US2733184A - Inject able penicillin repository prep ar a- - Google Patents
Inject able penicillin repository prep ar a- Download PDFInfo
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- US2733184A US2733184A US2733184DA US2733184A US 2733184 A US2733184 A US 2733184A US 2733184D A US2733184D A US 2733184DA US 2733184 A US2733184 A US 2733184A
- Authority
- US
- United States
- Prior art keywords
- penicillin
- oil
- aluminum
- salt
- innocuous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 title claims description 72
- 229940049954 Penicillin Drugs 0.000 title claims description 64
- 229960000626 benzylpenicillin Drugs 0.000 title claims description 64
- 230000003000 nontoxic Effects 0.000 claims description 40
- 231100000252 nontoxic Toxicity 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 40
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 38
- 230000001225 therapeutic Effects 0.000 claims description 38
- 230000035639 Blood Levels Effects 0.000 claims description 32
- 239000011780 sodium chloride Substances 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 22
- 230000003115 biocidal Effects 0.000 claims description 20
- 239000003921 oil Substances 0.000 description 74
- 235000019198 oils Nutrition 0.000 description 74
- 239000000203 mixture Substances 0.000 description 44
- 125000004432 carbon atoms Chemical group C* 0.000 description 22
- 239000000243 solution Substances 0.000 description 16
- 238000009472 formulation Methods 0.000 description 14
- WHRVRSCEWKLAHX-LQDWTQKMSA-N benzylpenicillin procaine Chemical compound [H+].CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 WHRVRSCEWKLAHX-LQDWTQKMSA-N 0.000 description 12
- 239000008280 blood Substances 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 150000002960 penicillins Chemical class 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 12
- 210000004369 Blood Anatomy 0.000 description 10
- LCSQKWUBQBQFIU-UHFFFAOYSA-H C(CCCCCCCCCCCCCCC)OP(=O)([O-])[O-].[Al+3].C(CCCCCCCCCCCCCCC)OP(=O)([O-])[O-].C(CCCCCCCCCCCCCCC)OP(=O)([O-])[O-].[Al+3] Chemical compound C(CCCCCCCCCCCCCCC)OP(=O)([O-])[O-].[Al+3].C(CCCCCCCCCCCCCCC)OP(=O)([O-])[O-].C(CCCCCCCCCCCCCCC)OP(=O)([O-])[O-].[Al+3] LCSQKWUBQBQFIU-UHFFFAOYSA-H 0.000 description 8
- 235000010210 aluminium Nutrition 0.000 description 8
- 229910052782 aluminium Inorganic materials 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 6
- 229940056360 Penicillin G Drugs 0.000 description 6
- -1 alkoxyalkyl alcohols Chemical class 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000006011 modification reaction Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 210000001124 Body Fluids Anatomy 0.000 description 4
- SYBDCHLLCMDAAT-UHFFFAOYSA-H C(CCCCCCCCC)OP(=O)([O-])[O-].[Al+3].C(CCCCCCCCC)OP(=O)([O-])[O-].C(CCCCCCCCC)OP(=O)([O-])[O-].[Al+3] Chemical compound C(CCCCCCCCC)OP(=O)([O-])[O-].[Al+3].C(CCCCCCCCC)OP(=O)([O-])[O-].C(CCCCCCCCC)OP(=O)([O-])[O-].[Al+3] SYBDCHLLCMDAAT-UHFFFAOYSA-H 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 229940037003 alum Drugs 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 235000013871 bee wax Nutrition 0.000 description 4
- 239000012166 beeswax Substances 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- HBEOVKSHQZVUQQ-UHFFFAOYSA-H dialuminum;octadecyl phosphate Chemical compound [Al+3].[Al+3].CCCCCCCCCCCCCCCCCCOP([O-])([O-])=O.CCCCCCCCCCCCCCCCCCOP([O-])([O-])=O.CCCCCCCCCCCCCCCCCCOP([O-])([O-])=O HBEOVKSHQZVUQQ-UHFFFAOYSA-H 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 230000002035 prolonged Effects 0.000 description 4
- 239000008159 sesame oil Substances 0.000 description 4
- 235000011803 sesame oil Nutrition 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KSTDNMVCVQWPJG-UHFFFAOYSA-L 2-phenoxyethyl phosphate Chemical compound [O-]P([O-])(=O)OCCOC1=CC=CC=C1 KSTDNMVCVQWPJG-UHFFFAOYSA-L 0.000 description 2
- ILRRQNADMUWWFW-UHFFFAOYSA-K Aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 2
- 229940063655 Aluminum stearate Drugs 0.000 description 2
- 235000017060 Arachis glabrata Nutrition 0.000 description 2
- 240000005781 Arachis hypogaea Species 0.000 description 2
- 235000010777 Arachis hypogaea Nutrition 0.000 description 2
- 235000018262 Arachis monticola Nutrition 0.000 description 2
- XKUHGWUNVLRAFF-UHFFFAOYSA-H C(C)C(COP(=O)([O-])[O-])CCCC.[Al+3].C(C)C(COP(=O)([O-])[O-])CCCC.C(C)C(COP(=O)([O-])[O-])CCCC.[Al+3] Chemical compound C(C)C(COP(=O)([O-])[O-])CCCC.[Al+3].C(C)C(COP(=O)([O-])[O-])CCCC.C(C)C(COP(=O)([O-])[O-])CCCC.[Al+3] XKUHGWUNVLRAFF-UHFFFAOYSA-H 0.000 description 2
- IXXDMDKMLOHTOU-UHFFFAOYSA-H C(CCCCC)OP(=O)([O-])[O-].[Al+3].C(CCCCC)OP(=O)([O-])[O-].C(CCCCC)OP(=O)([O-])[O-].[Al+3] Chemical compound C(CCCCC)OP(=O)([O-])[O-].[Al+3].C(CCCCC)OP(=O)([O-])[O-].C(CCCCC)OP(=O)([O-])[O-].[Al+3] IXXDMDKMLOHTOU-UHFFFAOYSA-H 0.000 description 2
- RCJVRSBWZCNNQT-UHFFFAOYSA-N Dichlorine monoxide Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 241001536352 Fraxinus americana Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010024769 Local reaction Diseases 0.000 description 2
- 240000007817 Olea europaea Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- INKCKTNGRWDRNF-UHFFFAOYSA-H P(=O)(OCCC1=CC=CC=C1)([O-])[O-].[Al+3].C1(=CC=CC=C1)CCOP(=O)([O-])[O-].C1(=CC=CC=C1)CCOP(=O)([O-])[O-].[Al+3] Chemical compound P(=O)(OCCC1=CC=CC=C1)([O-])[O-].[Al+3].C1(=CC=CC=C1)CCOP(=O)([O-])[O-].C1(=CC=CC=C1)CCOP(=O)([O-])[O-].[Al+3] INKCKTNGRWDRNF-UHFFFAOYSA-H 0.000 description 2
- DSVFTHYGOXNBRC-UHFFFAOYSA-H P(=O)(OCCCCOCC)([O-])[O-].[Al+3].C(C)OCCCCOP(=O)([O-])[O-].C(C)OCCCCOP(=O)([O-])[O-].[Al+3] Chemical compound P(=O)(OCCCCOCC)([O-])[O-].[Al+3].C(C)OCCCCOP(=O)([O-])[O-].C(C)OCCCCOP(=O)([O-])[O-].[Al+3] DSVFTHYGOXNBRC-UHFFFAOYSA-H 0.000 description 2
- ZDGKQAZUXAJSHD-UHFFFAOYSA-H P(=O)(OCCOCCCC)([O-])[O-].[Al+3].C(CCC)OCCOP(=O)([O-])[O-].C(CCC)OCCOP(=O)([O-])[O-].[Al+3] Chemical compound P(=O)(OCCOCCCC)([O-])[O-].[Al+3].C(CCC)OCCOP(=O)([O-])[O-].C(CCC)OCCOP(=O)([O-])[O-].[Al+3] ZDGKQAZUXAJSHD-UHFFFAOYSA-H 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- XVASOOUVMJAZNJ-MBNYWOFBSA-N Penicillin K Chemical compound S1C(C)(C)[C@H](C(O)=O)N2C(=O)[C@@H](NC(=O)CCCCCCC)[C@H]21 XVASOOUVMJAZNJ-MBNYWOFBSA-N 0.000 description 2
- GRLPQNLYRHEGIJ-UHFFFAOYSA-J Potassium alum Chemical compound [Al+3].[K+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRLPQNLYRHEGIJ-UHFFFAOYSA-J 0.000 description 2
- 241000022563 Rema Species 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- 210000002700 Urine Anatomy 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- XETZPLPGHHSRTG-UHFFFAOYSA-H [Al+3].P(=O)(OCCCCCCCC)([O-])[O-].C(CCCCCCC)OP(=O)([O-])[O-].C(CCCCCCC)OP(=O)([O-])[O-].[Al+3] Chemical compound [Al+3].P(=O)(OCCCCCCCC)([O-])[O-].C(CCCCCCC)OP(=O)([O-])[O-].C(CCCCCCC)OP(=O)([O-])[O-].[Al+3] XETZPLPGHHSRTG-UHFFFAOYSA-H 0.000 description 2
- RUQVDTINGPMNNK-UHFFFAOYSA-H [Al+3].[Al+3].CCCCCCCCCCCCOP([O-])([O-])=O.CCCCCCCCCCCCOP([O-])([O-])=O.CCCCCCCCCCCCOP([O-])([O-])=O Chemical compound [Al+3].[Al+3].CCCCCCCCCCCCOP([O-])([O-])=O.CCCCCCCCCCCCOP([O-])([O-])=O.CCCCCCCCCCCCOP([O-])([O-])=O RUQVDTINGPMNNK-UHFFFAOYSA-H 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 2
- 238000003556 assay method Methods 0.000 description 2
- 238000000498 ball milling Methods 0.000 description 2
- 101700050546 benM Proteins 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N carbodiimide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000003517 fume Substances 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 235000009973 maize Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 235000020232 peanut Nutrition 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000001814 pectin Substances 0.000 description 2
- 235000010987 pectin Nutrition 0.000 description 2
- 229920001277 pectin Polymers 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- ODCVCARXUNEYRT-UHFFFAOYSA-M phenyl propyl phosphate Chemical compound CCCOP([O-])(=O)OC1=CC=CC=C1 ODCVCARXUNEYRT-UHFFFAOYSA-M 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- IYNDLOXRXUOGIU-UHFFFAOYSA-M potassium;3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].O=C1N2C(C([O-])=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-UHFFFAOYSA-M 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 230000001235 sensitizing Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001954 sterilising Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
Classifications
-
- 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
- A61K31/41—Heterocyclic 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
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds 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
Definitions
- 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.
- This depot or repository composition when parenterally injected, is capable of holding any desired dose'of the therapeutically active substance, releasing it in the blood stream only gradually over an extended period of time so that large doses may be easily and conveniently administered by this method.
- 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 are maintained over a prolonged period of time, i. e.
- Another injectable preparation comprising a suspension of finely divided penicillin particles containing peanut oil having a hydrophilic substance such as pectin. dispersed therein, is consideredto obviate some of the disadvantagesof the Romansky formulation discussed supra but has likewise failed to provide the desired repository effect.
- an injectable substantially anhydrous repository penicillin composition comprising a therapeutically effective salt of penicillin-distr-iituated bra-vehicle composed of an innocuous, now-toxic oil and an aluminum salt of a phosphoric ester of an alcohol, said alcohol being selected from the group consisting of alkyl or arylalkyl alcohols possessing 6 to hypodermic needle.
- a therapeutically effective salt of penicillin-distr-iituated bra-vehicle composed of an innocuous, now-toxic oil and an aluminum salt of a phosphoric ester of an alcohol, said alcohol being selected from the group consisting of alkyl or arylalkyl alcohols possessing 6 to hypodermic needle.
- This preparation is further characterized by its excellent stability as it has been held at a temperature of 56 C. for a period of 2 months without any appreciable loss in potency or any physical change in appearance.
- the formulation is prepared by heating a mixture containing an aluminum salt of a phosphoric ester together with an innocuous, non-toxic oil such as for example sesame oil, at a temperature of about C. until the white color disappears and the mixture becomes somewhat translucent.
- the product is cooled and to it is added, a therapeutically active salt of'penicillin. This is followed by ball milling the mixture for about sixteen hours and the desired product in its final form is poured into a suitable container or receptacle.
- the aluminum salts utilizable in the present invention can be represented by the following formula:
- R is a member selected from the group consisting of an alkyl radical containing from 6 to 18 carbon atoms, an arylalkyl radical, 'an alkyloxyalkyl radical containing from 6 to 18 carbon atoms and an aryloxyalkyl radical.
- Specific compounds which are included within the purview of this invention include aluminum octadecylphosphate, aluminum cetylphosphate, aluminum hexylphosphate, aluminum 2-ethylhexylphosphate, aluminum lanrylphosphate, aluminum decyl-phosphate, aluminum [3 phenoxyethylphosphate, aluminum '7 phenylpropylphosphate, aluminum butyloxyethyl phosphate, aluminum ethoxybutyl phosphate, aluminum phenethyl phosphate, etc. 1
- sesame oil which is used in the prep aration of the formulation
- other injectable oils such as cottonseed, maize, peanut, olive, etc.
- the oil that is used in the formulation must be highly refined and contain a minimum amount of readily oxidizable material and moisture, the latter in amounts not exceeding 0.05%.
- the oil must be sterilized, sterilization being effected using any one of the well known conventional methods.
- 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 and preferably, less than 50 microns in size.
- the penicillin embodied in the preparation' may be a 4 mixtureof-one or 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 3 may-be a penicillin which' con'sists mainly or wholly of one-ofwthese.
- aspecificwpenicillinsw It is .preferable,-however, to use a penicillin which is rich in penicillin G, primarily because of the excellent therapeutic qualities ofthis specific s'alh
- The-penicillinused may be eitherin" 5 the form of amorphous penicill-iiii' or preferably inthe for m ofia cry'stallihperiicillih.L
- the protcctivegel is not hydrophilic inF nature'. Since the gel' is insoluble in the oil, it coats the 'particlesin -the oil so that'when thepreparation is brought into contact with th'e aqueous body fluids,- a slow penetration'of the penicillin salt is effected through this insoluble coating.
- This hot solution was added'with stirringto a hot solution of :45 grams of potassium aluminum sulfate (or 32 grams'of al'u minurn sulfa't'e' hydrate), arid boiled forten minutes .while i the "pH was adjusted to 5.0 to 6.0. The .mixture was thenfilteredjwash'ed with'w'ater and then dried in air.
- the "products are white'jinfusable powders that burn on'ignition' to? a voltiminous'whiteash.
- the hydrolysis is preferably efiec'ted I at ti-temperature ranging'btween 20 30 C.,' but temperaturesbetween0 90 C. likewise provide satisfactory 60 rsultsi
- the formatio'nof the aluminum salt is'preferably accomplished at'a temperature'ranging between" 80 '90" CI -but can proceed satisfactorily j'at' room temperatures oreven atteiiipera'turc's slightly-below. Anyjsolublealib mih'uin 'salt'or' doublesalts"'such"as" alum'sg'm'ay likewise' be used.
- the volume of solvents used is 'not critical.
- An intramuscularinjection of-0;25 cceof the formulation .prepared above contain ia g 75,000 units'of penicillinsproducedamaximum blood level of 0.09 unit per cc. of blood 96 hours after injection.
- Rabbit penicillin blood levels blfumeratonindlcates the number of animals showing-levels, denamw inator'ihdicates Iiurxib'erof 'aulma'ls injected.
- Theforegein g 'results' indicate that the aetionmf' benM cillin may be: greatlyprolonged-bythe intramusculawid jection of a mixture containing a therapeutic penicillin salt, an" aluminum -salt and'an innocuousnon-toxicoilr"
- pneumococeio infections are sim'ilzirly sue ce'ptible
- the injecti'on ofi ithesepreparations "ISKIYCMIJT" acterized by :only. slight-pain. and discomforttogethr the absence ofsoreness. at the :point of injection;
- ciumi-ianrlamineasalts i. es triethylaminefiidsb and famorphousgform. canulik'ewise' :be mam-.1 ny'mhe ree duo'tion ojcrystalline; particles itouless thantabml microns and preferably.less..than.about fifl-micronsgrtprpq longed blood leveis are obtained when the salts are dis persed in a vehicle composed of an aluminum salt and oil.
- compositions of penicillin salts in the vehicle composed of an aluminum salt 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 a therapeutic salt of penicillin, an innocuous non-toxic oil, and a gel of an innocuous non-toxic oil and a quantity of an aluminum salt ranging from 1 to by weight of the total volume of said oil, said aluminum salt being represented by the following formula:
- R is a member selected from the class consisting of an alkyl group containing from 6 to 18 carbon atoms, an arylalkyl group containing from 6 to 18 carbon atoms, an alkyloxyalkyl group containing from 6 to 18 carbon atoms and an aryloxyalkyl radical containing from 6 to 18 carbon atoms, the gel being insoluble in the first mentioned innocuous non-toxic oil.
- An injectable antibiotic preparation capable of maintaining efiective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and aluminum octadecylphosphate.
- An injectable antibiotic preparation capable of maintaining efiective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and agel of an innocuous non- 5 toxic oil and aluminum laurylphosphate;
- An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and aluminum decylphosphate.
- An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and aluminum octylphosphate.
- An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and an aluminum salt represented by the following formula:
- R is a member selected from the class consisting of an alkyl group containing from 6 to 18 carbon atoms, an arylalkyl group containing from 6 to 18 carbon atoms, an alkyloxyalkyl group containing from 6 to 18 carbon atoms and an aryloxyalkyl radical containing from 6 to 18 carbon atoms, the gel being insoluble in the first mentioned 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 a therapeutic salt of penicillin G coated with a gel of innocuous non-toxic oil and aluminum cetylphosphate, the amount of aluminum cetylphosphate present in the gel ranging from 1% to 15% by weight of the total amount of non-toxic oil present in the preparation.
Description
INJECTAI ILE PENICILLIN REPOSITORY PREPARA- TION CONTAINING OIL AND GELLED OIL William M. Ziegler, Clementon, N. J., assignor, by mesne assignments, to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application August 7, 1951,
Serial No. 240,796
7 Claims. (Cl. 167-65) 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 rapid- 1y absorbed in the body fluids and then eliminated in the urine. As a result, high levels of pencillin 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 18 carbon atoms, alkoxyalkyl alcohols possessing from 6 to 18 carbons and aryloxyalkyl alcohols.
This depot or repository composition, when parenterally injected, is capable of holding any desired dose'of the therapeutically active substance, releasing it in the blood stream only gradually over an extended period of time so that large doses may be easily and conveniently administered by this method.
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 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 antiobiotic material in this medium, particularly 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 suspension in a mixture of oil and beeswax (Romansky U. S; 2,443,778). However, the inclusion of wax inthis 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 difiicul ty, requiring some to 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 consideredto obviate some of the disadvantagesof 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 periods of time by the administration of an injectable substantially anhydrous repository penicillin composition comprising a therapeutically effective salt of penicillin-distr-ibuted bra-vehicle composed of an innocuous, now-toxic oil and an aluminum salt of a phosphoric ester of an alcohol, said alcohol being selected from the group consisting of alkyl or arylalkyl alcohols possessing 6 to hypodermic needle. By limiting the particle size of the peniciilin to a pre-determined 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.
This preparation is further characterized by its excellent stability as it has been held at a temperature of 56 C. for a period of 2 months without any appreciable loss in potency or any physical change in appearance.
The formulation is prepared by heating a mixture containing an aluminum salt of a phosphoric ester together with an innocuous, non-toxic oil such as for example sesame oil, at a temperature of about C. until the white color disappears and the mixture becomes somewhat translucent. The product is cooled and to it is added, a therapeutically active salt of'penicillin. This is followed by ball milling the mixture for about sixteen hours and the desired product in its final form is poured into a suitable container or receptacle.
The aluminum salts utilizable in the present invention can be represented by the following formula:
wherein R is a member selected from the group consisting of an alkyl radical containing from 6 to 18 carbon atoms, an arylalkyl radical, 'an alkyloxyalkyl radical containing from 6 to 18 carbon atoms and an aryloxyalkyl radical. Specific compounds which are included within the purview of this invention include aluminum octadecylphosphate, aluminum cetylphosphate, aluminum hexylphosphate, aluminum 2-ethylhexylphosphate, aluminum lanrylphosphate, aluminum decyl-phosphate, aluminum [3 phenoxyethylphosphate, aluminum '7 phenylpropylphosphate, aluminum butyloxyethyl phosphate, aluminum ethoxybutyl phosphate, aluminum phenethyl phosphate, etc. 1
In addition to the sesame oil which is used in the prep aration of the formulation, it has been found in practice that other injectable oils such as cottonseed, maize, peanut, olive, etc., may be similarly employed with highly satisfactory results. The oil that is used in the formulation must be highly refined and contain a minimum amount of readily oxidizable material and moisture, the latter in amounts not exceeding 0.05%. Before compounding, the oil must be sterilized, sterilization being effected using any one of the well known conventional methods.
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 and preferably, less than 50 microns in size.
The penicillin embodied in the preparation'may be a 4 mixtureof-one or 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 3 may-be a penicillin which' con'sists mainly or wholly of one-ofwthese. aspecificwpenicillinsw It, is .preferable,-however, to use a penicillin which is rich in penicillin G, primarily because of the excellent therapeutic qualities ofthis specific s'alh The-penicillinused may be eitherin" 5 the form of amorphous penicill-iiii' or preferably inthe for m ofia cry'stallihperiicillih.L
This preparation" difl'ers -markedlyfrom that disclosed in= U. 'S. 2,507193' wherein'pe'nicillin 'isnsuspended in an oil that ha's been gelled with aluminum stearate; in that th aluminu'm phosphate saItUs'ed in this.invention does not dissolve in the oil to produce a gel but instead, the oil"- dissolvesin ith alum inum' salt l forming an insoiuble gel-like materi'al thzit-apparently coatsthe penicil lin parti'clesi Likewiseythis new 'and highly'limpro'ved preparation is distinguishablei iromihat disclose'd in U. S.. 2,5'1 8,510 in -that: the protcctivegel is not hydrophilic inF nature'." Since the gel' is insoluble in the oil, it coats the 'particlesin -the oil so that'when thepreparation is brought into contact with th'e aqueous body fluids,- a slow penetration'of the penicillin salt is effected through this insoluble coating.
Additional ladvantages 'and' features of thisnew and highly improved preparati'onare set forth in-the following examplewhich' discloses the principleof the invention and the preferred embodiment of applying that principle." It-ise understood, however; that the example isfimerely illustrative :and not limitative in nature, being capable I of-various other-modifications:v 0
EXAMPLE The preparation of atypical gelling agent such as for example aluminum cetylphosphate is illustrated as fol lows-:-
To a solution of-24 grams of cetyl'alcohol in 20 cc. of benzene chilled in. anice bath was added 10 cc. of phosphorus 'oxychloride." The -resulting solution was allowed to stand until the-evolution of fumes of hydrogen chloride almost ceased and then the solution was heated to 70 C. for a few minutes. After cooling, the solution was poured onto 200 grams "of ice, and a 5% solution of sodium hydroxide was added from time to time to keep the pH between 3.0 and 8.0 while hydrolysis occurred. The'tinal solution was adjusted to a pH of 6.8 arid then heated to expel'the benzene. This hot solution was added'with stirringto a hot solution of :45 grams of potassium aluminum sulfate (or 32 grams'of al'u minurn sulfa't'e' hydrate), arid boiled forten minutes .while i the "pH was adjusted to 5.0 to 6.0. The .mixture was thenfilteredjwash'ed with'w'ater and then dried in air.
One-tenth mol quantities of "alcohols such. as .octadecyl, lauryl,'decyl,"octyl,"etc. can likewise be treated in the same fashion to secure corresponding aluminum salts.
The "products are white'jinfusable powders that burn on'ignition' to? a voltiminous'whiteash.
The alkylphosphoryl chloride can be prepared within temperatureeran tng trem 0 *cj but preferably between=25-'30 C. The hydrolysis is preferably efiec'ted I at ti-temperature ranging'btween 20 30 C.,' but temperaturesbetween0 90 C. likewise provide satisfactory 60 rsultsi The formatio'nof the aluminum salt is'preferably accomplished at'a temperature'ranging between" 80 '90" CI -but can proceed satisfactorily j'at' room temperatures oreven atteiiipera'turc's slightly-below. Anyjsolublealib mih'uin 'salt'or' doublesalts"'such"as" alum'sg'm'ay likewise' be used. The volume of solvents used is 'not critical.
FORMULATION 4 L grams of procaine penicillin. The mixture was then ball milled for. sixteen hours andtheniilledin It should be mentioned that the heating temperatures of the mixture containing the oil and aluminum phosphate salt are limited only by the cracking point of the various oils used.
The quantity of alumin'umsaltis preferably about 8% by weighfi: pf: volu'n'ie =of-' the oil iused sazisfaemry rema having 'likewise 'been obfained when "quantities ranging from 1 to l5% were used. An intramuscularinjection of-0;25 cceof the formulation .prepared above contain ia g 75,000 units'of penicillinsproducedamaximum blood level of 0.09 unit per cc. of blood 96 hours after injection.
The following table showsan' 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 alum'inum*salt" and 751000 units-bf peni cillin; Consequentbloodsamples'were takenat the"i1f-" tervalsindicated.- Blood levels were "determined byfa -microbiol'ogical plate assay -method *usin'g' S. 'luteli: A-
control was also drawn before injection;
Rabbit penicillin blood levels blfumeratonindlcates the number of animals showing-levels, denamw inator'ihdicates Iiurxib'erof 'aulma'ls injected.
Theforegein g 'results' indicate that the aetionmf' benM cillin may be: greatlyprolonged-bythe intramusculawid jection of a mixture containing a therapeutic penicillin salt, an" aluminum -salt and'an innocuousnon-toxicoilr" The preparations: herein= described are effective'agairist= many grampositive organisms; bothaerobic and anaero bic, .as. iwell as against gonococokand-t meningococcii Likewiseg. pneumococeio infections are sim'ilzirly sue ce'ptible The injecti'on ofi ithesepreparations "ISKIYCMIJT" acterized by :only. slight-pain. and discomforttogethr the absence ofsoreness. at the :point of injection;
While I the present invention has tbeen tdes'cribed -withh particular reference to .the use of ifcrystals iof procailreif penicillin,'fit is. understood that. other comm'erciallyiavail? able fisaltsliof penicillin such sassodium; we
ciumi-ianrlamineasalts i. es triethylaminefiidsb and famorphousgform. canulik'ewise' :be mam-.1 ny'mhe ree duo'tion ojcrystalline; particles itouless thantabml microns and preferably.less..than.about fifl-micronsgrtprpq longed blood leveis are obtained when the salts are dis persed in a vehicle composed of an aluminum salt and 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 the vehicle composed of an aluminum salt and oil can be prepared containing less than or more than 300,000 units of penicillin.
It is understood that the data and example 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 the nontoxic innocuous oil and aluminum salt 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, diiferent alnminum phosphate salts 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 a therapeutic salt of penicillin, an innocuous non-toxic oil, and a gel of an innocuous non-toxic oil and a quantity of an aluminum salt ranging from 1 to by weight of the total volume of said oil, said aluminum salt being represented by the following formula:
wherein R is a member selected from the class consisting of an alkyl group containing from 6 to 18 carbon atoms, an arylalkyl group containing from 6 to 18 carbon atoms, an alkyloxyalkyl group containing from 6 to 18 carbon atoms and an aryloxyalkyl radical containing from 6 to 18 carbon atoms, the gel being insoluble in the first mentioned innocuous non-toxic oil.
2. An injectable antibiotic preparation capable of maintaining efiective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and aluminum octadecylphosphate.
AIOH
3. An injectable antibiotic preparation capable of maintaining efiective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and agel of an innocuous non- 5 toxic oil and aluminum laurylphosphate;
4. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and aluminum decylphosphate.
5. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and aluminum octylphosphate.
6. An injectable antibiotic preparation capable of maintaining effective therapeutic blood levels over an extended period of time which comprises procaine penicillin, an innocuous non-toxic oil, and a gel of an innocuous nontoxic oil and an aluminum salt represented by the following formula:
wherein R is a member selected from the class consisting of an alkyl group containing from 6 to 18 carbon atoms, an arylalkyl group containing from 6 to 18 carbon atoms, an alkyloxyalkyl group containing from 6 to 18 carbon atoms and an aryloxyalkyl radical containing from 6 to 18 carbon atoms, the gel being insoluble in the first mentioned 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 a therapeutic salt of penicillin G coated with a gel of innocuous non-toxic oil and aluminum cetylphosphate, the amount of aluminum cetylphosphate present in the gel ranging from 1% to 15% by weight of the total amount of non-toxic oil present in the preparation.
References Cited in the file of this patent UNITED STATES PATENTS
Claims (1)
1. AN INJECTABLE ANTIBIOTIC PREPARATION CAPABLE OF MAINTAINING EFFECTIVE THERAPEUTIC BLOOD LEVELS OVER AN EXTENDED PERIOD OF TIME WHICH COMPRISES A THERAPEUTIC SALT OF PENICILLIN, AN INNOCUOUS NON-TOXIC OIL, AND A GEL OF AN INNOCUOUS NON-TOXIC OIL AND A QUANTITY OF AN ALUMINUM SALT RANGING FROM 1 TO 15% BY WEIGHT OF THE TOTAL VOLUME OF SAID OIL, SAID ALUMINUM SALT BEING REPRESENTED BY THE FOLLOWING FORMULA:
Publications (1)
Publication Number | Publication Date |
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US2733184A true US2733184A (en) | 1956-01-31 |
Family
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Application Number | Title | Priority Date | Filing Date |
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US2733184D Expired - Lifetime US2733184A (en) | Inject able penicillin repository prep ar a- |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2964448A (en) * | 1959-01-27 | 1960-12-13 | Anschel Joachim | Relaxin composition and process for preparing same |
US3016330A (en) * | 1955-11-10 | 1962-01-09 | Novo Terapeutisk Labor As | Therapeutical antibiotic composition |
US3105793A (en) * | 1956-11-28 | 1963-10-01 | Lobel Mervyn Joseph | Injectable medicinal composition |
US3242464A (en) * | 1961-07-31 | 1966-03-22 | Rca Corp | Data processing system |
US3494949A (en) * | 1967-01-03 | 1970-02-10 | Dow Chemical Co | Aluminum salts of alkyl orthophosphates |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2340331A (en) * | 1935-04-02 | 1944-02-01 | Lubri Zol Corp | Lubrication |
US2416985A (en) * | 1938-10-04 | 1947-03-04 | California Research Corp | Compounded mineral oil |
US2507193A (en) * | 1949-05-17 | 1950-05-09 | Bristol Lab Inc | Penicillin product |
-
0
- US US2733184D patent/US2733184A/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2340331A (en) * | 1935-04-02 | 1944-02-01 | Lubri Zol Corp | Lubrication |
US2416985A (en) * | 1938-10-04 | 1947-03-04 | California Research Corp | Compounded mineral oil |
US2507193A (en) * | 1949-05-17 | 1950-05-09 | Bristol Lab Inc | Penicillin product |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3016330A (en) * | 1955-11-10 | 1962-01-09 | Novo Terapeutisk Labor As | Therapeutical antibiotic composition |
US3105793A (en) * | 1956-11-28 | 1963-10-01 | Lobel Mervyn Joseph | Injectable medicinal composition |
US2964448A (en) * | 1959-01-27 | 1960-12-13 | Anschel Joachim | Relaxin composition and process for preparing same |
US3242464A (en) * | 1961-07-31 | 1966-03-22 | Rca Corp | Data processing system |
US3494949A (en) * | 1967-01-03 | 1970-02-10 | Dow Chemical Co | Aluminum salts of alkyl orthophosphates |
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