellmont, and
Otto Schnider, Basel, Switzerland, assignors to Hoffmann-La Roche Inc, Nutley, N. 3., a corporation of New Jersey No Drawing. Application Uctobcr 15, 1952, Serial No. 314,954
Claims priority, application Switzerland August 1, 1952 6 Claims. (Cl. 167--65) This invention relates to compositions of matter useful in therapy to produce analgesia. It relates especially to such compositions wherein undesired side effects common to analgesics, particularly respiratory depression, are diminished or suppressed by incorporation of material which antagonizes the tendency of the analgesic material to produce such side effects.
Morphine-type analgesics have found extensive medical application because of their fi"1cacy even in cases of very severe pain. However, overdoses of such analgesics often are attended by very serious side reactions. In addition, many people react even to minimal therapeutic doses by exhibiting similar side reactions, which are mainly evidenced in the form of respiratory depression, nausea, and vomiting. In the management of labor, analgesic medication administered to the mother often results in respiratory depression of the newborn infant.
The present invention rests upon the discovery that levo-3-hydroxy-N-allyl-rnorphinan, either in the form of the free base or in the form of its acid addition salts, has the characteristic of suppressing or eliminating undesired side reactions of morphine-type analgesics. Surprisingly, it has been found that this antagonistic effect of 3-hydroxy-N-allyl-morphinan is limited to the levo enantiomorph thereof; the dextro form having little or no antagonistic effect; and the racemic form having the activity only of its levo content.
The antagonistic effect of levo-3-hydroxy-N-allylmorphinan extends not only to the undesired side reactions of morphine-type analgesics but also extends to the analgesic activity itself. Accordingly, the dosage of the antagonist, levo-3-hydroxy-N-allylmorphinan, must be carefully proportioned with respect to the dosage of the analgesic material so as to diminish or suppress the side reactions without significantly influencing the desired analgesic action. Fortunately, the effect of a small proportion of levo-3-hydroxy-N-allyl-morphinan upon the side reactions, particularly the respiratory depressive effect, is considerable; whereas the antagonistic effect on the analgesic action, produced by that same small proportion of levo-3-hydroxy-N-allyl-morphinan, is small. It has been found that good results have been obtained when the proportion of levo-3-hydroxy-N-allyl-morphinan is from about to about by weight of the morphinetype analgesic material. It will be appreciated by those skilled in the art, however, that these numerical values are not absolutely limiting; and compositions wherein the proportion of analgesic material and antagonist material differs slightly from the range indicated above, but which exhibit the desirable qualities indicated in this disclosure, are equivalent to the compositions described in detail herein and are comprehended within the scope of the invention disclosed in this specification.
Accordingly, the present invention provides compositions of matter containing as essential therapeutic ingredients morphine-type analgesic material and antagonist maicrial selected from the group consisting of levo-3-hydroxy-N-allyl-morphinan and its acid addition salts, the effective content of levo-3-hydroxy-N-allyl-morphinan in said compositions being from about 0.5 percent to about 10 percent by weight of said analgesic material.
Morphine-type analgesics includes morphine itself and analgesically active derivatives and synthetic substitutes therefor, as discussed in parts II and III of a paper by Bergel and Morrison in Quarterly Reviews of the Chemical Society, vol. II, pages 349-382 (194-8), and in a paper by Eddy in Journal of the American Pharmaceutical Association (Scientific Edition) vol. 39, pages 245251 (1950). Illustrative morphine-type analgesics include morphine and its derivatives, 3-hydroxy-N-methyl-morphinan, 1-methyl-4-phenyl-piperidine-4carboxylic acid ethyl ester, 1,3-dimethyl-4-phenyl-4-propionoxypiperidine, 1-methyl-4- (m-hydroxyphenyl) -piperidine-4- ethyl ketone, 4,4-diphenyl-6-dimethylamino-heptan-3-one and acid addition salts thereof. It will be understood by those skilled in the art that these analgesic materials can be used either as the free bases or in the form of their acid addition salts, and can be used individually or in combination with each other when desirable. Moreover, since these compounds typically exhibit optical isomerism, it will be understood that any of the optically active or racemic forms possessing significant analgesic activity can be used in practicing the invention. Mixtures of free bases and salts, or of racemic and optically active forms, or of analgesics having different chemical constitutional formuias, or any combination of tl foregoing materials, can be employed.
Similarly, since racemic 3-hydroxy-Nallyl-1norphinan exhibits the antagonistic effect discussed. above, in consequence of its content of the levo enantiomorph, it should be understood that the levo content of the compositions of the invention may be present in whole or in part as a constituent of racemic 3-hydroxy-N-allyl-rnorphinan. Likewise, the antagonist may be used either in the form of the free base 3-hydroxy-N-allyl-morphinan, or in the form of an acid addition salt of 3-hydroxy-N allyl-mon phinan, or as a mixture of the base and acid addition salts thereof, either levo or racemic.
The total content of antagonist material present in compositions of matter according to the invention should provide from about 0.5 percent by weight to about 10 percent by Weight of the free base levo-3-hydroxy-N allyl'morphinan, based upon the total weight of analgesic material in the composition. In addition to their analgesic content and antagonist content, it will be obvious to those skilled in the art that compositions of matter according to the invention may also be formulated to contain pharmaceutical adjuvant material of various sorts, e. g. carriers, buffers, antiseptics, flavoring agents, stabilizers, diluents and the like.
A preferred aspect of the invention relates to compositions of matter containing as essential therapeutic ingredients: analgesic material selected from the group consisting of morphine, dihydrodesoxymorphine, 3-hydroxy- N--methyl-morphinan, 1-methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester, l,3-dimethyl-4-phenyl-4-propionoxy-riperidine, 1-methyl-4-(m-hydroxyphenyl -piperidinetethyl ketone, 4,4-diphenyl-6-dimethylaminoheptan-3- one and acid addition salts thereof; and antagonist maerial selected from the group consisting of levo-3-hydroxyl-sllyl-morphinan and its acid addition salts; the effective cor out of levo-3-hydroxy-N-ally1-morphinan in said composit. .n being from about 0.5 percent to about 19 percent by weight of said analgesic material.
A particularly preferred embodiment of the invention relates to compositions of matter in dosage unit form consisting essentially of an acid addition salt of levo-3- hydroxy-Nanethyl-morphinan, an acid addition salt of 3 lave-3-hydroxy-N-allyl-morphinan, and pharmaceutical adjuvant material, the proportion of said levo-3-hydroxy- N-allyl-morphinan to said levo-3-hydroxy-N-methylmorphinan being from about 0.5 percent to about 10 percent by weight.
A second particularly preferred embodiment of the in vention relates to compositions of matter in dosage unit form consisting essentially of an acid addition salt of racemic-3-hydroxy-N-methyl-morphinan, an acid addition salt of levo-3-hydroxy-N-allyl-rnorphinan, and pharmaceutical adjuvant material, the proportion of said levo-3-hydroxy-N-allyhmorphinan to said racemic-3-hydroxy-N- methyl-morphinan being from about 0.5 percent to about 10 percent by weight.
The invention is further disclosed in the following examples, which are illustrative but not limitative thereof.
Example 1 To a paste prepared from 54 g. of cornstarch, were added 1.5 g. of levo-3-hydroxy-N-methyl-morphinan tartrate, 0.1 g. of levo-3-hydroxy-N-allyl-morphinan tartrate, 90 g. of milk sugar, 4.2 g. of talc, and 0.2 g. stearin. The ingredients were mixed homogeneously, the whole granulated through a sieve, dried, and made up into tablets, each weighing 150 mg. and each containing 1.5 mg. of levo-3-hydroxy-N-methyl-morphinan tartrate and 0.1 mg. levo-3-hydroxy-N-allyl-morphinan tartrate.
Another type of tablets was made, exactly similar to those described above, except that the 1.5 mg. of levo- 3-hydroxy-N-methyl-morphinan tartrate was replaced by 3.0 mg. of racemic-3-hydroxy-N-methyl-morphinan tartrate.
Tablets similar to those described above were made by substituting 20 mg. of morphine hydrochloride for the 1.5 mg. of levo-3-hydroxy-N-methyl-morphinan tartrate.
Tablets similar to those described above were also made by substituting mg. of 1-methyl-4-(m-hydroxyphenyl)- piperidine-4-ethyl-ketone hydrochloride for the 1.5 mg. of levo-3hydroxy-N-methyl-morphinan tartrate.
Example 2 3 g. of dihydrodesoxymorphine hydrobromide, and 0.1 g. of levo-3-hydroxy-IJ-allyl-rnorphinan hydrobromide were dissolved in a mixture of cc. of water and 30 cc. of ethanol, and mixed with 2000 g. of cocoa butter and 100 g. of white wax to form a homogeneous mass. From the latter were prepared suppositories each containing 3 mg. of dihydrodesoxymorphine hydrobromide and 0.1 mg. of levo-3-hydroXy-N-allyl-morphinan hydrobromide.
Example 3 A solution was prepared from double distilled water containing in each cc. 4 mg. of dihydrodesoxymorphine hydrobromide, and 0.1 mg. of levo-3-hydroxy-N-allylmorphinan hydrobromide. The solution was filled into ampuls and heated for minutes at 95 C. in order to sterilize the same.
Example 4 In 900 cc. of double distilled water were dissolved 0.8 g. of p-hydroxy-benzoic acid methyl ester 0.1 g. of p-hydroxy-benzoic acid propyl ester 3.0 g. of levo-3-hydroxy-N-methyl-morphinan tartrate 0.15 g. of levo-3-hydroxy-N-allyl-morphinan tartrate.
The solution was set to pH 6.0 by adding approximately 7.4 cc. of normal NaOH, adjusted to 1000 cc. with double distilled water and filled into 1 cc. ampuls.
Example5 9 g. of levo-3-hydroxy-N-methyl-morphinan tartrate,
and 0.45 g. of lev0-3 hydroxy-N-allyl-morphinan tartrate were dissolved in 165 cc. of ethanol, 2.4 g. of p-hydroxy benzoic acid methyl ester and 0.3 g. of p-hydroxy benzoic acid propyl ester were added, the clear solution was set to 3000 cc. with double distilled water, and filtered. This solution can be prescribed for administration as a drops solution. Twenty drops, corresponding to about 1 cc., contain 3 mg. of levo-3-hydroxy-N-methyl-morphinan tartrate and 0.15 mg. of 3-hydroxy-N-allyl-morphinan tartrate.
We claim:
1. A composition of matter in a form for administration by injection containing as essential therapeutic ingredients: analgesic material selected from the class consisting of morphine, dihydrodesoxymorphine, 3-hydroxy-N-methylmorphinan, 1-methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester, l,3dimethyl-4-phenyl-4-propionoxy-piperidine, l-methyl-4-(m-hydroxyphenyl) piperidine4-ethyl ketone, 4,4-diphenyl-6-dimethylamino-heptan-3-one and acid addition salts thereof; and antagonist material selected from the group consisting of levo-3-hydroxy-N-allylmorphinan and its acid addition salts; the effective content of levo-3-hydroxy-N-allyl-morphinan in said composition being from about 0.5 percent to about 10 percent by Weight of said analgesic material.
2. A composition of matter in dosage unit form for administration by in ection consisting essentially of an acid addition salt of 1evo-3-hydroxy-N-methyl-morphinan, an acid addition salt of levo-3-hydroxy-N-allyl-morphinan, and pharmaceutical adjuvant material, the proportion of said levo3-hydroxy-N-allyl-morphinan to said levo-3-hydroxy-N-methyl-morphinan being from about 0.5 percent to about 10 percent by weight.
3. A composition of matter in dosage unit form for administration by injection consisting essentially of an acid addition salt of racemic-3-hydroxy-N-methyl-morphinan, an acid addition salt of levo-3-hydroxy-N-allyl-morphinan, and pharmaceutical adjuvant material, the proportion of said levo-3-hydroxy-N-allyl-morphinan to said racemic-3 hydroxy-N-methyl-morphinan being from about 0.5 percent to about 10 percent by weight.
4. A composition of matter in a form for administration by injection containing as essential therapeutic ingredients morphine-type analgesic material and antagonist material selected from the group consisting of levo-3-hydroxy-N-allyl-rnorphinan and its acid addition salts, the effective content of levo-3-hydroxy-N-allyl-morphinan in said composition being from about 0.5 percent to about 10 percent by weight of said analgesic material.
5. A composition according to claim 4 wherein said morphine-type analgesic material comprises a substantial 1 proportion of levo-3-hydroxy-N-methyl-morphinan.
6. A composition according to claim 4 wherein said morphine-type analgesic material comprises a substantial proportion of an acid addition salt of levo-3-hydroxy-N- methyl-morphinan.
Claims (1)
- 4. A COMPOSITION OF MATTER IN A FORM FOR ADMINISTRATION BY INJECTION CONTAINING AS ESSENTIAL THERAPEUTIC INGREDIENTS MORPHINE-TYPE ANALGESIC MATERIAL AND ANTAGONIST MATERIAL SELECTED FROM THE GROUP CONSISTING OF LEVO-3-HYDROXY-N-ALLYL-MORPHINAN AND ITS ACID ADDITION SALTS, THE EFFECTIVE CONTENT OF LEVE-3-HYDROXY-N-ALLYL-MORHPINAN IN SAID COMPOSITION BEING FROM ABOUT 0.5 PERCENT TO ABOUT 10 PERCENT BY WEIGHT OF SAID ANALGESIC MATERIAL.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2770569X | 1952-08-01 |
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| US2770569A true US2770569A (en) | 1956-11-13 |
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| US314954A Expired - Lifetime US2770569A (en) | 1952-08-01 | 1952-10-15 | Analgesic compositions |
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|---|---|---|---|---|
| US3285922A (en) * | 1962-01-26 | 1966-11-15 | Research Corp | N-cyclopropylmethyl-and -cyclobutyl-methyl-morphinans |
| US3301855A (en) * | 1963-04-22 | 1967-01-31 | Ciba Geigy Corp | Derivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline |
| US3320262A (en) * | 1964-09-22 | 1967-05-16 | Lewenstein | 14 hydroxy morphine and codeine carboxymethyloximes |
| US3493657A (en) * | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
| US3966940A (en) * | 1973-11-09 | 1976-06-29 | Bristol-Myers Company | Analgetic compositions |
| US5321012A (en) * | 1993-01-28 | 1994-06-14 | Virginia Commonwealth University Medical College | Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance |
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| USRE39300E1 (en) | 1993-01-28 | 2006-09-19 | Virginia Commonwealth University Medical College Of Virginia | Inhibiting the development of tolerance to and/or dependence on an addictive substance |
| US20060280801A1 (en) * | 2004-09-16 | 2006-12-14 | Kronenthal Richard L | Compositions and method for the reduction of post-operative pain |
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| US3493657A (en) * | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
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| US3320262A (en) * | 1964-09-22 | 1967-05-16 | Lewenstein | 14 hydroxy morphine and codeine carboxymethyloximes |
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