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Vasodilator drug mixtures and excipient therefor

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US3096242A
US3096242A US3044460A US3096242A US 3096242 A US3096242 A US 3096242A US 3044460 A US3044460 A US 3044460A US 3096242 A US3096242 A US 3096242A
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petn
mixture
excipient
drug
weight
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Young Aubrey Allyn
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Zeneca Inc
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Zeneca Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/148Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with compounds of unknown constitution, e.g. material from plants or animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/929Vasodilator

Description

United States Patent 3,096,242 VASODELATGR DRUG MIXTURES AND EXClllENT TEEREFOR Aubrey Allyn Young, Tamaqua, Pa., assignor to Atlas Chemical Industries, Inc, Wilmington, Del., :1 corporation of Delaware N0 Drawing. Filed May 20, 1960, Ser. No. 30,444 16 Claims. (Cl. 161-65) This invention relates to mixtures useful in compounding vasodilator materials and specifically, it relates to drug mixtures containing pentaerythritol tetranitrate (PETN) in concentrations which heretofore would have been thought tobe too'sensitive' to percussion for normal drug use.

This application is a continuation-in-part of application 831,059, filed August 3, 1959, now abandoned.

The use of PETN as a vasodilator compound is well known in the pharmaceutical field. Pure PETN may explode if subjected to percussion. When used for medicinal purposes, PETN is usually highly diluted with an inert additive such as lactose. In order to insure", as much as possible, safe handling of such vasodilator mixtures from the initial compounding of the ingredients to the ultimate use by the consumer, the percentage of PETN to inert additive prior to this invention was relatively small. Generally this ratio was within the range of from 7'll% by weight of PETN to the weight of the mixture and less frequently some mixtures on the market have included up to 20% by weight of PETN to the weight of the mixture. The mixtures are usually dispensed to the consumer in the form of pills or tablets.

It is an object of this invention to provide a PETN drug mixture which is adequately insensitive to percussion and which contains a higher percent by weight of PETN than was heretofore thought possible.

It is another object of this invention to provide an insensitive high PETN-to-excipient ratio drug mixture which when granulated facilitates the required dosage of vasodilator to be given in tablets of smaller size than are now administered.

It is a further object of this invention to provide a high PETN-to-excipient ratio drug mixture which is insensitive and which when granulated facilitates the incorporation, by the compounder, of additional drugs, as desired, without excessively increasing the final tablet size.

It is a further object of this invention to provide excipients suited to use as a component in vasodilator drug mixtures which contain PETN, and which have the property of desensitizing a higher percent of PETN by weight than was heretofore thought possible.

Still further objects and the entire scope of applicability of the present invention will become apparent from the detailed description given hereinafter.

It has been found that a satisfactory PETN drug mixture which contains a higher percent by weight of PETN to Weight of excipient than heretofore was though possible may be compounded by utilizing an excipient component comprised of a high percent by weight of a member of the group consisting of a mixture of lactose plus a highly a highly porous material.

According to the present invention a simple drug mixture which may contain up to 40% by weight of PETN and which is adequately insensitive to percussion by a #8 blasting detonator can be compounded by simply mixing the PETN component and an excipient comprised of a high percent by weight of mannitol or a mixture of mannitol and a highly porous material.

Generally, simple drug mixtures are processed further by a granulation operation wherein the excipient and PETN are mixed with an aqueous liquid to a paste, the

.porous material, mannitol and a mixture of mannitol plus i ice paste dried and ground to form a dry material of small particle size.

It has been found that a satisfactory PETN drug mixture which contains up to 35% by weight of PETN which is suited to use in granulation and which is adequately insensitive to percussion can be compounded by utilizing an excipient comprised of a high percent by weight of mannitol or a mixture of mannitol and a highly porous material as an excipient.

It has been found that a satisfactory PETN drug mixture which contains up to 25% of PETN which is suited to granulation and which is adequately insensitive to percussion can be compounded by utilizing an excipient comprised of a high percent by weight of powderedlactose and a highly porous material. The term powdered lactose as used herein means a product of a size which more than 50% will pass a 200 U.S.S. screen.

It has been found that a satisfactory PETN drug mixture which contains up to 20% by weight of PETN which is suited to granulation and which is adequately insensitive to percussion can be compounded by utilizing an excipient comprised of a high percent by weight of a mixture of granular lactose and a highly porous material. The referred to granular lactose is free flowing in form and comprised of relatively large particles. The term granular lactose as used herein means a product of a size which less than 40% will pass a 200 U.S.S.

screen.

Activated clays are particularly suited to use in this invention, as the highly porous material. Activated clays are generally mixtures of calcium and aluminum silicates or magnesium and aluminum silicates and have a large surface area to weight ratio. Examples of activated clays which are suited to use as an excipient component in the desensitized mixtures of this invention are the various activated fullers earth and activated attapulgus clay. For example those marketed by Minerals and Chemicals Corporation under the trademarks of Attacote, Pharmasorb Regular, Pharmasorb Colloidal and Attasorb LVM (LVM meaning low volatile matter) are eminently satisfactory. The following is a compilation of some of the physical characteristics of these last mentioned products:

In addition to the above clays, diatomaceous earth, silica gel and activated carbon may be listed as examples of highly porous materials suited to use as a component in the excipients of this invention. Although particulate, highly porous materials having an average particle size of from about 0.1 to about 10.0 microns are particularly suited to use in the mixtures of the present invention, a preferred size range of such particulate material is from about 0.01 to about 200 microns.

The vasodilator mixtures of the present invention comprise mixtures of PETN with an excipient, comprised of a high percent by Weight of a member of the group consisting of (1) a mixture comprised of lactose and a finely divided, highly porous material, (2) mannitol or (3) a mixture comprised of mannitol and a finely divided, highly porous material, in an amount that will cause the mixture to be insensitive to detonation with a #8 blasting detonator. In a nongranulated mixture the percent by weight of PETN to excipient may be as high as 40%. The granulated mixtures contemplated by this invention include drug mixtures wherein the percent by weight of PETN to excipient ranges between 20 and 35 Although porous materials such as those enumerated above, which have surface areas much greater than their volume would require, are excellent desencitizers for PETN, it is preferred to use an excipient which includes at least 80% by Weight of lactose or mannitol in order that the final product will have good disintegration propertics. Good tablet disintegration properties are desirable to facilitate efficient drug action in the body when the final product is ingested. Tablets made from excipient mixtures comprised of mannitol and excipient mixtures comprised of lactose or mannitol in combinaiton with the above-described materials, as contrasted with tablets made from excipients containing only finely divided, highly porous inorganic materials show much improved disintegration properties.

Mannitol, alone, or mixtures of lactose or mannitol with the above-described materials have improved packing properties as compared to excipients containing 100% of the finely ground, highly porous materials; A drug mixture which has good packing properties indicates that the drug mixture will facilitate a normal and satisfactory tableting operation.

The drug mixtures contemplated by this invention may consist of PETN and mannitol, PETN and mixtures of lactose and finely divided highly porous materials, PETN and mixtures of mannitol and finely ground, highly porous materials, or thay may comprise the foregoing mixtures with minor amounts of other excipients such as sugars, starch, and the like. The amount of mannitol or the amount of lactose or mannitol and finely ground, highly porous material in the excipient is suflicient to make the mixture immune to detonation with a #8 blasting detonator.

Generally, about 10% by weight of a finely divided, highly porous material in the excipient mixture decreases the sensitivity of granulated mixtures of the drug mixture to detonation by a #8 blasting detonator that comtests conducted using powdered non-granulated mixtures containing high percentage by weight of PETN (35 and with various excipients. Tests 1 and 2 are shown for comparative purposes and should not be considered as examples of the present invention. In Test 1 the excipient was composed of 100% lactose and in Test 2 the excipient was comprised of 100% activated clay. In test 1, 35% by weight of PETN was added to an excipient composed of 100% lactose. The PETN was added to the excipient in the form of an acetone solution. The addition was made by adding the acetone-PETN solution to the excipient in several increments. After each increment Was added, the acetone carrier was evaporated by mixing the materials in a current of warm air. By this process, a final mixture of PETN and excipient was obtained. This mixture was then packed into a cylindrical paper dynamite cartridge 2" in diameter and 8" in length, and the packing behavior noted. In the case of the 100% lactose excipient, the packing behavior was good. The sensitivity of the material was tested by placing the filled cartridge in a horizontal position on a lead plate, /2 x 2 /2 x 15 /2", and priming the cartridge with a #8 blasting detonator. The detonator was then fired. This test is much more severe than any treatment to which such a mixture would normally be subjected in a tableting machine or other mechanical device used to process or tablet PETN containing drug mixtures. The deformation of the lead plate assists in determining the extent of detonation. In a partial detonation, the primed end of the cartridge detonates, but the detonation fails to propagate the entire length of the cartridge. When the 35 PETN-% lactose mixture of Test 1 was tested by this means, a complete detonation was obtained.

The other tests were conducted similarly.

The mixtures shown in Tests 3 through 12 are examples of dry mixtures of this invention. It will be observed that they are all characterized by a high degree of insensitivity to detonation despite a high content of sensitive ingredient.

TABLE I Powdered Mixtures Percent Test No. b

Exeipient (percent by weight of total excipient) 2" x 8 cartridge test Y weight PETN Attacote 1 Man- Lactose nitol Starch Diatomaeeous earth Activated carbon Attasorb LVM 1 Packing Detonation Goo Complete.

Very poor Failure.

l Trademark of Minerals and Chemicals Corp. of America.

pared to the sensitivity of prior art drug mixtures about 5% by weight additional PETN may be safely included in mixtures of the present invention.

A preferred excipient of this invention which when granulated may contain up to 35% by weight of PETN In many compounding operations, the vasodilator mixture which contains explosive substances is made into tablets by a wet granulation process. In such process the vasodilator mixture is made into a paste by the addition of aqueous liquids. The resultant paste facilitates addition of other medicinal compounds, coloring agents, and the like. The paste is then dried, generally in sheet form, ground and tableted. In order to determine the effect of the wet granulation process on the sensitivity of the mixtures of this invention, a series of tests were conducted on granulated vasodilator mixtures.

The following data shown in Table II was collected in a series of sensitivity tests conducted on granulated drug mixtures in pipe assemblies. An assembly consisted of a x 6" iron pipe nipple with a malleable pipe cap attached on one end. In conducting the tests, one level tablespoon of a granulated drug mixture to be tested was placed in an assembly and tamped in the bottom with a tamp stick. A #8 blasting detonate-r was then placed in the assembly with the end of the detonator against the tamped mixture. The assembly was then filled with the granulated drug mixture to be tested and the assembly tapped by hand to settle the mixture. The open end of the filled assembly was closed by masking tape and the assembly fired in a horizontal position. In test 13, for example, a granulated drug mixture composed of 25% by Weight of PETN in a granular lactose excipient was tested by placing a level tablespoon of the mixture in the closed end of a pipe assembly. The mixture was tamped with a tamping stick. A #8 blasting detonator was then placed in the assembly so that the base portion of the detonator contacted the surface of the tamped mixture. The assembly was then filled with additional drug mixture and settled in the assembly by hand tapping. The open end of the filled assembly was closed by masking tape and the assembly placed in a hori- I. After the before described pasting operation, the resultant pastes were spread on aluminum trays, in layers averaging about Mr" thick, and dried in a drying chamber. The dried sheets were ground to pass a No. 10 sieve (U.S.S.). The resultant material was then packed into 2 x 8" paper cylinders and, as in the tests previously described and shown in Table I, the packing behavior noted and the sensitivity tested. For example, in Test 16, a 35% by weight mixture of PETN and an excipient composed of mannitol, 10% starch and 10% LVM (activated clay) was prepared. A 500 gm. sample of the mix was made into a paste by the addition of 240 ml. of water. The paste was thoroughly mixed and poured into sheets about A" thick to dry. After drying, the sheets were ground to pass a #10 sieve. The resultant mix was then tested for packing behavior and sensitivity as described before. Test 16 showed that the mixture was insensitive to detonation by failure in the sensitivity test.

The mixture tested in Tests 16 through 23, and 25 through 27 are examples of products of this invention.

TABLE III Paste Granulations Excipient (percent by weight of total excipient) 2 x 8 cartridge test Percent Water Test PETN per 500 No. by weight Lac- Man- Attasorb Diatom- Actlg. mix Qattose nitol Starch LVM 1 aceous vated Packing tridge Detonation earth carbon weight 240 Very good 334 Failure. 235 -do 361 Do. 332 D0. 370 Do. 347 Do. 355 Do. 365 Do. 394 Do. 08 Heavy partial. 382 Failure. 378 D0. 367 D0.

l Trademark of Minerals & Chemicals Corp. of America.

zontal position for firing the detonator. After the detonator was fired, both the detonation and the damage to the pipe assembly were noted. In test 13, a mixture comprised of 20% PETN in lactose, wherein the lactose was granular in nature, the detonation was complete, the pipe cap was destroyed and severe side wall damage was sustained by the pipe portion of the assembly. Tests 14 and 15 were conducted similarly. The mixtures tested in tests 14 and 15 are examples of products of this inventron. It will be observed that these mixtures remain insensitive despite containing a high percent PETN.

TABLE II Test Granulated mix- N 0. ture, percent by Detonation Damage to pipe assembly Weight 13-..- 20% PE TN, 80% Almost Pipe cap destroyed, severe granularlactose. complete damage to side w pipe, mixture completely gone from pipe. 14"" 20% PETN, 70% None Pipe cap intact and still granular lactose, attached, slight wall 10% ATIAS- damage of pipe, much of ORB LVM 1 the drug mixture remained in the pipe. l5 PETN, do Pipe cap detached but 58.5% mannitol, intact, side wall split, 6.5% ATTAS- bulging damage to pipe, ORB LVM most of drug mixture remained in the pipe.

I Trademark of Minerals & Chemicals Corp. of America.

The following sensitivity data, compiled in Table III, was collected on granulated drug mixtures. The granulated mixtures shown in this table were compounded by wet granulating dry drug mixtures prepared in the same general manner as the dry mixtures summarized in Table It will be observed that they retain their insensitivity despite being subjected to a granulation process.

What is claimed is:

l. A drug mixture containing at least 20% by' weight of PETN desensitized by an excipient in which the PETN is uniformly distributed, said excipient being selected from the group consisting of (l) lactose and a finely divided, highly porous material, (2) mannitol, and (3) mannitol and a finely divided, highly porous material, wherein the finely divided, highly porous material in (l) and (3) is selected from the group consisting of activated clay, diatomaceous earth, silica gel and activated carbon.

2. A drug mixture containing at least 20% by weight of PETN desensitized by an excipient in which the PETN is uniformly distributed, said excipient being selected from the group consisting of (l) lactose and a highly porous material (2) manni-tol, and (3) mannitol and a highly porous material wherein the highly porous material in (1) and (3) is activated clay.

3. A drug mixture containing at least 20% by Weight of PETN desensitized by an excipient in which the PETN is uniformly distributed, said excipient being comprised of lactose and highly porous material which is selected from the group consisting of activated clay, diatomaceous earth, silica gel and activated carbon, to the extent that said mixture is insensitive to detonation by a #8 detonator.

4. A drug mixture containing at least 20% by weight of PETN desensitized by an excipient in which the PETN is uniformly distributed, said excipient being comprised of lactose and activated clay, to the extent that the said mixture is insensitive to detonation by a #8 blasting detonator.

Z? 5. A drug mixture containing about 20% by weight of PETN and an excipient in which the PETN is uniformly distributed, said excipient being comprised of about 90% lactose and activated clay.

6. A drug mixture containing at least about 25% by Weight of PETN and having therein an excipient in which the PETN is uniformly distributed, said excipient being comprised of mannitol in an amount that said mixture is insensitive to detonation by a #8 blasting detonator.

7. A drug mixture containing at least about 25% by Weight of PETN, and an excipient in which the PETN is uniformly distributed, said excipient being comprised of mannitol and a highly porous material to the extent that said mixture is insensitive to detonation by a #8 blasting detonator.

8. The drug mixture described in claim 7 wherein the highly porous material is a material selectedfrom the group consisting of activated clay, diatomaceous earth, silica gel and activated carbon.

9. A drug mixture containing about 35% by Weight of PETN, and an excipient in which the PETN is uniformly distributed, said excipient being comprised of about 90% by weight of mannitol and about 10% by weight of activated clay.

10. A drug mixture containing about 35% by Weight of PETN, and an excipient in which the PETN is uniformly distributed, said excipient being comprised of at least about 80% mannito-l, and about 10% activated clay.

11. A drug mixture containing about 35% by weight of PETN, and an excipient in which the PETN is uniformly distributed, said excipient containing about 90% mannitol and about 10% activated carbon.

12. An excipient adapted for use in PETN-containing vasodilator drug mixtures selected from the group con:

sisting of (1) lactose and a highly porous material, and

mannitol and (2) a highly porous material whereinthe highly porous material in (l) and (2) is selected from the group consisting of activated clay, diatomaceo'us earth, silica gel and activated carbon.

13. An excipient adapted for use in PETN-containing vasodilator drug mixtures comprised of lactose and a highly porous material selected from the group consisting of activated clay, diatomaceous earth, silica gel and activated carbon.

14. An excipient adapted for use in PETN-containing vasodilator drug mixtures containing about by weight of lactose and about 10% by Weight of activated clay.

15. An excipient adapted for use in PETN-containing vasodilator drug mixtures containing about 90% mannitol and 10% of a highly porous material selected from the group consisting of activated clay, diatomaceous earth, silica gel and activated carbon.

16. An excipient adapted for use in PETN-containing vasodilator drug mixtures which comprises mannitol and a highly porous material wherein the highly porous material is a material selected from the group consisting of activated clay, diatomaceous earth, silica gel and activated carbon.

References Cited in the file of this patent UNITED STATES PATENTS Re. 5,799 Nobel Mar. 17, 1874 78,317 Nobel May 26, 1868 2,963,402 Nalin et al Dec. 6, 1960 OTHER REFERENCES Remingtons Practice of Pharmacy, 11th Ed., 1956, Mack Pub. Co., Easton, Pa, pp. 377, 754-757.

Atlas Organic Nitrate Drug Mixtures, Pharmaceutical Bulletin CD---4M-4/59, copyright 1959, Atlas Powder (30., Wilmington 99, Del., 6 pp.

Atlas 35% PentaErythritol T etraNitrate (PETN),

Pharm. Bulletin CD-ISS, 4M, 10-59, copyright 1959,

Atlas Powder Co., Wilmington 99, Del., 4 pp.

Claims (1)

1. A DRUG MIXTURE CONTAINING AT LEAST 20% BY WEIGHT OF PETN DESENSITIZED BY AN EXCIPIENT IN WHICH THE PETN IS UNIFORMLY DISTRIBUTED, SAID EXCIPIENT BEING SELECTED FROM THE GROUP CONSISTING OF (1) LACTOSE AND A FINELY DIVIDED, HIGHLY POROUS MATERIAL, (2) MANNITOL, AND (3) MANNITOL AND A FINELY DIVIDED, HIGHLY POROUS MATERIAL, WHEREIN THE FINELY DIVIDED, HIGHLY POROUS MATERIAL IN (1) AND (3) IS SELECTED FROM THE GROUP CONSISTING OF ACTIVATED CALY, DIATOMACEOUS EARTH, SILICA GEL AND ACTIVATED CARBON.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3338787A (en) * 1964-02-24 1967-08-29 Hercules Inc Vasodilator drug mixture and excipient therefor
US3419571A (en) * 1966-04-06 1968-12-31 Warner Lambert Pharmaceutical Method for relieving coronary insufficiency
US4260596A (en) * 1979-08-13 1981-04-07 Bristol-Myers Company Edible unit dosage form consisting of outer mannitol shell and inner liquid or gel center and method for manufacturing the same
EP0104877A2 (en) 1982-09-29 1984-04-04 Ici Americas Inc. Organic nitrate drug mixtures resistant to detonation by fire
US4486193A (en) * 1981-07-22 1984-12-04 Alza Corporation Method for treating ischemic conditions by administering drug by two routes
DE3333639A1 (en) * 1983-09-17 1985-03-28 Dynamit Nobel Ag Preparing for the nitroestern koronartherapie
US4704119A (en) * 1983-02-03 1987-11-03 Alza Corporation Method comprising transdermal and buccal treatment of angina
US4812313A (en) * 1981-06-29 1989-03-14 Alza Corporation Method for lessening the incidence of anginal attacks
US4834979A (en) * 1981-06-29 1989-05-30 Alza Corporation Medical bandage for administering beneficial drug
US4846826A (en) * 1981-07-22 1989-07-11 Alza Corporation Method for treating ischemic conditions
US4849226A (en) * 1981-06-29 1989-07-18 Alza Corporation Method for increasing oxygen supply by administering vasodilator
US4954344A (en) * 1981-06-29 1990-09-04 Alza Corporation Method for treating nocturnal angina
EP0653045A1 (en) * 1993-03-08 1995-05-17 The Regents Of The University Of California Non-detonable and non-explosive explosive simulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US78317A (en) * 1868-05-26 Improved explosive compound
US2963402A (en) * 1955-01-18 1960-12-06 Nysco Lab Inc Sustained release medicament

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US78317A (en) * 1868-05-26 Improved explosive compound
US2963402A (en) * 1955-01-18 1960-12-06 Nysco Lab Inc Sustained release medicament

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3338787A (en) * 1964-02-24 1967-08-29 Hercules Inc Vasodilator drug mixture and excipient therefor
US3419571A (en) * 1966-04-06 1968-12-31 Warner Lambert Pharmaceutical Method for relieving coronary insufficiency
US4260596A (en) * 1979-08-13 1981-04-07 Bristol-Myers Company Edible unit dosage form consisting of outer mannitol shell and inner liquid or gel center and method for manufacturing the same
US4849226A (en) * 1981-06-29 1989-07-18 Alza Corporation Method for increasing oxygen supply by administering vasodilator
US4812313A (en) * 1981-06-29 1989-03-14 Alza Corporation Method for lessening the incidence of anginal attacks
US4954344A (en) * 1981-06-29 1990-09-04 Alza Corporation Method for treating nocturnal angina
US4834979A (en) * 1981-06-29 1989-05-30 Alza Corporation Medical bandage for administering beneficial drug
US4846826A (en) * 1981-07-22 1989-07-11 Alza Corporation Method for treating ischemic conditions
US4486193A (en) * 1981-07-22 1984-12-04 Alza Corporation Method for treating ischemic conditions by administering drug by two routes
EP0104877A2 (en) 1982-09-29 1984-04-04 Ici Americas Inc. Organic nitrate drug mixtures resistant to detonation by fire
EP0104877A3 (en) * 1982-09-29 1985-11-06 Ici Americas Inc Organic nitrate drug mixtures resistant to detonation by fire
US4704119A (en) * 1983-02-03 1987-11-03 Alza Corporation Method comprising transdermal and buccal treatment of angina
EP0137978A3 (en) * 1983-09-17 1986-10-08 Dynamit Nobel Aktiengesellschaft Nitroester preparation for coronary therapy
EP0137978A2 (en) * 1983-09-17 1985-04-24 Dynamit Nobel Aktiengesellschaft Nitroester preparation for coronary therapy
DE3333639A1 (en) * 1983-09-17 1985-03-28 Dynamit Nobel Ag Preparing for the nitroestern koronartherapie
EP0653045A1 (en) * 1993-03-08 1995-05-17 The Regents Of The University Of California Non-detonable and non-explosive explosive simulators
EP0653045A4 (en) * 1993-03-08 1995-09-27 Univ California Non-detonable and non-explosive explosive simulators.

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