US2734844A - Injectable penicillin repository prepara- - Google Patents

Injectable penicillin repository prepara- Download PDF

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US2734844A
US2734844A US2734844DA US2734844A US 2734844 A US2734844 A US 2734844A US 2734844D A US2734844D A US 2734844DA US 2734844 A US2734844 A US 2734844A
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penicillin
ferric
oil
salt
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

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  • This invention relates to pharmaceutical preparations. More particularly, this invention relates to injectable therapeutic compositions containing penicillin which will prolong the therapeutic blood levels of penicillin, and to a process for the preparation of these compositions.
  • Another injectable preparation comprising a suspension of finely divided penicillin particles containing peanut oil having a hydrophilic substance such as pectin dispersed therein, is considered to obviate some of the disadvantages of the Romansky formulation discussed supra but has likewise failed to provide the desired repository effect.
  • the preparation is characterized by a low viscosity at room temperature being highly fluid in nature and thus can be very easily injected parenterally by means of a hypodermic needle.
  • the antibiotic By limiting the particle size of the penicillin to av predetermined range, the antibiotic remains in suspension and does not settle out. Injections of the aforedescribed composition containing 75,000 units of penicillin in animals have provided blood levels in excess of 0.03 unit per cc. of blood for periods of time in excess of 96 hours.
  • the formulation is prepared by heating a mixture containing the ferric salt of a higher fatty acid together with an innocuous, non-toxic oil such as for example sesame oil, at a temperature ranging between 100175 C. until the desired reaction, i. e. swelling of the salts or slight thickening of the oil, has occurred.
  • the prod uct is cooled and to it is then added a therapeuticallyactive salt of penicillin. This is followed by ball milling the mixture for a period of about sixteen hours and the desired product in its final form is then poured into a suitable container or receptacle.
  • higher fatty acid is defined as a fatty acid containing 16 to 18 carbon atoms.
  • Specific salts which are included within the purview of this invention include ferric suboleate, ferric substearate, ferric subpalrnitate, ferric sublinoleate, etc.
  • the prefix su is meant to indicate the fact that these compounds contain substantially all of the stearate, oleate, etc. in the monoform with but minor or inconsequential amounts of the stearate, oleate, etc. in the ii-form.
  • the injectable formulation contains the penicillin salt in a finely divided state in which the particle size of the salt is of mixed sizes, but wherein substantially all of the particles of penicillin are between 1 to 200 microns in size, andpreferably, less than 5Q microns in size.
  • the Parana. em od ed i th P ep rat n may be a more of these specific penicillins such as are commonly obtained in the production of penicillin G, K, or any of the other known penicillins, or it may be a penicillin which consists mainly or wholly of one of these specific penicillins. It is preferable, however, to use a penicillin which is rich in penicillin G, primarily because of the excellent therapeutic qualities of this specific salt.
  • the penicillin used may be either in the form of amorphous penicillin or preferably in the form of a crystalline penicillin.
  • This preparation differs markedly from that disclosed in U. S. 2,507,193 wherein penicillin is suspended in an oil that has been gelled with aluminum stearate, in that the ferric salt used in this invention does not dissolve" in the oil to produce a gel but instead, the oil dissolves in the ferric salt thus forming an insoluble gel-like material that apparently coats the penicillin particles.
  • the protective gel is not hydrophilic in nature. Since the gel is insoluble in the oil, it coats the particles in the oil so that when the preparation is brought into contact with the aqueous body fluids, a slow penetration of the penicillin salt is effected through this insoluble coating.
  • EXAMPLE I One gram of ferric substearate was added to 50 cc. of sesame oil which had been warmed to 100 C. The mixture was heated to a tempearture of 125 C. for fifteen minutes and then allowed to cool.
  • EXAMPLE II One gram of ferric suboleate was added to 50 cc. of sesame oil which had been warmed to 100 C. The mixture was heated to a temperature of 125 C. for fifteen minutes and then allowed to cool.
  • EXAMPLE III One gram of ferric subpalmitate was added to 50 cc. of sesame oil which had been warmed to 100 C. The mixture was heated to a temperature of 125 C. for fifteen minutes and then allowed to cool.
  • the quantity of ferric salt that is used is preferably about 2% by weight of volume of the oil used, satisfactory results having likewise been obtained when quantities ranging from 1 to were used.
  • the following table shows an average of the animals indicating penicillin blood levels of 0.03 unit per cc. or above at the indicated hour after an intramuscular injection of 0.25 cc. of a formulation containing varying amounts of a metallic salt and 75,000 units of penicillin. Consequent blood samples were taken at the'intervals indicated. Blood levels were determined by a microbiological plate assay method using S. lutea. A control was also drawn before injection.
  • the preparations herein described are effective against many gram positive organisms, both aerobic and anaerobic, as well as against gonococci and meningococci. Likewise, pneumococ'cic infections are similarly susceptible. The injection of these preparations is characterized by only slight pain and discomfort together with the absence of soreness at the point of injection.
  • compositions of penicillin salts in a vehicle composed of'a ferric salt of a higher fatty acid and oil can be prepared containing less than or more than 300,000 units of penicillin.
  • -An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of a therapeutic salt of penicillin coated with a gel comprising an innocuous non-toxic oil dissolved in a ferric salt of a higher fatty acid, thecoated particles being dispersed in an innocuous non-toxic oil, the amount of ferric salt ranging from 1 to by weight of the total amount of innocuous non-toxic oil.
  • An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil and ferric suboleate, the coated particles being dispersed in an innocuous non-toxic oil.
  • An injectable antibiotic preparation capable of maintaining efiective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil and ferric subpalmitate, the coated particles being dispersed in an innocuous non-toxic oil.
  • An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil dissolved in ferric substearate, the coated particles being dispersed in an innocuous non-toxic oil and the amount of ferric substearate ranging from 1 to 10% by weight of the total amount of innocuous non-toxic oil.
  • An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil dissolved in ferric substearate, the coated particles being dispersed in an innocuous non-toxic oil and the amount of ferric substearate being about 2% by weight of the total amount of innocuous non-toxic oil.
  • An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin substantially all of which are less than about 200 microns in size, the particles being coated with a gel comprising an innocuous non-toxic oil dissolved in ferric substearate and the coated particles being dispersed in an innocuous non-toxic oil, the quantity of ferric substearate being about 2% by weight of the total amount of innocuous non-toxic oil.
  • An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises an innocuous non-toxic oil having dispersed therein particles of procaine penicillin and a gel of an innocuous non-toxic oil and a ferric salt selected from the group consisting of ferric suboleate and ferric substearate, said gel being insoluble in said first mentioned non-toxic oil and containing an amount of ferric salt ranging from 1% to 10% by weight of the total amount of non-toxic oil.

Description

United States Patent INJECTABLE PENICILLIN REPOSITORY PREPARA- TION CONTAINING OIL AND GELLED OlL No Drawing. Application October 18, 1951, Serial No. 251,992
7 Claims. (Cl. 16765) This invention relates to pharmaceutical preparations. More particularly, this invention relates to injectable therapeutic compositions containing penicillin which will prolong the therapeutic blood levels of penicillin, and to a process for the preparation of these compositions.
In the past, a common method for the administration of penicillin involved the introduction of penicillin in physiologic saline or water through the intramuscular route. This method was highly unsatisfactory in that the penicillin had a tendency to decompose or was rapidly absorbed in the body fluids and then eliminated in the urine. As a result, high levels of penicillin endured in the blood for only brief periods of time. To effect a high blood level of penicillin, it was necessary to give frequent injections of the antibiotic. In view of the fact that satisfactory results in the therapeutic use of penicillin are secured only when effective blood levels are maintained over a prolonged period of time, i. e. several days,
the inconvenience and obvious disadvantages of this method precluded its widespread acceptance and use. Further disadvantages included the poor stability of penicillin in physiologic saline and also the loss in potency of the antibiotic material in this medium, particue larly at elevated temperatures.
Numerous attempts have been made to overcome the disadvantages of the foregoing method, but none of them has been highly satisfactory. For example, the advantages of prolonged therapeutic blood levels of penicillin following a single injection has been established by the use of a composition containing penicillin in sus pension in a mixture of oil and beeswax (Romansky: U. S. 2,443,778). However, the inclusion of wax in this vehicle was found to be disagreeable to the patient and was proved to be the apparent cause of a number of unfavorable local reactions such as sensitization of the patient together with the resulting allergic reactions. Numerous cases of fibrosis were likewise reported. Further, the residual beeswax was dissolved with great difficulty, requiring some 25 to 30 days for complete assimilation, and in extreme cases, necessitating removal by surgery.
Another injectable preparation, disclosed in U. S. 2,518,510, comprising a suspension of finely divided penicillin particles containing peanut oil having a hydrophilic substance such as pectin dispersed therein, is considered to obviate some of the disadvantages of the Romansky formulation discussed supra but has likewise failed to provide the desired repository effect.
It has now been discovered that effective therapeutic blood levels of penicillin can be obtained for prolonged ,eriods of time by the administration of an injcctable substantially anhydrous repository penicillin composition comprising a therapeutically effective salt of penicillin mixture of one or g 2,734,844 1 Patented Feb. 14, 1956 distributed in a vehicle composed of an innocuous, nonto Oi nd a fe i sa o a hi he fatt a i h depot or repository summa w n p e l y j ted, i capab e o o n a y de ed do o the therapeutically active substance, releasing it in the blood st eam o ly gradually over an extended period of time i. e. several days. Thus, .by .using this method and the repository composition set forth above, large doses of the antibiotic material providing therapeutically effective blood levels for as long as 4 days may be easily and conveniently administered.
The preparation is characterized by a low viscosity at room temperature being highly fluid in nature and thus can be very easily injected parenterally by means of a hypodermic needle. By limiting the particle size of the penicillin to av predetermined range, the antibiotic remains in suspension and does not settle out. Injections of the aforedescribed composition containing 75,000 units of penicillin in animals have provided blood levels in excess of 0.03 unit per cc. of blood for periods of time in excess of 96 hours.
The formulation is prepared by heating a mixture containing the ferric salt of a higher fatty acid together with an innocuous, non-toxic oil such as for example sesame oil, at a temperature ranging between 100175 C. until the desired reaction, i. e. swelling of the salts or slight thickening of the oil, has occurred. The prod uct is cooled and to it is then added a therapeuticallyactive salt of penicillin. This is followed by ball milling the mixture for a period of about sixteen hours and the desired product in its final form is then poured into a suitable container or receptacle.
For the purpose of this invention, the term, higher fatty acid, is defined as a fatty acid containing 16 to 18 carbon atoms. Specific salts which are included Within the purview of this invention include ferric suboleate, ferric substearate, ferric subpalrnitate, ferric sublinoleate, etc.
The preferred salts used in the preparation of the above indicated vehicle are:
l?e( 0H)2OCOC17Hap. Ferric substearate Fo(Old)gQQQCr7l-lsa-Ferric suboleate with some Fe(OH) (OCOCrzHa5)2 probably present (H33) In referring to the aforementioned compounds as ferric substearate, ferric suboleate, etc, the prefix su is meant to indicate the fact that these compounds contain substantially all of the stearate, oleate, etc. in the monoform with but minor or inconsequential amounts of the stearate, oleate, etc. in the ii-form.
In addition to the sesame oil which is used in the prepa ration of the formulation, it has been found in practice that other injectable oils such as cottonseed, peanut, corn, olive, etc., may be similarly employed with highly satisfactoryresults. The oilthat is used in the formulation must be highly refined and contain a minimum amount of eadi ox tlizablsmat r al nd, o tur the l t in emwatsnot we n 995% Be r po n n t oil must be sterilised, sterilization being effected using n o e of the we -lsm m ion m t d The injectable formulation contains the penicillin salt in a finely divided state in which the particle size of the salt is of mixed sizes, but wherein substantially all of the particles of penicillin are between 1 to 200 microns in size, andpreferably, less than 5Q microns in size.
The Parana. em od ed i th P ep rat n may be a more of these specific penicillins such as are commonly obtained in the production of penicillin G, K, or any of the other known penicillins, or it may be a penicillin which consists mainly or wholly of one of these specific penicillins. It is preferable, however, to use a penicillin which is rich in penicillin G, primarily because of the excellent therapeutic qualities of this specific salt. The penicillin used may be either in the form of amorphous penicillin or preferably in the form of a crystalline penicillin.
This preparation differs markedly from that disclosed in U. S. 2,507,193 wherein penicillin is suspended in an oil that has been gelled with aluminum stearate, in that the ferric salt used in this invention does not dissolve" in the oil to produce a gel but instead, the oil dissolves in the ferric salt thus forming an insoluble gel-like material that apparently coats the penicillin particles. Likewise, this new and highly improved preparation is distinguishable from that disclosed in U. S. 2,518,510 in that the protective gel is not hydrophilic in nature. Since the gel is insoluble in the oil, it coats the particles in the oil so that when the preparation is brought into contact with the aqueous body fluids, a slow penetration of the penicillin salt is effected through this insoluble coating.
Additional advantages and features of this new and highly improved preparation are set forth in the following examples which disclose the principle of the invention and the preferred embodiment of applying that principle. It is understood, however, that the examples are merely illustrative and not limitative in nature, being capable of various other modifications:
EXAMPLE I One gram of ferric substearate was added to 50 cc. of sesame oil which had been warmed to 100 C. The mixture was heated to a tempearture of 125 C. for fifteen minutes and then allowed to cool.
Ten grams of procaine penicillin was added to 22.5 grams of the mixture prepared above and the resulting mixture was ball milled for sixteen hours. After this period of time, the mixture was then poured into suitable vials or containers.
EXAMPLE II One gram of ferric suboleate was added to 50 cc. of sesame oil which had been warmed to 100 C. The mixture was heated to a temperature of 125 C. for fifteen minutes and then allowed to cool.
Ten grams of procaine penicillin was added to 22.5 grams of the mixture prepared above and the resulting mixture was ball milled for sixteen hours. After this period of time, the mixture was then poured into suitable vials or containers.
EXAMPLE III One gram of ferric subpalmitate was added to 50 cc. of sesame oil which had been warmed to 100 C. The mixture was heated to a temperature of 125 C. for fifteen minutes and then allowed to cool.
Ten grams of procaine penicillin was added to 22.5 grams of the mixture prepared above and the resulting mixture was ball milled for sixteen hours. After this period of time, the mixture was then poured into suitable vials or containers.
The quantity of ferric salt that is used is preferably about 2% by weight of volume of the oil used, satisfactory results having likewise been obtained when quantities ranging from 1 to were used. An intramuscular injection of 0.25 cc. of the formulation prepared above containing 75,000 units of penicillin, produced a maximum blood level of 0.14 unit per cc. of blood 96 hours after injection.
The following table shows an average of the animals indicating penicillin blood levels of 0.03 unit per cc. or above at the indicated hour after an intramuscular injection of 0.25 cc. of a formulation containing varying amounts of a metallic salt and 75,000 units of penicillin. Consequent blood samples were taken at the'intervals indicated. Blood levels were determined by a microbiological plate assay method using S. lutea. A control was also drawn before injection.
Rabbit penicillin blood levels 1 One animal died.
The foregoing results indicate that the action of penicillin may be greatly prolonged by the intramuscular injection of a mixture containing a therapeutic penicillin salt, a ferric salt of a higher fatty acid, and an innocuous non-toxic oil.
The preparations herein described are effective against many gram positive organisms, both aerobic and anaerobic, as well as against gonococci and meningococci. Likewise, pneumococ'cic infections are similarly susceptible. The injection of these preparations is characterized by only slight pain and discomfort together with the absence of soreness at the point of injection.
While the present invention has been described with particular reference to the use of crystals of procaine penicillin, it is understood that other commercially available salts of penicillin such as sodium, potassium, calcium and amine salts, i. e., triethylamine, in crystalline and amorphous form, can likewise be used.
By the reduction of crystalline particles to less than about 200 microns and preferably less than about 50 microns, prolonged blood levels are obtained when the salts are dispersed in a vehicle composed of a ferric salt of a higher fatty acid and an oil.
It should likewise be mentioned that therapeutic salts of penicillin of any desired potency may be employed. However, to produce satisfactory penicillin blood levels for extended periods of time, it is preferred to use highly potent products. Compositions of penicillin salts in a vehicle composed of'a ferric salt of a higher fatty acid and oil can be prepared containing less than or more than 300,000 units of penicillin.
It is understood that the data and examples herein given are intended to be exemplary only in character, the invention being directed essentially to the incorporation of an available penicillin salt in a vehicle comprising a nontoxic innocuous oil and a ferric salt of a higher fatty acid as disclosed herein.
It will be apparent, therefore, that the invention is capable of being employed with varying constituents such as for example, different salts of penicillin, different ferric salts of higher fatty acids, and different oil vehicles. It is obvious from the foregoing that the invention is capable of various modifications and that, therefore, it is intended and desired to embrace within the scope of this invention such modifications and changes that are necessary to adapt it to varying conditions and uses, as defined by the scope'of the appended claims.
I claim:
1. -An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of a therapeutic salt of penicillin coated with a gel comprising an innocuous non-toxic oil dissolved in a ferric salt of a higher fatty acid, thecoated particles being dispersed in an innocuous non-toxic oil, the amount of ferric salt ranging from 1 to by weight of the total amount of innocuous non-toxic oil.
2. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil and ferric suboleate, the coated particles being dispersed in an innocuous non-toxic oil.
3. An injectable antibiotic preparation capable of maintaining efiective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil and ferric subpalmitate, the coated particles being dispersed in an innocuous non-toxic oil.
4. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil dissolved in ferric substearate, the coated particles being dispersed in an innocuous non-toxic oil and the amount of ferric substearate ranging from 1 to 10% by weight of the total amount of innocuous non-toxic oil.
5. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin coated with a gel comprising an innocuous non-toxic oil dissolved in ferric substearate, the coated particles being dispersed in an innocuous non-toxic oil and the amount of ferric substearate being about 2% by weight of the total amount of innocuous non-toxic oil.
6. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises particles of procaine penicillin substantially all of which are less than about 200 microns in size, the particles being coated with a gel comprising an innocuous non-toxic oil dissolved in ferric substearate and the coated particles being dispersed in an innocuous non-toxic oil, the quantity of ferric substearate being about 2% by weight of the total amount of innocuous non-toxic oil.
7. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises an innocuous non-toxic oil having dispersed therein particles of procaine penicillin and a gel of an innocuous non-toxic oil and a ferric salt selected from the group consisting of ferric suboleate and ferric substearate, said gel being insoluble in said first mentioned non-toxic oil and containing an amount of ferric salt ranging from 1% to 10% by weight of the total amount of non-toxic oil.
References Cited in the file of this patent UNITED STATES PATENTS Buckwalter May 9, 1950 OTHER REFERENCES Reinhold, New

Claims (1)

1. AN INJECTABLE ANTIBIOTIC PREPARATION CAPABLE OF MAINTAINING EFFECTIVE THERAPEUTIC BLOOD LEVELS OVER AN EXTENDED PERIOD OF TIME WHICH COMPRISES PARTICLES OF A THERAPEUTIC SALT OF PENICILLIN COATED WITH A GEL COMPRISING AN INNOCUOUS NON-TOXIC OIL DISSOLVED IN A FERRIC SALT OF A HIGHER FATTY ACID, THE COATED PARTICLES BEING DISPERSED IN AN INNOCUOUS NON-TOXIC OIL, THE AMOUNT OF FERRIC SALT RANGING FROM 1 TO 10% BY WEIGHT OF THE TOTAL AMOUNT OF INNOCUOUS NON-TOXIC OIL.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3016330A (en) * 1955-11-10 1962-01-09 Novo Terapeutisk Labor As Therapeutical antibiotic composition
US3044931A (en) * 1960-01-27 1962-07-17 Geigy Chem Corp Aryloxy acetic acid amides: process for parenteral application
US3531565A (en) * 1969-09-25 1970-09-29 American Cyanamid Co Stable adjuvant emulsion compositions comprising hydrated salts of a polyvalent metallic cation and a higher fatty acid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2507193A (en) * 1949-05-17 1950-05-09 Bristol Lab Inc Penicillin product

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2507193A (en) * 1949-05-17 1950-05-09 Bristol Lab Inc Penicillin product

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3016330A (en) * 1955-11-10 1962-01-09 Novo Terapeutisk Labor As Therapeutical antibiotic composition
US3044931A (en) * 1960-01-27 1962-07-17 Geigy Chem Corp Aryloxy acetic acid amides: process for parenteral application
US3531565A (en) * 1969-09-25 1970-09-29 American Cyanamid Co Stable adjuvant emulsion compositions comprising hydrated salts of a polyvalent metallic cation and a higher fatty acid

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