EP0050650A1 - Prolonged action drug formulation - Google Patents

Prolonged action drug formulation

Info

Publication number
EP0050650A1
EP0050650A1 EP19810901250 EP81901250A EP0050650A1 EP 0050650 A1 EP0050650 A1 EP 0050650A1 EP 19810901250 EP19810901250 EP 19810901250 EP 81901250 A EP81901250 A EP 81901250A EP 0050650 A1 EP0050650 A1 EP 0050650A1
Authority
EP
European Patent Office
Prior art keywords
drug
derivative
combination
formulation
improvement
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.)
Withdrawn
Application number
EP19810901250
Other languages
German (de)
French (fr)
Inventor
James Swarbrick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Southern California USC
Original Assignee
University of Southern California USC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by University of Southern California USC filed Critical University of Southern California USC
Publication of EP0050650A1 publication Critical patent/EP0050650A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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

  • drugs have been encapsulated in polymer or in slowly- dissolving coating material, or have been dispersed in an insoluble or slowly-dissolving matrix.
  • Prolonged activity formulations designed for subcutaneous and intramuscular injection have been prepared by using polymers to complex
  • the present invention provides a prolonged ac ⁇ tion drug formulation in which a chemical derivative of the desired drug is utilized.
  • concentration of the drug derivative is such as to provide only minor pharmacological activity.
  • the derivative retains its identity, but in combination with desired quantities of the drug itself, serving by such combination to impede the release of the drug.
  • the desired drug is dispersed in a suitable chemical derivative which has a reduced aqueous solubility and reduced dissolution rate.
  • the pharmacological activity of the modified drug is minor relative to the activity of the drug with which it is in combination, there is little likelihood of pharmacological and biochemical changes in the derivative; there is thus a cost savings through reduced toxicity testing and dosage development time.
  • the relationship between drug release and concentration in the combination can be readily deter ⁇ mined and customized for any particular application by simple changes in concentration and/or the manner by which the drug and derivative are placed in combination.
  • the derivative will eventually break down and be removed undergoing a reaction such as hydrolysis to reform the original drug.
  • the prolonged action drug formulation of the present invention comprises, in combi ⁇ nation, a pharmacologically effective amount of a drug in solid form and a solid chemical derivative of the drug in a concentration which is sufficient to substantially pro ⁇ long the time during which the drug is pharmacologically active but having at that concentration only minor pharma cological activity relative to the drug.
  • the combination is preferably a substantially intimate and uniform mixtur for example obtained by physical admixture fallowed by compaction and comminution, or by coprecipitation from a common solution, or the drug and derivative can be melted together to form a fused solid; alternatively, the deriva tive can be coated onto, or otherwise encapsulate, par- tides of the drug.
  • the combination has particular use ⁇ fulness when administered subcutaneously or intramuscu ⁇ larly.
  • the aqueous solubility (in pH 7 phosphate buffered solution) of the derivative should be less than 0.20 mg./ml., preferably less than 0.01 mg./ml.
  • the drug will generally constitute about. 25-95 weight percent of the combination.
  • a pharmacologically appropriate derivative of the following drugs that are amenable to chemical modification: steroids, neuroleptics , beta-lactam antibiotics, antileprotics, antimalarials , hypoglycemics, narcotics and narcotic antagonists.
  • the main invention is exemplified with reference to the antileprotic drug diaminodiphenyl sulfone, commonly known as dapsone. This is the drug of choice in the treat ⁇ ment of leprosy, having strong pharmacological activity against the bacillus Mycobacterium leprae. Typical dosage is 50-100 milligrams per day for a period of five years or longer.
  • acedapsone is reported by Sinkula as having an aqueous solubility (pH 7 phosphate buffered solution) of 0.003 mg./ml.
  • acedapsone When used as a "prodrug", i.e., a compound which is biotransformed into its pharmacologically active form, sufficient amount of the derivative must be used to provide the required dosage amount of the parent drug.
  • the acedapsone serves not as the source of the dapsone but physically as a matrix or coating to con ⁇ trol the release of the dapsone with which it is present in combination.
  • the required amount of acedapsone is much lower than when it is used as a prodrug.
  • O PI acedapsone has only minor pharmacological activity rela ⁇ tive to the dapsone component.
  • steroid drug testosterone can be combined with the derivative testos ⁇ terone cypionate
  • the neuroleptic drug fluphenazine can be combined with the derivative fluphenazine decanoate
  • the beta-lactam antiobiotic drug benzylpenicillin can be combined with the derivative benzathine penicillin G
  • the antimalarial drug cycloguanil can be combined with the derivative cycloguanil pamoate
  • the hypoglycemic drug insulin can be combined with the alkanedioic acid deriva ⁇ tive of insulin
  • the analgesic propoxythene can be com ⁇ bined with the derivative propoxythene napsylate
  • the narcotic antagonist naloxone can be combined with the derivative naloxone napsylate.
  • the components should preferably be intimately and uniformly dispersed which can be accomplished by compaction of a simple admixture and comminution.
  • a simple admixture and comminution As an alternative to physical admixture, one can obtain a sub ⁇ stantially intimate and uniform combination by coprecipi- tation of the drug with the derivative.
  • the coprecipitate is prepared by either removing the solvent in vacuo or adding a liquid iscible with the solvent but in which both drug and the derivative have only a low solubility.
  • Another method of combining the components is to melt the combination to form a fused solid upon cooling,
  • the combination can be used in accordance with any procedure in which the drug or prodrug has been used.
  • it can be suspended in aqueous solution or in oil, as appropriate, and injected as a suspension.
  • the material can be implanted in the form of a pellet or as a thin wafer, or injected as microcap- sules. Because a substantially smaller amount of the derivative is used in the present context than as a pro- drug, one can stay within reasonable bounds of injection volume, for example 2 ml or less for subcutaneous injec ⁇ tion and 5 ml or less for intramuscular injection.
  • Example II The procedure of Example I is repeated except that the combination is obtained by coprecipitation of the dapsone and acedapsone from common solution. In this regard, one can dissolve both dapsone and acedapsone in the minimum amount of the solvent dimethylformamide. A coprecipitate is formed on the addition of an excess of water, separated by filtration and subsequently dried. The resultant combination is treated as in Example I.
  • a combination is obtained by physically admixin in a mortar and pestle 0.5 grams of dapsone and 0.5 grams of acedapsone. The combination is compressed in a suitab punch and die assembly to -a pellet weighing 1.0 grams eac The pellets are then implanted subcutaneously, the wound being sutured for complete enclosure of the implant. Because of the biodegradable nature of the component, no subsequent recovery of the implant is required.

Abstract

Le temps pendant lequel un medicament est pharmacologiquement actif est prolonge en combinant le medicament avec un derive chimique du medicament ayant une faible activite pharmacologique par rapport au medicament.The time during which a drug is pharmacologically active is extended by combining the drug with a chemical derivative of the drug having low pharmacological activity compared to the drug.

Description

PROLONGED ACTION DRUG FORMULATION
Background and Summary of the Invention
Medical science has long recognized the desir- ability of prolonging the time during which a drug is pharmacologically active. A significant advantage is to decrease the frequency with which the patient has to take the drug or be given the drug. This is particularly important when patient compliance problems are encountered such as psychiatric patients or with the senile. Extend¬ ing the pharmacological activity of the drug can have significant therapeutic benefits, for example, by permitting a patient to sleep undisturbed throughout the night. Perhaps most significantly, the patient is exposed to less total active drug during any given period of time, minimizing or eliminating local and systemic side effects. Prolonged action drug formulations have utility in veteri¬ nary medicine, particularly in the treatment of free- ranging animals . A variety of methods have been devised in an attempt to increase drug release time, including oral, parenteral and topical application techniques. For example, drugs have been encapsulated in polymer or in slowly- dissolving coating material, or have been dispersed in an insoluble or slowly-dissolving matrix. Prolonged activity formulations designed for subcutaneous and intramuscular injection have been prepared by using polymers to complex
$NAT\θ5> or absorb the drug molecules in solution. Other tech¬ niques include suspension of polymer particles into which the drug is dispersed, suspension of microcapsules of the drug, use of solutions or suspensions of the drug in oil, 5 or emulsions with oil, and implanting various slow releas devices or pellets. These and other methods for provid¬ ing prolonged activity are described in "Sustained and Controlled Release Drug Delivery Systems" by J. R. Robinson, Marcel Dekker, Inc., New York, 1978 (Volume 6
10. of "Drugs and the Pharmaceutical Sciences Series", edited by J. Swarbrick) .
Most pertinent to the present development are the methods described by Anthony A. Sinkula in Chapter 6 of the foregoing test relating to the chemical approach
15 to sustained drug delivery; that Chapter 6 is incorporate herein by reference. Such methods are based on localiza¬ tion of the drug in a biological depot or site within the organism with slow release to provide the active form of the drug over an extended length of time. The author
20 describes preparation of chemical derivatives of a wide variety of drugs to increase the sustained release pro¬ perty of the drug molecule. In many cases, the parent molecule is regenerated in vivo by a hydrolytic mechanism While the chemical approach would seem to offer hope for
25 wide variety of custom tailored prolonged action drugs, when the derivative is formulated so as to provide a significant level of drug delivery, there are a number" of drawbacks pointed out by Sinkula. For example, the resul ing changes in the physicoche'mical properties of the modi
30 fied drug may well p'roduce pharmacological and biochemica changes different from those found in the parent drug molecule. The predictability of these changes is difficu to assess, and frequently it is not possible to alter onl one property of the drug. It will be appreciated that
35 the foregoing problems arise as a result of attempting to U [ -r, provide a modified drug at a concentration level having substantial pharmacological activity.
The present invention provides a prolonged ac¬ tion drug formulation in which a chemical derivative of the desired drug is utilized. However, in the present inven¬ tion as compared to the prior use of drug derivatives, the concentration of the drug derivative is such as to provide only minor pharmacological activity. Rather than simply relying upon regeneration of the drug by decomposition of the derivative, in the present invention, for an extended period of time the derivative retains its identity, but in combination with desired quantities of the drug itself, serving by such combination to impede the release of the drug. Succinctly, the desired drug is dispersed in a suitable chemical derivative which has a reduced aqueous solubility and reduced dissolution rate.
It will be appreciated that there are several advantages to the present invention. In particular, since the pharmacological activity of the modified drug is minor relative to the activity of the drug with which it is in combination, there is little likelihood of pharmacological and biochemical changes in the derivative; there is thus a cost savings through reduced toxicity testing and dosage development time. The relationship between drug release and concentration in the combination can be readily deter¬ mined and customized for any particular application by simple changes in concentration and/or the manner by which the drug and derivative are placed in combination. In contrast to some prior art vehicles which are not biode- gradable, the derivative will eventually break down and be removed undergoing a reaction such as hydrolysis to reform the original drug.
OMPI More particularly, the prolonged action drug formulation of the present invention comprises, in combi¬ nation, a pharmacologically effective amount of a drug in solid form and a solid chemical derivative of the drug in a concentration which is sufficient to substantially pro¬ long the time during which the drug is pharmacologically active but having at that concentration only minor pharma cological activity relative to the drug. The combination is preferably a substantially intimate and uniform mixtur for example obtained by physical admixture fallowed by compaction and comminution, or by coprecipitation from a common solution, or the drug and derivative can be melted together to form a fused solid; alternatively, the deriva tive can be coated onto, or otherwise encapsulate, par- tides of the drug. The combination has particular use¬ fulness when administered subcutaneously or intramuscu¬ larly.
The aqueous solubility (in pH 7 phosphate buffered solution) of the derivative should be less than 0.20 mg./ml., preferably less than 0.01 mg./ml. Dependin upon the particular derivative and parent drug, the drug will generally constitute about. 25-95 weight percent of the combination.
The prior art has used a variety of terms to characterize long-acting formulations. While one could draw distinctions between phrases such as "sustained action", "controlled release", "delayed release" and the like, as a practical matter, these terms can be used some what interchangeably. In this specification, the term "prolonged action" will be used to indicate all long-acti formulations, that is, formulations that have pharmacokin etic characteristics such that the formulation provides a extended length of release time than is normally found fo the released drug itself. Detailed Description It will be appreciated that the underlying concept of the present invention has applicability to a wide variety of drugs. In particular, one could utilize as the chemical derivative component a pharmacologically appropriate derivative of the following drugs that are amenable to chemical modification: steroids, neuroleptics , beta-lactam antibiotics, antileprotics, antimalarials , hypoglycemics, narcotics and narcotic antagonists. The main invention is exemplified with reference to the antileprotic drug diaminodiphenyl sulfone, commonly known as dapsone. This is the drug of choice in the treat¬ ment of leprosy, having strong pharmacological activity against the bacillus Mycobacterium leprae. Typical dosage is 50-100 milligrams per day for a period of five years or longer. Because of the chronic nature of this disease, a variety of derivative repository drugs have been proposed as substitutes for dapsone. These are described by Sinkula, supra, with optimum depot activity obtained with the diacetyl derivative of dapsone, 4', 4' ' '-sulfonyl- bisacetanilide, commonly known as acedapsone. Acedapsone is reported by Sinkula as having an aqueous solubility (pH 7 phosphate buffered solution) of 0.003 mg./ml.
When used as a "prodrug", i.e., a compound which is biotransformed into its pharmacologically active form, sufficient amount of the derivative must be used to provide the required dosage amount of the parent drug. In accord¬ ance with the present invention by combining acedapsone with dapsone, the acedapsone serves not as the source of the dapsone but physically as a matrix or coating to con¬ trol the release of the dapsone with which it is present in combination. In such context, the required amount of acedapsone is much lower than when it is used as a prodrug. ' At the concentration used in combination with dapsone, the
O PI acedapsone has only minor pharmacological activity rela¬ tive to the dapsone component.
Other suitable parent drug-derivative combina¬ tions can be provided. • For example: the steroid drug testosterone can be combined with the derivative testos¬ terone cypionate; the neuroleptic drug fluphenazine can be combined with the derivative fluphenazine decanoate; the beta-lactam antiobiotic drug benzylpenicillin can be combined with the derivative benzathine penicillin G; the antimalarial drug cycloguanil can be combined with the derivative cycloguanil pamoate; the hypoglycemic drug insulin can be combined with the alkanedioic acid deriva¬ tive of insulin; the analgesic propoxythene can be com¬ bined with the derivative propoxythene napsylate; and the narcotic antagonist naloxone can be combined with the derivative naloxone napsylate.
Further examples can be constructed by consider ing the aqueous solubility of various drug derivatives. In general, derivatives that are more soluble than 0.20 mg./ml. show little depot activity and therefore would be of little interest for the present combinations . Compoun of solubility below 0.20 mg./ml., preferably 0.01 mg./ml. or lower, are suitable candidates. Experimentally, one could determine the pharmacological activity of the deri- vative candidate and of the drug and combinations thereof to generate a simple concentration relationship so that a particular formulation can be customized.
The components should preferably be intimately and uniformly dispersed which can be accomplished by compaction of a simple admixture and comminution. As an alternative to physical admixture, one can obtain a sub¬ stantially intimate and uniform combination by coprecipi- tation of the drug with the derivative. For example, one can dissolve the drug and the derivative in a suitable solvent. The coprecipitate is prepared by either removing the solvent in vacuo or adding a liquid iscible with the solvent but in which both drug and the derivative have only a low solubility. Another method of combining the components is to melt the combination to form a fused solid upon cooling,
The combination can be used in accordance with any procedure in which the drug or prodrug has been used. For example, it can be suspended in aqueous solution or in oil, as appropriate, and injected as a suspension.
Alternatively, the material can be implanted in the form of a pellet or as a thin wafer, or injected as microcap- sules. Because a substantially smaller amount of the derivative is used in the present context than as a pro- drug, one can stay within reasonable bounds of injection volume, for example 2 ml or less for subcutaneous injec¬ tion and 5 ml or less for intramuscular injection.
The following examples will further illustrate the invention.
EXAMPLE I
One can combine 0.5 grams of diaminodiphenyl sulphone (dapsone) with 0.5 grams of 4' ,4' ' '-sulfonylbi- acetanilide (acedapsone) by physical admixture using a morter and pestle. The mixture is then compressed and broken down to particles of a size that can be readily injected. The resulting mixture is suspended in 3 ml of water for injection to serve as a subcutaneous or intra¬ muscular injection. A person suffering from leprosy is given an intramuscular injection of 3 ml (containing 1 gram of the combination) , the injection being repeated only once per month. EXAMPLE II The procedure of Example I is repeated except that the combination is obtained by coprecipitation of the dapsone and acedapsone from common solution. In this regard, one can dissolve both dapsone and acedapsone in the minimum amount of the solvent dimethylformamide. A coprecipitate is formed on the addition of an excess of water, separated by filtration and subsequently dried. The resultant combination is treated as in Example I.
EXAMPLE III
A combination is obtained by physically admixin in a mortar and pestle 0.5 grams of dapsone and 0.5 grams of acedapsone. The combination is compressed in a suitab punch and die assembly to -a pellet weighing 1.0 grams eac The pellets are then implanted subcutaneously, the wound being sutured for complete enclosure of the implant. Because of the biodegradable nature of the component, no subsequent recovery of the implant is required.
EXAMPLES IV - X The precedure of Example I can be repeated but substituting the following amounts of the listed drug and derivative:
Ex.No. Drug AAmmoouunntt DDeerriivvaattiivvee Amount
IV testosterone 50mg. testosterone 15Omg. cypionate V fluphenazine 95mg. fluphenazine 5mg. decanoate VI benzylpencillin 800mg. benazthine 20Omg. pencillin G
VII cycloguanil 200mg. cycloguanil lOOmg. pamoate
VIII insulin 4mg. alkanedioic 2mg. acid derivative
IX propoxythene 30mg. propoxythene lOmg. napsylate X naloxone 0.4mg. naloxone 0.2mg. napsylate
It will be appreciated that the above listing of drugs and derivatives is not intended to be comprehensive, but merely representative of the wide variety of drugs and derivatives which can be used to constitute a combination of this invention. Those skilled in the art will know or will be able to determine by routine experimentation the many other specific drugs and derivatives that are also suitable.

Claims

THE CLAIMS
1. A prolonged action drug formulation compris ing, in combination: a pharmacologically effective amount of a drug in solid form; and a solid chemical derivative of said drug in a concentration which is sufficient to substantially prolon the time during which said drug is pharmacologically ac¬ tive and having at said concentration minor pharmacologi¬ cal activity relative to said drug.
2. The formulation of claim 1 in which said combination comprises a substantially intimate and unifor admixture of said drug and said derivative as a matrix.
3. The formulation of claim 1 in which said combination is a solid obtain by fusion.
4. The formulation of claim 1 in which said dr and derivative combination is obtained by coprecipitation from a common solution thereof.
5. The formulation of claim 1 in which said derivative is coated onto particles of said drug.
6. The formulation of any one of claims 1-5 in which the aqueous solubility of said derivative is less than 0.20 mg./ml.
7. The formulation of claim 6 in which the aqueous solubility of said derivative is less than 0.01 mg./ml.
8.. The formulation of claim 6 in which said drug constitutes about 25-95 weight percent of said combination.
9. The formulation of any one of claims 1-5 in which said drug is diaminodiphenyl sulfone and said derivative is 4 ' ,4 ' ' '-sulfonylbisacetanilide. *
10. A prolonged action drug formulation compris¬ ing diaminodiphenyl sulfone in combination with 4',4'' '- sulfonylbisacetanilide, said diaminodiphenyl sulfone constituting about 25-95 weight percent of said combina¬ tion.
11. The formulation of claim 10 in which said diaminodiphenyl sulfone constitutes at least 50% of said combination.
12. In a method for subcutaneously or intra¬ muscularly administering pharmacologically effective amounts of drug in solid form, the improvement according to which said drug is placed in combination with^a solid chemical derivative of said drug in a concentration suffi¬ cient to substantially prolong the time during which said drug is pharmacologically active and having at said con¬ centration minor pharmacological activity relative to said drug.
13. The improvement of claim 12 in which said derivative is substantially intimately and uniformly ad¬ mixed with said drug to form a matrix.
14. The improvement of claim 12 in which said drug and derivative are melted together to form a fused solid.
15. The improvement of claim 13 in which said drug and derivative are coprecipitated from a -common solution to form said admixture.
16. The improvement of claim 12 in which said combination is obtained by coating said derivative onto particles of said drug.
17. The improvement of any one of claims 12-16 in which the aqueous solubility of said derivative is les than 0.20 mg./ml.
18. The improvement of claim 17 in which the aqueous solubility of said derivative is less than 0.01 mg./ml.
19. The improvement of claim 17 in which said drug constitutes about 25-95 weight percent of said combination.
20. The improvement of any one of claims 12-16 which said drug is diaminodiphenyl sulfone and said deriv tive is 4', 4' ' '-sulfonylbisacetanilide.
21. In a method for subcutaneously or intra¬ muscularly administering pharmacologically effective amounts of diaminodiphenyl sulfone, the improvement where to prolong the time during said diaminodiphenyl sulfone i pharmacologically active, comprising combining said diaminodiphenyl sulfone with 4' ,4' ' '-sulfonylbisacetanili so as to constitute said diaminodiphenyl sulfone about 25-95 weight percent of the resultant combination.
22.The improvement of claim 21 in which said diaminodiphenyl sulfone constitutes at least 50% of said combination.
EP19810901250 1980-04-21 1981-04-20 Prolonged action drug formulation Withdrawn EP0050650A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14227980A 1980-04-21 1980-04-21
US142279 1980-04-21

Publications (1)

Publication Number Publication Date
EP0050650A1 true EP0050650A1 (en) 1982-05-05

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Family Applications (1)

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Country Status (2)

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EP (1) EP0050650A1 (en)
WO (1) WO1981002975A1 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5079007A (en) * 1987-07-29 1992-01-07 The Upjohn Company Controlled release of antibiotic salts from an implant
GB0027357D0 (en) 2000-11-09 2000-12-27 Bradford Particle Design Plc Particle formation methods and their products
GB0208742D0 (en) 2002-04-17 2002-05-29 Bradford Particle Design Ltd Particulate materials
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
EP2425819A1 (en) 2007-02-11 2012-03-07 MAP Pharmaceuticals Inc Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile
US9808030B2 (en) 2011-02-11 2017-11-07 Grain Processing Corporation Salt composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8102975A1 *

Also Published As

Publication number Publication date
WO1981002975A1 (en) 1981-10-29

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