USRE25502E - Method for the treatment of - Google Patents
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- USRE25502E USRE25502E US25502DE USRE25502E US RE25502 E USRE25502 E US RE25502E US 25502D E US25502D E US 25502DE US RE25502 E USRE25502 E US RE25502E
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- United States
- Prior art keywords
- seizures
- treatment
- febrile
- phenylbarbital
- seizure
- Prior art date
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- 206010010904 Convulsion Diseases 0.000 description 23
- 206010039911 Seizure Diseases 0.000 description 19
- 208000002091 Febrile Seizure Diseases 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drugs Drugs 0.000 description 12
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 8
- ILORKHQGIMGDFN-UHFFFAOYSA-N Phetharbital Chemical compound O=C1C(CC)(CC)C(=O)NC(=O)N1C1=CC=CC=C1 ILORKHQGIMGDFN-UHFFFAOYSA-N 0.000 description 8
- 230000002566 clonic Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 206010015037 Epilepsy Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010028334 Muscle spasms Diseases 0.000 description 3
- 235000001188 Peltandra virginica Nutrition 0.000 description 3
- 206010034759 Petit mal epilepsy Diseases 0.000 description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N Phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 3
- 229960002695 Phenobarbital Drugs 0.000 description 3
- 244000197580 Poria cocos Species 0.000 description 3
- 235000008599 Poria cocos Nutrition 0.000 description 3
- 208000005392 Spasm Diseases 0.000 description 3
- 230000001773 anti-convulsant Effects 0.000 description 3
- 230000001754 anti-pyretic Effects 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 230000000985 convulsing Effects 0.000 description 3
- 230000002920 convulsive Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic Effects 0.000 description 3
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 240000002268 Citrus limon Species 0.000 description 2
- 206010009346 Clonus Diseases 0.000 description 2
- CXOFVDLJLONNDW-UHFFFAOYSA-N Epinat Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 2
- 206010016284 Febrile convulsion Diseases 0.000 description 2
- FWJKNZONDWOGMI-UHFFFAOYSA-N Metharbital Chemical compound CCC1(CC)C(=O)NC(=O)N(C)C1=O FWJKNZONDWOGMI-UHFFFAOYSA-N 0.000 description 2
- 229960002057 Metharbital Drugs 0.000 description 2
- 229960002036 Phenytoin Drugs 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- IRYJRGCIQBGHIV-UHFFFAOYSA-N Trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 description 2
- 229960004453 Trimethadione Drugs 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 150000007656 barbituric acids Chemical class 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001256 tonic Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N Acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 241000209134 Arundinaria Species 0.000 description 1
- 241000349774 Bikinia letestui Species 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- 206010024855 Loss of consciousness Diseases 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- 229960004815 Meprobamate Drugs 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- 208000006625 Myoclonic Epilepsy Diseases 0.000 description 1
- 229940068918 Polyethylene Glycol 400 Drugs 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 230000003444 anaesthetic Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 239000011436 cob Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002977 hyperthermial Effects 0.000 description 1
- 230000001665 lethal Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028527 righting reflex Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
Definitions
- This invention relates to a preparation for the alleviation of clonic type seizures such as febrile convulsions.
- Treatments available at the present time are unsatisfactory, often being inadequate to control the convulsions and difficult to apply.
- One method frequently used is to cool the patient by means of ice packs.
- Another method is to place the patient under heavy sedation by means of anesthetic barbiturates until loss of consciousness is approached. Hospitalization is frequently required.
- Certain anticonvulsants, such as diphenylhydantoin may actually exacerbate the seizures.
- the ideal drug for use against febrile convulsions should not only diminish sensitivity to these seizures but should have antipyretic action. Since many barbituric acids derivatives are antipyretics a number of these were examined. Two test procedures were employed. The more fundamentals of these involves a study of the action of drugs against spasms resulting from artificial fever in mice. Since, however, there is experimental correlation between drugs eifective against epilepsy and those effective against metrazol-produced spasms, the primary screen was against metrazol spasms.
- N-phenylbarbital (B.W. No. 40l) is unique in this series of N-substituted barbitals, as a compound with marked activity against metrazolinduced clonic seizures.
- the protective index, or ratio of the toxic to the effective dose, of 4.2 was higher than that of phenobarbital, trimethadione, and metharbital, and accordingly indicates a higher degree of safety.
- N-phenylbarbital had a unique action different from that of even very close relatives (note Nos. 4024). Accordingly the more fundamental test procedure was applied to this compound in comparison with drugs of known properties.
- Febrile seizures were induced in mice by means of a microwave diathermy generator.
- a generalized seizure response was obtained when the body temperature was raised to F.
- the threshold convulsive temperature was independent of the rate of temperature rise.
- the pattern of febrile seizure was principally clonic type.
- a tonic component observed at higher temperatures was mild, spasmodic, and unsustained.
- Drugs were tested for their ability (1) to modify the threshold convulsive temperature (2) to abolish the seizure completely and (3) to retard the rate of rise in body temperature in the presence of hyperthermic stimulus.
- trimethadione, meprobamate and phenobarbital of value in the treatment of petit mal and myoclonic epilepsies, were eflective in the control of febrile seizures, but large and toxic doses were required to abolish the clonus completely.
- Such drugs are also effective against the clonic metrazol-induced seizure.
- Diphenylhydantoin which is ineffective against experimental metrazol seizures, and in petit mal and is used primarily for treatment of tonic major seizures, failed to control the febrile convulsion and indeed, exacerbated the clonic pattern.
- Acetazolamide raised the threshold convulsive temperature but did not abolish clonus completely; it was also inactive against metrazol-induced seizures.
- N-phenylbarbital proved remarkably effective against both metrazol and fever-induced seizures. In addition. it was strongly antipyretic and its action was relatively rapid on oral administration. Compared with phenobarbital and metharbital, its toxicity was low and its protective theraupeutic index (ratio of toxic to effective dose) was high.
- the compound has the additional advantage of being free from toxic sideefifects at doses which elfectively protect against febrile convulsions.
- the Side-effects which often may be observed with other compounds may be detected by the following tests: (1) the righting reflex test, (2) the positional sense test, (3) the gait stance test. (4) the muscle tone test, and (5) the equilibrium test. Graded oral doses gave a TD of 190 lug/kg. for these neural toxicity tests. The lethal action of B.W. 401 required much higher doses. The LD was found to be 900 mg./kg.
- the required dose level is of the order of 3 to 5 mg./kg. three times a day. Roughly, 5()100 mg. in each dose would be given to children and about twice as much to adults.
- the drug may be presented in capsules, tablets or in the form of an elixir or syrup. The latter is of particular convenience in treating young children.
- EXAMPLE 1 Five hundred and thirty g. of N-phenylbarbital is ground thoroughly and sifted through a 60 mesh sieve. It is then mixed with 116.6 g. of dried potato starch and again passed through a 60 mesh sieve. The powder is then granulated twice each time with 80 cc. of percent *Feculose" solution. Feculose is the tradename of a partially degraded starch preparation consisting largely of starch and high-molecular dextrins. The granules are dried overnight at 110 F. and broken up so as to pass through a 24 mesh sieve. To this was added a mixture passed through a mesh sieve of 13.25 g. of dried potato starch and 7.95 g. of stearic acid. The whole was mixed thoroughly and fed into a tabletting machine using No. 74 scored punches. The tablets so prepared Weigh 139.5 mg. and contain each mg. of drug.
- EXAMPLE 2 Ten g. of N-phenylbarbital is dissolved in 200 cc. of U.S.P. alcohol and to this is added with stirring 200 cc. each of glycerine, propylene glycol and polyethylene glycol 400. A few cc. of lemon extract is then added and the solution is made up to 1 liter with water.
- EXAMPLE 3 Ten g. of N-phenylbarbital is dissolved in 350 cc. of U.S.P. alcohol and to this is added cc. of glycerine, 300 cc. of propylene glycol and 100 cc. of 80% cane syrup (U.S.R.). A few cc. of lemon extract are then added and the solution is made up to 1 liter with water.
- a method for the treatment of febrile convulsions which comprises the administration of N-phenylbarbital.
- a method for the treatment of febrile convulsions which comprises the administration of 35 rng/kg. of N-phenylbarbital.
- a method for the treatment of (Ionic type Seizures which comprises the administration of N-phenylharbl'tal to a patient suffering from this condition.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent 25,502 METHOD FOR THE TREATMENT OF CLONIC TYPE SEIZURES Edwin J. de Beer, deceased, late of Tuckahoe, N.Y., by
Helen I. de Beer, executrix, Tuckahoe, N.Y.; said Erlwin J. de Beer assignor to Burroughs Wellcome & Co. (U.S.A.) Inc., Tuckahoe, N.Y., a corporation of New York No Drawing. Original No. 2,955,073, dated Oct. 4, 1960, Ser. No. 738,982, June 2, 1958. Application for reissue Sept. 20, 1962, Ser. No. 225,961
4 Claims. (Cl. 167-65) Matter enclosed in heavy brackets appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.
This invention relates to a preparation for the alleviation of clonic type seizures such as febrile convulsions.
This condition occurs frequently and is especially a matter of concern in children. In susceptible individuals a rise in body temperature to levels of about 101 F. or somewhat higher is attended by severe convulsive seizures. The convulsive movements may cause bodily injury, severe cardiovascular damage, or even death. It is believed that these febrile convulsions are closely related to epileptic seizures and that a damage resulting fro-m febrile convulsions in childhood predisposes toward epilepsy in later life.
Treatments available at the present time are unsatisfactory, often being inadequate to control the convulsions and difficult to apply. One method frequently used is to cool the patient by means of ice packs. Another method is to place the patient under heavy sedation by means of anesthetic barbiturates until loss of consciousness is approached. Hospitalization is frequently required. Certain anticonvulsants, such as diphenylhydantoin may actually exacerbate the seizures.
The ideal drug for use against febrile convulsions should not only diminish sensitivity to these seizures but should have antipyretic action. Since many barbituric acids derivatives are antipyretics a number of these were examined. Two test procedures were employed. The more fundamentals of these involves a study of the action of drugs against spasms resulting from artificial fever in mice. Since, however, there is experimental correlation between drugs eifective against epilepsy and those effective against metrazol-produced spasms, the primary screen was against metrazol spasms.
Method: Experimental seizures were induced in animals by means of pentylenetetrazol (metrazol) and the new compounds were tested for their ability to prevent al seizure activity. Metrazol was employed since the seizures produced are mainly clonic in pattern and drugs effective against such experimental seizures have been found to show some activity clinically in the treatment of petit mal and other minor convulsive disorders.
In the preliminary screening test, doses of 10, 100, and 600 rug/kg. of each drug were administered orally to groups of mice, and anticonvulsant activity was tested at 1, 2, and 3 hours after dosing. Any signs of toxicity, such as depression and incoordination, were noted.
Results: The anticonvulsant potency and toxicity of each new drug was expressed as the percentage of animals protected from the seizure and the percentage showing toxicity, within the dose range of 10 to 600 mg./kg.
Results were as follows:
Percentage otanimals protected against, metmzol seizure Percentage Showing Toxicity B.W. Compound Number Derivative N-Plienylbdrbilul N-lhenylneonfil N-ololyib:trbilril N-m-Tolylbarbital.
These results show that N-phenylbarbital (B.W. No. 40l) is unique in this series of N-substituted barbitals, as a compound with marked activity against metrazolinduced clonic seizures.
In further detailed testing, the following results were obtained:
The protective index, or ratio of the toxic to the effective dose, of 4.2 was higher than that of phenobarbital, trimethadione, and metharbital, and accordingly indicates a higher degree of safety.
It will be observed that of the above series of barbituric acid derivatives tested, N-phenylbarbital had a unique action different from that of even very close relatives (note Nos. 4024). Accordingly the more fundamental test procedure was applied to this compound in comparison with drugs of known properties.
Febrile seizures were induced in mice by means of a microwave diathermy generator. In animals between 3 and 4 weeks of age, a generalized seizure response was obtained when the body temperature was raised to F. The threshold convulsive temperature was independent of the rate of temperature rise. The pattern of febrile seizure was principally clonic type. A tonic component observed at higher temperatures was mild, spasmodic, and unsustained. Drugs were tested for their ability (1) to modify the threshold convulsive temperature (2) to abolish the seizure completely and (3) to retard the rate of rise in body temperature in the presence of hyperthermic stimulus.
As shown below, trimethadione, meprobamate and phenobarbital, of value in the treatment of petit mal and myoclonic epilepsies, were eflective in the control of febrile seizures, but large and toxic doses were required to abolish the clonus completely. Such drugs are also effective against the clonic metrazol-induced seizure. Diphenylhydantoin, which is ineffective against experimental metrazol seizures, and in petit mal and is used primarily for treatment of tonic major seizures, failed to control the febrile convulsion and indeed, exacerbated the clonic pattern. Acetazolamide raised the threshold convulsive temperature but did not abolish clonus completely; it was also inactive against metrazol-induced seizures.
N-phenylbarbital proved remarkably effective against both metrazol and fever-induced seizures. In addition. it was strongly antipyretic and its action was relatively rapid on oral administration. Compared with phenobarbital and metharbital, its toxicity was low and its protective theraupeutic index (ratio of toxic to effective dose) was high.
The compound has the additional advantage of being free from toxic sideefifects at doses which elfectively protect against febrile convulsions. The Side-effects which often may be observed with other compounds may be detected by the following tests: (1) the righting reflex test, (2) the positional sense test, (3) the gait stance test. (4) the muscle tone test, and (5) the equilibrium test. Graded oral doses gave a TD of 190 lug/kg. for these neural toxicity tests. The lethal action of B.W. 401 required much higher doses. The LD was found to be 900 mg./kg.
For treatment of febrile convulsions in humans the required dose level is of the order of 3 to 5 mg./kg. three times a day. Roughly, 5()100 mg. in each dose Would be given to children and about twice as much to adults. The drug may be presented in capsules, tablets or in the form of an elixir or syrup. The latter is of particular convenience in treating young children.
EXAMPLE 1 Five hundred and thirty g. of N-phenylbarbital is ground thoroughly and sifted through a 60 mesh sieve. It is then mixed with 116.6 g. of dried potato starch and again passed through a 60 mesh sieve. The powder is then granulated twice each time with 80 cc. of percent *Feculose" solution. Feculose is the tradename of a partially degraded starch preparation consisting largely of starch and high-molecular dextrins. The granules are dried overnight at 110 F. and broken up so as to pass through a 24 mesh sieve. To this was added a mixture passed through a mesh sieve of 13.25 g. of dried potato starch and 7.95 g. of stearic acid. The whole was mixed thoroughly and fed into a tabletting machine using No. 74 scored punches. The tablets so prepared Weigh 139.5 mg. and contain each mg. of drug.
EXAMPLE 2 Ten g. of N-phenylbarbital is dissolved in 200 cc. of U.S.P. alcohol and to this is added with stirring 200 cc. each of glycerine, propylene glycol and polyethylene glycol 400. A few cc. of lemon extract is then added and the solution is made up to 1 liter with water.
EXAMPLE 3 Ten g. of N-phenylbarbital is dissolved in 350 cc. of U.S.P. alcohol and to this is added cc. of glycerine, 300 cc. of propylene glycol and 100 cc. of 80% cane syrup (U.S.R.). A few cc. of lemon extract are then added and the solution is made up to 1 liter with water.
What 1 claim is:
1. A method for the treatment of febrile convulsions which comprises the administration of N-phenylbarbital.
2. A method for the treatment of febrile convulsions which comprises the administration of 35 rng/kg. of N-phenylbarbital.
3. A method for the treatment of (Ionic type Seizures which comprises the administration of N-phenylharbl'tal to a patient suffering from this condition.
4. A method as set fort/1 in claim 3, in which the clom'c seizure is peril ma].
References Cited in the file of this patent or the original patent.
Bush: J. Pharmacol.. vol. 68, 1940, pp. 278283 (thru Che'm. Abst., vol. 34, 2458).
Hjort: J. PharmacoL, vol. 35, 1929, pp. 164 (thru Chem. Abst. 23, 3024).
Cecil: Textbook of Medicine, 7th ed., 1948, p. 28, \V. B. Saunders Co.
Cecil: Textbook of Medicine, 9th ed. 1955, pp. 1486 1487.
Williams: Detoxication Mechanisms, 1947, pp. 219- 220, John Wiley and Sons, Inc., NY.
Irwin: J. P'harm. Exptl. Then, July 1958, pp. 206211.
Daly: Staff Meeting Mayo Clinic, May 15, 1957, vol. 32, No. 10, p. 260.
Publications (1)
Publication Number | Publication Date |
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USRE25502E true USRE25502E (en) | 1963-12-24 |
Family
ID=2094412
Family Applications (1)
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US25502D Expired USRE25502E (en) | Method for the treatment of |
Country Status (1)
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3242167A (en) * | 1962-09-24 | 1966-03-22 | Ici Ltd | Certain 11-substituted amino-5, 6-dihydro-6-oxo-morphanthridine compounds |
US9901576B2 (en) | 2015-11-20 | 2018-02-27 | West-Ward Pharmaceuticals International Limited | Stable formulation of phenobarbital sodium injection |
-
0
- US US25502D patent/USRE25502E/en not_active Expired
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3242167A (en) * | 1962-09-24 | 1966-03-22 | Ici Ltd | Certain 11-substituted amino-5, 6-dihydro-6-oxo-morphanthridine compounds |
US9901576B2 (en) | 2015-11-20 | 2018-02-27 | West-Ward Pharmaceuticals International Limited | Stable formulation of phenobarbital sodium injection |
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