CA1100042A - Absorbable pharmaceutical compositions based on poly(alkylene oxalates) - Google Patents
Absorbable pharmaceutical compositions based on poly(alkylene oxalates)Info
- Publication number
- CA1100042A CA1100042A CA304,044A CA304044A CA1100042A CA 1100042 A CA1100042 A CA 1100042A CA 304044 A CA304044 A CA 304044A CA 1100042 A CA1100042 A CA 1100042A
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- CA
- Canada
- Prior art keywords
- polymer
- drug
- composition
- alkylene
- poly
- 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.)
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
ABSTRACT
Absorbable polymers derived from alkylene oxalates are formulated with drugs and introduced into the body to provide a slow, sustained release of the drug over an extended period of time in accordance with the rate of absorption of the poly-mer. Polymers of alkylene oxalates, particularly wherein the alkylene moiety is C3 to C16, are biodegradable in animal tissue and absorb with minimal adverse tissue reaction.
Absorbable polymers derived from alkylene oxalates are formulated with drugs and introduced into the body to provide a slow, sustained release of the drug over an extended period of time in accordance with the rate of absorption of the poly-mer. Polymers of alkylene oxalates, particularly wherein the alkylene moiety is C3 to C16, are biodegradable in animal tissue and absorb with minimal adverse tissue reaction.
Description
liO0~42 BACKGROUND OF THE IilVENTION
Field of the Invention This invention relates to novel polymer-drug compounds and their use in providing sustained release drug delivery to human and other warm-blooded animals. The polymer-drug compounds provide a mechanism whereby the rate of release and availability of the drug may be regulated so that the quantity of a drug which is released at a particular time or at a particular site is rela-tively constant and uniform over extended p~riods of time.
Descri~tion of Prior Art Drugs are conventionally administered orally or via in-jection, often at a site remote from the target. Over a rela-tively short period of time, the drug diffuses into the cir-culation system of the patient and is distributed to the various organs, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise irreversibly removed from the organism by excretion or chemical deactivation.
When drugs are delivered orally or by injection, the level and duration of availability of the drug cannot be con-trolled independently; only the size and frequency of the dose can be manipulated. Typically, there is an initially high con-centration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.
ET~-432 110~)042 In controlled sustained delivery, a formulation of the drug and a carrier is administered to the patient by injection or implantation. The carrier forms a drug reservoir that pro-tects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled sustained delivery of a drug prevents undesir-able peaking of blood levels and makes the drug available at an optimum and uniform concentration over an extended period of time. Only the released drug is subject to removal via meta-bolism and excretion.
U.S. Patent Nos. 3,773,919, 3,755,558, and 3,997,512describe formuLations of various polylactides, polyglycolides and copolymers o glycolide and lactide with some well-known drugs in order to achieve slow release of the drugs when im-planted or applied topically to humans. These compositions aredesigned to release the drug over an extended period of time as the polymer of the mixture is slowly absorbed in the system.
The polymer itself is nonreactive to body tissue and degrades into harmless products which are metaboLized or excreted by the host body.
We have discovered that polymers of alkylene oxalate are also absor~ed slowly in animal tissue without significant ad-verse tissue reaction.
Polymers of poly(alkylene oxalates) and the preparation thereof are described in the art. Carothers et al, J. Amer.
Chem. Soc. 52, 3292 (1930), for example, describes the ester interchange reaction of diols such as ethylene glycol, llO~Q~2 1,3-propanediol, or 1,4-butanediol with diethyl oxalate to yield a mixture of monomer, soluble polymer and insoluble polymer. ~he reaction of oxalic acid and an alkylene glycol to form polyester resins is described in U.S. Patent No. 2,111,762, while the prepa-ration of polyesters of fiber-forming quality from dicarboxylic acids and diols is described in U.S. Patent No. 2,952,652. The reaction of ethylene glycol with oxalic acid to form fiber-forming polymer was described recently in J. Polym.Sci.,Polym.Chem. Ed., 15, 1855 (1977). Superpolyest-ers of fiber-forming quality and de-rived from dibasic acids plus glycols are described in U.S. PatentNos. 2,071,250 and '251. Linear polyesters of oxalic acid have been reported as having high melting points, being soluble in many solvents, capable of forming films, and readily hydrolyzed [Sav~xv et al, Polym. Sci. USSR 6, 1475 (19643].
There was, however, no appreciation in the prior art of the absorbability of poly(alkylene oxalate) polymers in animal tissue, and no suggestion for the use of poly(alkylene oxalate) polymers in surgical applications. In particular, there has been no suggestion in the art to utilize polymers of alkylene oxalates in the preparation of absorbable polymer-drug compositions in ac-cordance with the present invention.
SUM~RY
Pharmaceutical depot compositions for parenteral admini-stration of effective amounts of d~ugs over an extended period of time comprise mix~ures and combinations of one or more drugs with absorbable polymers of alkylene oxalate. The polymers are conve-niently prepared by known polymerization techniques. Polymers and drugs are utilized as physical mixtures or as chemically bonded llOOQ42 compounds. The polymer-drug composition may be administered to the patient by implantation as a solid pellet, by injection as a suspension in a biologically acceptable fluid, or by other convenient means.
Thus, in accordance with the present teachings, a pharmaceutical depot composition is provided for parenteral administration of effective amounts of a drug which is to be released slowly over an extended period of time and which comprises a combination of:
a) from 1 to 99% by weight of a composition of a drug in an effective depot amount greater than the single dose amount, and b) a solid, absorbable polymer which is non-reactive toward body tissue and which undergoes biodegradation in the presence of body fluids into products which are metabolized or excreted by the body without adverse body reaction, the absorbable polymer which is employed is a poly(alkylene-oxylate) having the formula O O
~ R - O - C - C - O ~
wherein R is a C3 to C16 alkylene and n is the degree of polymerization resulting in a polymer inherent viscosity of at least 0.20 determined at 25C on a 0.1 g/dl solution of polymer in CHC13 or hexafluoroisopropanol.
~`
DESCRIPTION OF T~E INVENTION
The formulations of this invention are absorbable, non-irritating pharmaceutical compositions consisting of one or more drugs intimately mixed with or chemically bonded to an absorbable polymer. When implanted in an animal system, effective amounts of the drug are released at a predetermined rate over an extended period of time as the polymer is absorbed in the system. The in-vention is of particular value for drugs that require prolonged admin~stration as, for example, certain fertility-control drugs or ho~mones used for hormone-replacement therapy~
The novel formulations of the present invention per-mit Ihe continuous release of drugs over an extended period of time from the sites of parenteral administration and minimize the rrequency and thus the discomfort and inconvenience asso-cia~d with conventional injection formulations. The poly(alkylene oxalate) polymers undergo biodegradation in the body into products which are nonreactive toward body tissue, and can be designed, by controlling molecular weight and compo-cition~ to undergo hydroly-sis and release drug from the depot at a desired rate.
The Drug The term "drug" is intended in its broadest sense as de-fined in the ~ederal Food, Drug and Cosmetic .~ct, Section 201(2)g:
-Sa-~3 1 1 lO QO ~ ~ ETH-432 1) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacop~eia of the United States, or official National Formulary, or any supplement of any of them; and
Field of the Invention This invention relates to novel polymer-drug compounds and their use in providing sustained release drug delivery to human and other warm-blooded animals. The polymer-drug compounds provide a mechanism whereby the rate of release and availability of the drug may be regulated so that the quantity of a drug which is released at a particular time or at a particular site is rela-tively constant and uniform over extended p~riods of time.
Descri~tion of Prior Art Drugs are conventionally administered orally or via in-jection, often at a site remote from the target. Over a rela-tively short period of time, the drug diffuses into the cir-culation system of the patient and is distributed to the various organs, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise irreversibly removed from the organism by excretion or chemical deactivation.
When drugs are delivered orally or by injection, the level and duration of availability of the drug cannot be con-trolled independently; only the size and frequency of the dose can be manipulated. Typically, there is an initially high con-centration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.
ET~-432 110~)042 In controlled sustained delivery, a formulation of the drug and a carrier is administered to the patient by injection or implantation. The carrier forms a drug reservoir that pro-tects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled sustained delivery of a drug prevents undesir-able peaking of blood levels and makes the drug available at an optimum and uniform concentration over an extended period of time. Only the released drug is subject to removal via meta-bolism and excretion.
U.S. Patent Nos. 3,773,919, 3,755,558, and 3,997,512describe formuLations of various polylactides, polyglycolides and copolymers o glycolide and lactide with some well-known drugs in order to achieve slow release of the drugs when im-planted or applied topically to humans. These compositions aredesigned to release the drug over an extended period of time as the polymer of the mixture is slowly absorbed in the system.
The polymer itself is nonreactive to body tissue and degrades into harmless products which are metaboLized or excreted by the host body.
We have discovered that polymers of alkylene oxalate are also absor~ed slowly in animal tissue without significant ad-verse tissue reaction.
Polymers of poly(alkylene oxalates) and the preparation thereof are described in the art. Carothers et al, J. Amer.
Chem. Soc. 52, 3292 (1930), for example, describes the ester interchange reaction of diols such as ethylene glycol, llO~Q~2 1,3-propanediol, or 1,4-butanediol with diethyl oxalate to yield a mixture of monomer, soluble polymer and insoluble polymer. ~he reaction of oxalic acid and an alkylene glycol to form polyester resins is described in U.S. Patent No. 2,111,762, while the prepa-ration of polyesters of fiber-forming quality from dicarboxylic acids and diols is described in U.S. Patent No. 2,952,652. The reaction of ethylene glycol with oxalic acid to form fiber-forming polymer was described recently in J. Polym.Sci.,Polym.Chem. Ed., 15, 1855 (1977). Superpolyest-ers of fiber-forming quality and de-rived from dibasic acids plus glycols are described in U.S. PatentNos. 2,071,250 and '251. Linear polyesters of oxalic acid have been reported as having high melting points, being soluble in many solvents, capable of forming films, and readily hydrolyzed [Sav~xv et al, Polym. Sci. USSR 6, 1475 (19643].
There was, however, no appreciation in the prior art of the absorbability of poly(alkylene oxalate) polymers in animal tissue, and no suggestion for the use of poly(alkylene oxalate) polymers in surgical applications. In particular, there has been no suggestion in the art to utilize polymers of alkylene oxalates in the preparation of absorbable polymer-drug compositions in ac-cordance with the present invention.
SUM~RY
Pharmaceutical depot compositions for parenteral admini-stration of effective amounts of d~ugs over an extended period of time comprise mix~ures and combinations of one or more drugs with absorbable polymers of alkylene oxalate. The polymers are conve-niently prepared by known polymerization techniques. Polymers and drugs are utilized as physical mixtures or as chemically bonded llOOQ42 compounds. The polymer-drug composition may be administered to the patient by implantation as a solid pellet, by injection as a suspension in a biologically acceptable fluid, or by other convenient means.
Thus, in accordance with the present teachings, a pharmaceutical depot composition is provided for parenteral administration of effective amounts of a drug which is to be released slowly over an extended period of time and which comprises a combination of:
a) from 1 to 99% by weight of a composition of a drug in an effective depot amount greater than the single dose amount, and b) a solid, absorbable polymer which is non-reactive toward body tissue and which undergoes biodegradation in the presence of body fluids into products which are metabolized or excreted by the body without adverse body reaction, the absorbable polymer which is employed is a poly(alkylene-oxylate) having the formula O O
~ R - O - C - C - O ~
wherein R is a C3 to C16 alkylene and n is the degree of polymerization resulting in a polymer inherent viscosity of at least 0.20 determined at 25C on a 0.1 g/dl solution of polymer in CHC13 or hexafluoroisopropanol.
~`
DESCRIPTION OF T~E INVENTION
The formulations of this invention are absorbable, non-irritating pharmaceutical compositions consisting of one or more drugs intimately mixed with or chemically bonded to an absorbable polymer. When implanted in an animal system, effective amounts of the drug are released at a predetermined rate over an extended period of time as the polymer is absorbed in the system. The in-vention is of particular value for drugs that require prolonged admin~stration as, for example, certain fertility-control drugs or ho~mones used for hormone-replacement therapy~
The novel formulations of the present invention per-mit Ihe continuous release of drugs over an extended period of time from the sites of parenteral administration and minimize the rrequency and thus the discomfort and inconvenience asso-cia~d with conventional injection formulations. The poly(alkylene oxalate) polymers undergo biodegradation in the body into products which are nonreactive toward body tissue, and can be designed, by controlling molecular weight and compo-cition~ to undergo hydroly-sis and release drug from the depot at a desired rate.
The Drug The term "drug" is intended in its broadest sense as de-fined in the ~ederal Food, Drug and Cosmetic .~ct, Section 201(2)g:
-Sa-~3 1 1 lO QO ~ ~ ETH-432 1) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacop~eia of the United States, or official National Formulary, or any supplement of any of them; and
2) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
3) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and
4) articles intended for use as a component of any article specified in clauses 1, 2 or 3; but does not include devices or their components, parts, or accessories.
Classes of drug which may be specifically mentioned in-clude agents affecting the central nervous system, e.g., narcot-ics, such as, for example, morphine; narcotic antagonists, such as naloxone; antipsychotic agents, such as chlorpromazine and molindone; antianxiety agents, such as sodium pentobarbital, antidepressants, such as imipramine hydrochloride; stimulants, such as methyl phenadate and nikethamide; hallucinogens; anal-gesics, such as numorphan, meperidine, and morphine; and anorexigenic agents.
Other classes are pharmacodynamic agents, e.g., anti-hypertensive agents as reserpine, and chlorisondamine chloride, and antianginal agents, such as papaverine, and drugs ~or therapy ll~Q0~2 of pulmonary disorders, such as theophylline ethylenediamine salt and epinephrine. Additional classes are chemotherapeutic agents, e.g., antiviral; antiparasitic, such as emetine hydro-chloride and stibophen; antifungal agents, such as cycloheximide;
and antineoplastic agents, such as triethylene thiophosphoramide;
agents affecting metabolic diseases and endocrine functions, e.g.
prostaglandins; athersclerosins, such as heparin; steroids and biologically related compounds; polypeptides, such as bacitracin, polymixin B sulfate, and sodium colistimethate; natural and synthetic hormones, such as estradiol dipropionate, progesterone, and hydroxy progesterone caproate; steroid and nonsteriodal anti-inflammatory agents, such as gold sodium thiomalate and hydro-cortisone sodium succinate; and agents affecting thrombosis, such as crystalline trypsin; vitamins, such as vitamin B12; anti-epilepsy agents, such as phenobarbital; and the like. It should be understood that the specific drugs mentioned by name are illustrative and not limitative.
Endrocrine agents comprise a particularly useful class of compounds in this învention and can be defined either as natural hormones or as synthetic drugs that to some extent act like, or antagonize, natural hormones. Endocrine agents include, but are not limited to, both steroids and nonsteroids that func-tion as fertility-control agents; progestogens, estrogens, andro-gens, antiandrogens, corticoids, anabolic agents, and anti-inflammatory agents.
Examples of specific endocrine agents that can be used in the formulations of the invention are set forth in U.S. Patent No. 3,773,919, particularly Columns 3 to 7.
ll~QQ`~2 ETH-432 The Absorbable Polymer Polymers useful in the preparation of polymer-drug compounds of the present invention are comprised of units having the general formula:
O O
Il 11 ~ R - O - C - C ~ ~n wherein R is a C3 to C16 alkylene, st preferably C4 to C10 S alkylene, and n is the degree of polymerization resulting in a polymer having an inherent viscosity of at least 0.20 determined at 25C on a 0.1 g/dl solution of polymer in CHC13 or hexafluoro-isopropanol.
Alkylene oxalate polymers of the present invention are conveniently prepared by an ester interchange reaction between an alkylene diol and a lower ester of oxalic acid in the pres-ence of an ester interchange catalyst. The diol is preferably a C3 to C16 alkylene diol, and the ester of oxalic acid prefer-ably diethyl oxalate. The ester interchange is preferably con-ducted in two stages wherein the reactants are first heated with stirring under a nitrogen atmosphere to form a prepolymer with the removal of ethanol, followed by postpolymerization under heat and reduced pressure to obtain a final polymer of the desired molecular weight.
The preparation of useful polymers of alkylene oxalate is further illustrated by the following examples. The following analytical methods were used to obtain the data reported in the .
ll~)QQ42 examples. Inherent viscosity (~inh) of polymer was determined at 25C on a 0.1 g/dl solution of polymer in chloroform or hexa-fluoroisopropynol (HFIP). A DuPont 990 DSC apparatus was used to determine the melting temperatures (Tm) of polymer in nitrogen, using a 4 mg sample and a heating rate of 10 or 20C/min as specified. Crystallinity was determined by the method of Hermans and Weidinger and the diffractometer patterns were resolved with a DuPont 310 curve analyzer.
In vitro hydrolysis of polymer discs (about 1.2 g, 2.2 cm diameter)` and monofilaments (8-25 mil) were conducted in a phos-phate buffer of pH 7.25 at 37C.
In vivo absorption (muscle) was demonstrated by melt extruding the polymer into filaments and implanting two 2 cm seg-ments of a filament into the left gluteal muscles of female Long-Evans rats. The implant sites were recovered after periods of60, 90, and 120 and 180 days and examined microscopically to de-termine the extent of absorption. In vivo absorption (subcutane-ous) is a nonhistological technique in which continuous observa-tion of the biological degradation of segments of the filament were made by implanting two filaments, 2 cm long, into the abdomi-nal subcutis of young female rats. The implants are readily visi-ble when the skin is wetted with propylene glycol and extent of absorption can be determined by subjective visual examination.
EXAMPLES
General Polymerization Procedure Diethyl oxalate was heated with a selected diol in a mechanically-stirred reactor using a stannous alkanoate or an organic titanate as a catalyst. The reaction was conducted _g_ llO~Q42 under a nitrogen atmosphere at suitable temperatures until a substantial portion of the calculated amount o~ ethanol was ob-tained. Postpolymerization of the resulting prepolymer was then continued under reduced pressure using a suitable heating scheme.
At the end of the postpolymerization period, the molten polymer was allowed to cool slowly at room temperature, isolate~, ground and redried at 25 to 80C (depending on the polymer Tm) - in vacuo for at least one day. Detailed experimental conditions for the preparation of representative samples of linear poly-alkylene oxalates and important properties of the resulting poly-mers are presented below.
Poly(trimethylene oxalate) Distilled 1,3-propanediol (17.48 g, 0.23 mole) and diethyl oxalate (29.2 g, 0.2 mole) were mixed with a catalytic amount of stannous oxalate (4.1 mg, 0.02 mmole) under nitrogen.
The mixture was heated with stirring while allowing the result-ing ethanol to distill at 150, 120 and liOC for 0.5, 2 and 4 hours, respectively. The resulting polymer was then cooled to about 100C and the pressure was reduced to 0.1 mm. The poly-merization was continued ln vacuo at 150, 160, 180 and 200C
for 1, 3, l and 2 hours, respectively. The polymeric product was recovered as a clear, soft materiai.
Polymer Characterization ~inn in CHC13 = 0.57;
DSC ~20C/min): Tg = -iC
~lOQ~4Z
Poly(tetramethylene oxalate) Diethyl oxalate (36.5 g, 0.25 mole) was mixed with 1,4-butanediol (45 g, 0.5 mole) and a 1 percent solution of tetrakis(2-ethylhexyl) titanate (TOT) catalyst (1 ml, 0.012 mmole) and transferred to a resin kettle under a dry nitrogen atmosphere.
A prepolymer was formed by heating the reaction mixture under a nitrogen atmosphere for 2 hours each at 140 and 160C while al-lowing the formed ethanol to distill. The mixture was then heated under reduced pressure (2-3 mm Hg) at '60 and 180C for 20 and 2 hours, respectively. The polymer melt was slow-cooled, quenched in liquid nitro~en, isolated and ground. The ground polymer was redried at room temperature, in vacuo.
Polymer Characterization ~inh in HFIP = o.g5 DSC (20C/min): Tg = 4 5; Tc = 22; Tm = 105C
In vivo properties: Subcutaneous implantation of 12.9 mil filaments in rats indicated that 50 per-cent of their apparent mass was absorbed in the first 9 days, and 10 percent remained after 15 days, and absorption was substantially complete after 28 days.
Q4~
EX~MPLE 3 Poly(hexamethylene oxalate) Distilled diethyl oxalate (73.1 g, 0.500 mole~ was mixed with 1,6-hexanediol (61.2 g, 0.519 mole) and stannous octoate catalyst (0.33 M in toluene; 0.3 ml, 0.1 mmole) under a S dry nitrogen atmosphere in a glass reactor equipped with a mechanical stirrer. A prepolymer was formed by heating the mix-ture at 120C for 2 hours and then at 160C for 3 hours under nitrogen at l atmosphere while allowing the formed ethanol to distill. The prepolymer was then heated for one hour in vacuo (0.1 mm Hg) at 80 and then 90C. The postpolymerization of the polymer melt was completed by heating at 100, 115, 135, 150, 170, 190 and 200C for 2, 1, 1.5, 4, 6, 1 and 6.5 hours, re-spectively. The polymer was allowed to cool at room temperature, quenched in liquid nitrogen, isolated and ground. The ground polymer was dried in vacuo at room temperature.
Polymer Characterization ~inh in CHC13 = 0.83 DSC (10C/min): Tm = 70C
In vivo evaluation: Subcutaneous implantation of 8.7 mil filaments in rats indicated that ab-sorption of the fiber was about 20% complete after 42 days, and that after 121 days absorption was substantially complete.
Poly(octamethylene oxalate) Using a similar system to that of Example 3, distilled diethyl oxalate (109.6 g, 0.750 mole), distilled 1,8-octanediol (113.6 g, 0.777 mole) and stannous octoate cataLyst (0.33 M in toluene - O.455 ml, 0.150 mmole) were mixed under a dry nitrogen atmosphere in a glass reactor equipped with a mechanical stirrer.
A prep~lymer was formed by heating the mixture at 120C for 12 hours under nitrogen while allowing the formed ethanol to distill. Prior to postpolymerization, the product was heated for 1 hour at 90C and 0.1 mm Hg. The postpolymerization of the stirred polymer melt was completed by heating at 110, 135, 150, 170 and 200C for 3.5, 2.5, 4.5, 0.5 and 5 hours, respectively at 0.1 mm Hg. The polymer was cooled, quenched in liquid nitro-gen, isolated, gxound and dried in vacuo at room temperature.
The polymer was then heated at 60C in vacuo for one hour and finally at 200C for 6 hours to yield the final product.
Polymer Characterization ~inh in CHC13 = 0.88 DSC (10C/min): Tm = 75C
In vivo evaluation: Filaments (8.8 mil) im-planted into the gluteal muscles of rats showed no evidence of absorption up to the 42nd day.
After 119 days, there was evidence of minimal ab-sorption of some of the filaments.
E~YAMPLE 5 Poly(decamethylene oxalate) l,10-Decanediol (87.1 g, 0.5 mole) was mixed with di-ethyl oxalate (58.4 g, 0.4 mole) and a solution of TOT catalyst in toluene (0.012 mmole) under a nitrogen atmosphere. The re-action mixture was heated with stirring while allowing the re-sulting ethanol to distill at 120, 130 and 140C for 4, 2.5 and 2 hours respectively. The pressure was then reduced to 0.5 mm while heating to 190C for 20 minutes. The polymerization was continued ln vacuo at 190 and 210C for 4 and 13 hours, respec-tively. The polymer was recovered and characterized as follows:
Polymer Characterization ~inh in CHC13 = 0.45 DSC (10C/min): Tm = 77.5C
In vitro hydrolysis data: Melt extruded filaments had a weight loss of 1, 11, 38 and 62 percent after 6, 17, 44 and 177 days, respectively.
110~0~2 EX~IPLE 6 Poly(dodecamethylene oxalate) Distilled diethyl oxalate (14.6 g, 0.100 mole) was mixed with 1,12-dodecanediol (20.8 g, 0.103 mole) and stannous octoate catalyst (0.33 M in toluene - 0.061 ml, 0.02 mmole) under a dry nitrogen atmosphere in a glass reactor equipped for magnetic stirring. The prepolymer was formed after heating thè
mixture at 120C for 3 hours and 160C for 2 hours under nitro-gen at 1 atmosphere while allowing the formed ethanol to distill.
The mixture was then heated for 6 hours in vacuo (0.1 mm Hg) at 200C and then 210C for 2 hours. ~he postpolymerization of the polymer melt was completed after heating at 200C for 5 addi-tional hours. The polymer was cooled at room temperature and recovered.
Polymer Characterization ~inh in CHC13 = 0.57 DSC (20C/min): Tm = 31C
Poly(hexadecamethylene oxalate) Using a similar system to that used for Example 6, di-ethyl oxalate ~8.0 g, 0.055 mole), 1,16-hexadecanediol (14.6 g, 0.057 mole) and stannous octoate catalyst (0.33 ~ in toluene -0.033 ml, 0.01 mmole) were mixed under an atmosphere o dry nitrogen in a glass reactor equipped for ~agnetic stirring. The 110~042 prepolymer was formed after heating the mixture at 120C for 3 hours and then at 160C for 2 hours under nitrogen at 1 atmo-sphere while allowing the formed ethanol to distill. The mix-ture was then heated in vacuo at 0.1 mm Hg and at 200, 210 and 230C for 2, 2 and 3 hours, respectively. The postpolymerization of the stirred polymer melt was completed after heating at 200C
for 4 additional hours. The polymer was cooled and recovered.
Polymer Characterization ~inh in CHC13 = 0.45 DSC (20C/min): Tm = 95C, Tg = 40C
While the preceding examples have been directed to the preparation of specific homopolymers of poly(alkylene oxalates), these examples are for purposes of illustration only and are not limiting of the invention. Copolymers of C3 to C16 alkylene oxalate with up to about S0 percent by weight of one or more other monomers copolymerizable therewith to produce nontoxic and absorbable polymers, and physical mixtures of such homopolymers and copolymers, are likewise included within the present inven-tion. For example, mixtures of poly(alkylene oxalate) with polymers of lactide and/or glycolide are useful in the prepara-tion of compositions wherein the rate of absorption can be con-trolled by varying the relative proportions or the constituents.
.
Polymers of the present invention are adversely affected by moisture and are accordingly preferably prepared and stored -~ in a substantially moisture free environment and in hermetically sealed packages. Polymers which have been dried under vacuum at elevated temperatures and subsequently stored under vacuum or in . .
-~ a dry nitrogen en~ironment are found to be quite storage stable.
.
Preparation and Administration of `~ PolYmer-Drug Compositions ~
The drug and the polymer can be mixed, and the intimacy of mixing, particle size, and particle shape of the formulation ; ~ ,, .
~ ~can be varied, by any of a number of known methods. Intimacy of ~.-mixing, particle size, and particle shape of the formulations of the invention will depend~to some extent on the intended use.
- ~High homogeneity can be obtained by~mixing the components in the , molten~state, cooling, and grinding the resulting solid.- A
formulation so obtained is suitable for injection as 0.1 ~ to 1000 p particles suspended in saline solution or a pharmaceuti-cally acceptable oil. In some cases particles with cores of pure drug coated with various thic~nesses ~f polymer can be preferred . ~
for de}ayed~and/or sustained release. Relatively large pellets 10 mm) may be preferred for re~Jersible implantation in animals by surgery or by injection as projectiles. For this use adequate homogeneity can usually be realized by grlnding or milling the drug and the polymer together be~ore forming pellets under pres-sure. Known techniques of encapsulation,including microencapsu-lation, can be used to mix the polymer and the drug. The .
11~QQ42 formulations of this invention provide a slow, steady release of drug in contradistinction to conventional preparations which generally produce a rapid surge followed by a fairly quick decline in drug effect.
Polymer-drug mixtures of the invention may contain pharmaceutically acceptable inert additives such as plasticizers.
Typical plasticizers are Carbowax ~ polyethylene glycols, glycer-ides and ethylcellulose.
The relative proportions of the drug and poly(alkylene oxalate) polymer can be varied over a wide range depending on the desired effect. Since the drug will be released over an ex-tended period of time, the quantity of drug may be greater than the conventional single dose and the polymer must not break down or become absorbed by the body so rapidly as to release undue quantities of drug. The polymer-drug composition may range from 1 percent of drug and 99 percent of the polymer to 99 percent of drug and 1 percent of the polymer. Preferred compositions include 1 part of drug and from 4 to 20 parts of polymer.
These formulations can be injected as fluid suspensions by syringe into subcutaneous cellular tissue or muscular tissue, or implanted in pellet form subcutaneously or intramuscularly.
Liquid vehicles useful for suspensions of the drug-polymer formulation include water or aqueous solutions such as normal sodium chloride solution or sodium carboxymethyl cellulose in water. Oils such as sesame oil or peanut oil containing, if desired, dissolved adjuvants such as benzyl alcohol, may also be used to prepare suspensions of the polymer-drug formulation.
11000~2 ~ L}~ 2 Drug compounds of the classes mentioned earlier ma~ be coated, embedded, or intimately mixed in or with a matrix of one or a combination of different chain-length biodegradable poly-mers to give a drug-polymer mixture which will provide a control-led sustained release of the drug compound over a period of 8 hours to 2 months or longer when administered parenterally.
Coating, embedding or intimately mixing the drug com-pound with the polymer can be accomplished in the following ways:
(A) Coating the discrete drug particles or drug-particle aggregates, agglomerates or flocs by:
(1) Spray drying: Finely divided drug particles are suspended in a solvent system in which the drug is not soluble containing the dissolved polymer and other agents, e.g., extenders, plasticizers, dyes, etc., in the drug/
polymer ratio from 1/99 to 99/1, followed by spray dry-ing. For example: Drug particles 0.2 to 10 microns in size and equal to the weight of polymer used are sus-pended in a solvent solution of polymer in such a con-centration so as to give a liquid viscosity suitable for atomizing. The drug-polymer mixture is spray-dried using conventional methods of atomizing, e.g., centrifugal wheel, pressure, and two-fluid nozzle using appropriate drying conditions and temperatures that do not exceed the softening point of the polymer and do not exceed the melting point or decomposition point of the drug. Sol vents useful in preparing solutions of the pol-ymers of --1~--the present invention include, but are not limited to, hexafluoroisopropyl alcohol, hexafluoroacetone, trichloro-ethane, tetrachloroethane, trifluoroacetone, toluene, di-- chloroethane, chloroform, and methylene chloride.
(2) Pan coating or fluid-bed coating: Place granules or pellets, 5 microns to 20 mm, preferably between 0.25 and 10 mm diameter, in a rotating coating pan or fluid-bed drier, and apply polymer (dissolved in a carrier to a suitable viscosity for spraying) by spraying until a suitable coating quantity has been deposited to give the required release-rate characteristics. For example:
granules of drug are prepared b-~ extrusion of a wet granu-lation or other suitable methods known to the art, and dried. 16-to-4Q Mesh granules are placed in a rotating coating pan and a solution of polymer, dissolved in a suit-able nonaqueous volatile solvent, is sprayed onto the mov-ing granules with a continuous fine spray under conditions known to the art, until a coating giving the desired re-lease rate has been applied. The granules are then dried.
(3) Microencapsulation: Suspend drug particles, granules or pellets (.1 to 2000 microns diameter) in a solvent system in which the drug is not soluble, and which contains the polymer in solution. Add an agent incompatible with the polymer-solvent system, such as an incompatible polymer, a nonsolvent for the polymer, or a salt, or vary conditions such as temperature and pressure~ One ox a combination of the above will pre-cipitate the polymer, coating the drug particles, granules or pellets.~ For example: 0.5 to 25 micron drug particles are suspended in a low viscosity solution of the polymer in a suitable solvent in which the drug is not soluble. A miscible solvent in which the polymer is not soluble, such as hexane, is then added slowly to precipitate the polymer. The coated particles are fil-tered and washed with hexane and allowed to dry. The lQ powder is stored for use in the suitable dosage form.
(B) Embedding The polymer or polymer mixture is melted and a nonheat-labile drug is suspended and thoroughly dispersed in the melt. The melt is congealed by spraying, or in a mass and ground into small particles to give a polymer matrix with the drug embedded. ~or example: the poly(alkylene oxalate) polymer is melted and 0.5-to-400-micron (preferably 0.5 to 25 micron) drug particles are suspend-ed and thoroughly dispersed in the molten polymer in a concentration necessary to give the desired release rate patterns. The polymer is solidified by cooling and ground into small pieces 1 to 200 microns in size.
(C) Intimate mixin~
The drug and polymer are dissolved in a common solvent and the solvent is removed in some suitable way ET~-432 ~lOQQ4Z
(spray-drying, flash-evaporation, etc.). For example:
the drug and polymer are dissolved in the solvent in a 1:1 ratio and to a concentration of 2~. The solvent is flash-evaporated and the resulting film is scraped from the flask and powdered.
The above sustained-release powder, granular or pellet forms may be included in the following type formulations:
(1) Suspensions: Active ingredients of low solubility which have been embedded in or coated with the polymer and are in a finely divided state, 200 microns diameter or less, preferably S0 microns or less, may be sus-pended in a suitable pharmaceutical vehicle for injec-tion. This vehicle may also contain suspending and thickening agents, e.g., methyl cellulose, and preserva-tives. These ingredients are combined to give a stable suspension which will release the active ingredient over the time period desired.
(2) Emulsions: Active inqredients insoluble in oil in fine powder form, preferably 10 microns or less, are tnoroughly dispersed in a suitable oil, which is, in turn, emulsi~ied in an external aqueous phase (oil in water) using suitable emulsifying agents, e.g., tri-ethanolamine oleate, polyoxyethylene sorbitan monooleate, acacia, gelatin, etc. The aqueous ?hase may also con-tain agents such as ?rotective colloids and 2reserva-tives, ~ormulated to give a stable emulsion which will ET~-432 ~10QQ42 provide a controlled release of the active ingredient over the time period desired.
(3) Aqueous suspensions: The acti~e ingredient em-bedded and/or coated with the polymer in a particle S size no greater tllan 200 microns and preferably no grea~er than 50 microns is suspended in an aqueous solu-tion which may contain thickening agents, e.g., carboxy-methylcellulose; preservatives, e.g., phenol; suspending agents, e.g., oolyvinylpyrrolidone; surface active agents; buffers and dextrose or saline to adjust for isotonicity.
(4) ~onaqueous suspensions: Lhe active ingredient em-bedded and/or coated with the polymer in a particle size usually no greater than 200 microns and preferably no greater than 50 microns is suspended in a suitable oil, etc. The suspension may contain presérvatives, e.g., chlorbutanol or methylparaben ana ?ropylparaben mixtures, and suspendlng agents such as aluminum l~ono-stearate.
In both the aqueous and nonaqueous preparations, the final product is sterilized by ~eat, radiation, ethylene oxide or other suitable means prior to use.
The use of absorbable polymer-drug formulations in the controlled administration of fertility controL agents over ~100Q42 extended periods of time is well-known. U.S. Patent No.
3,773,919, for example, describes the combination of poly-L-lactide polymers with endocrine agents such as 17 ~-estradiol;
2q, 17a-diethynyl-A-nor-S~-androstane-2p,17~-diol; 17~-estra-S diol; 6,6-difluoro-17d-ethynyl-17~-hydroxyestr-4-en-3-one;
and 17~-hydroxyestr-4-en-3-one adamantane-l'-methanolcarbonate.
The poly(alkylene oxalate) polymers of the present invention are effectively substituted for the poly-L-lactide polymers of U.S.
Patent No. 3,?73,919 to obtain an alternative polymer-drug com-position of similar effect.
Classes of drug which may be specifically mentioned in-clude agents affecting the central nervous system, e.g., narcot-ics, such as, for example, morphine; narcotic antagonists, such as naloxone; antipsychotic agents, such as chlorpromazine and molindone; antianxiety agents, such as sodium pentobarbital, antidepressants, such as imipramine hydrochloride; stimulants, such as methyl phenadate and nikethamide; hallucinogens; anal-gesics, such as numorphan, meperidine, and morphine; and anorexigenic agents.
Other classes are pharmacodynamic agents, e.g., anti-hypertensive agents as reserpine, and chlorisondamine chloride, and antianginal agents, such as papaverine, and drugs ~or therapy ll~Q0~2 of pulmonary disorders, such as theophylline ethylenediamine salt and epinephrine. Additional classes are chemotherapeutic agents, e.g., antiviral; antiparasitic, such as emetine hydro-chloride and stibophen; antifungal agents, such as cycloheximide;
and antineoplastic agents, such as triethylene thiophosphoramide;
agents affecting metabolic diseases and endocrine functions, e.g.
prostaglandins; athersclerosins, such as heparin; steroids and biologically related compounds; polypeptides, such as bacitracin, polymixin B sulfate, and sodium colistimethate; natural and synthetic hormones, such as estradiol dipropionate, progesterone, and hydroxy progesterone caproate; steroid and nonsteriodal anti-inflammatory agents, such as gold sodium thiomalate and hydro-cortisone sodium succinate; and agents affecting thrombosis, such as crystalline trypsin; vitamins, such as vitamin B12; anti-epilepsy agents, such as phenobarbital; and the like. It should be understood that the specific drugs mentioned by name are illustrative and not limitative.
Endrocrine agents comprise a particularly useful class of compounds in this învention and can be defined either as natural hormones or as synthetic drugs that to some extent act like, or antagonize, natural hormones. Endocrine agents include, but are not limited to, both steroids and nonsteroids that func-tion as fertility-control agents; progestogens, estrogens, andro-gens, antiandrogens, corticoids, anabolic agents, and anti-inflammatory agents.
Examples of specific endocrine agents that can be used in the formulations of the invention are set forth in U.S. Patent No. 3,773,919, particularly Columns 3 to 7.
ll~QQ`~2 ETH-432 The Absorbable Polymer Polymers useful in the preparation of polymer-drug compounds of the present invention are comprised of units having the general formula:
O O
Il 11 ~ R - O - C - C ~ ~n wherein R is a C3 to C16 alkylene, st preferably C4 to C10 S alkylene, and n is the degree of polymerization resulting in a polymer having an inherent viscosity of at least 0.20 determined at 25C on a 0.1 g/dl solution of polymer in CHC13 or hexafluoro-isopropanol.
Alkylene oxalate polymers of the present invention are conveniently prepared by an ester interchange reaction between an alkylene diol and a lower ester of oxalic acid in the pres-ence of an ester interchange catalyst. The diol is preferably a C3 to C16 alkylene diol, and the ester of oxalic acid prefer-ably diethyl oxalate. The ester interchange is preferably con-ducted in two stages wherein the reactants are first heated with stirring under a nitrogen atmosphere to form a prepolymer with the removal of ethanol, followed by postpolymerization under heat and reduced pressure to obtain a final polymer of the desired molecular weight.
The preparation of useful polymers of alkylene oxalate is further illustrated by the following examples. The following analytical methods were used to obtain the data reported in the .
ll~)QQ42 examples. Inherent viscosity (~inh) of polymer was determined at 25C on a 0.1 g/dl solution of polymer in chloroform or hexa-fluoroisopropynol (HFIP). A DuPont 990 DSC apparatus was used to determine the melting temperatures (Tm) of polymer in nitrogen, using a 4 mg sample and a heating rate of 10 or 20C/min as specified. Crystallinity was determined by the method of Hermans and Weidinger and the diffractometer patterns were resolved with a DuPont 310 curve analyzer.
In vitro hydrolysis of polymer discs (about 1.2 g, 2.2 cm diameter)` and monofilaments (8-25 mil) were conducted in a phos-phate buffer of pH 7.25 at 37C.
In vivo absorption (muscle) was demonstrated by melt extruding the polymer into filaments and implanting two 2 cm seg-ments of a filament into the left gluteal muscles of female Long-Evans rats. The implant sites were recovered after periods of60, 90, and 120 and 180 days and examined microscopically to de-termine the extent of absorption. In vivo absorption (subcutane-ous) is a nonhistological technique in which continuous observa-tion of the biological degradation of segments of the filament were made by implanting two filaments, 2 cm long, into the abdomi-nal subcutis of young female rats. The implants are readily visi-ble when the skin is wetted with propylene glycol and extent of absorption can be determined by subjective visual examination.
EXAMPLES
General Polymerization Procedure Diethyl oxalate was heated with a selected diol in a mechanically-stirred reactor using a stannous alkanoate or an organic titanate as a catalyst. The reaction was conducted _g_ llO~Q42 under a nitrogen atmosphere at suitable temperatures until a substantial portion of the calculated amount o~ ethanol was ob-tained. Postpolymerization of the resulting prepolymer was then continued under reduced pressure using a suitable heating scheme.
At the end of the postpolymerization period, the molten polymer was allowed to cool slowly at room temperature, isolate~, ground and redried at 25 to 80C (depending on the polymer Tm) - in vacuo for at least one day. Detailed experimental conditions for the preparation of representative samples of linear poly-alkylene oxalates and important properties of the resulting poly-mers are presented below.
Poly(trimethylene oxalate) Distilled 1,3-propanediol (17.48 g, 0.23 mole) and diethyl oxalate (29.2 g, 0.2 mole) were mixed with a catalytic amount of stannous oxalate (4.1 mg, 0.02 mmole) under nitrogen.
The mixture was heated with stirring while allowing the result-ing ethanol to distill at 150, 120 and liOC for 0.5, 2 and 4 hours, respectively. The resulting polymer was then cooled to about 100C and the pressure was reduced to 0.1 mm. The poly-merization was continued ln vacuo at 150, 160, 180 and 200C
for 1, 3, l and 2 hours, respectively. The polymeric product was recovered as a clear, soft materiai.
Polymer Characterization ~inn in CHC13 = 0.57;
DSC ~20C/min): Tg = -iC
~lOQ~4Z
Poly(tetramethylene oxalate) Diethyl oxalate (36.5 g, 0.25 mole) was mixed with 1,4-butanediol (45 g, 0.5 mole) and a 1 percent solution of tetrakis(2-ethylhexyl) titanate (TOT) catalyst (1 ml, 0.012 mmole) and transferred to a resin kettle under a dry nitrogen atmosphere.
A prepolymer was formed by heating the reaction mixture under a nitrogen atmosphere for 2 hours each at 140 and 160C while al-lowing the formed ethanol to distill. The mixture was then heated under reduced pressure (2-3 mm Hg) at '60 and 180C for 20 and 2 hours, respectively. The polymer melt was slow-cooled, quenched in liquid nitro~en, isolated and ground. The ground polymer was redried at room temperature, in vacuo.
Polymer Characterization ~inh in HFIP = o.g5 DSC (20C/min): Tg = 4 5; Tc = 22; Tm = 105C
In vivo properties: Subcutaneous implantation of 12.9 mil filaments in rats indicated that 50 per-cent of their apparent mass was absorbed in the first 9 days, and 10 percent remained after 15 days, and absorption was substantially complete after 28 days.
Q4~
EX~MPLE 3 Poly(hexamethylene oxalate) Distilled diethyl oxalate (73.1 g, 0.500 mole~ was mixed with 1,6-hexanediol (61.2 g, 0.519 mole) and stannous octoate catalyst (0.33 M in toluene; 0.3 ml, 0.1 mmole) under a S dry nitrogen atmosphere in a glass reactor equipped with a mechanical stirrer. A prepolymer was formed by heating the mix-ture at 120C for 2 hours and then at 160C for 3 hours under nitrogen at l atmosphere while allowing the formed ethanol to distill. The prepolymer was then heated for one hour in vacuo (0.1 mm Hg) at 80 and then 90C. The postpolymerization of the polymer melt was completed by heating at 100, 115, 135, 150, 170, 190 and 200C for 2, 1, 1.5, 4, 6, 1 and 6.5 hours, re-spectively. The polymer was allowed to cool at room temperature, quenched in liquid nitrogen, isolated and ground. The ground polymer was dried in vacuo at room temperature.
Polymer Characterization ~inh in CHC13 = 0.83 DSC (10C/min): Tm = 70C
In vivo evaluation: Subcutaneous implantation of 8.7 mil filaments in rats indicated that ab-sorption of the fiber was about 20% complete after 42 days, and that after 121 days absorption was substantially complete.
Poly(octamethylene oxalate) Using a similar system to that of Example 3, distilled diethyl oxalate (109.6 g, 0.750 mole), distilled 1,8-octanediol (113.6 g, 0.777 mole) and stannous octoate cataLyst (0.33 M in toluene - O.455 ml, 0.150 mmole) were mixed under a dry nitrogen atmosphere in a glass reactor equipped with a mechanical stirrer.
A prep~lymer was formed by heating the mixture at 120C for 12 hours under nitrogen while allowing the formed ethanol to distill. Prior to postpolymerization, the product was heated for 1 hour at 90C and 0.1 mm Hg. The postpolymerization of the stirred polymer melt was completed by heating at 110, 135, 150, 170 and 200C for 3.5, 2.5, 4.5, 0.5 and 5 hours, respectively at 0.1 mm Hg. The polymer was cooled, quenched in liquid nitro-gen, isolated, gxound and dried in vacuo at room temperature.
The polymer was then heated at 60C in vacuo for one hour and finally at 200C for 6 hours to yield the final product.
Polymer Characterization ~inh in CHC13 = 0.88 DSC (10C/min): Tm = 75C
In vivo evaluation: Filaments (8.8 mil) im-planted into the gluteal muscles of rats showed no evidence of absorption up to the 42nd day.
After 119 days, there was evidence of minimal ab-sorption of some of the filaments.
E~YAMPLE 5 Poly(decamethylene oxalate) l,10-Decanediol (87.1 g, 0.5 mole) was mixed with di-ethyl oxalate (58.4 g, 0.4 mole) and a solution of TOT catalyst in toluene (0.012 mmole) under a nitrogen atmosphere. The re-action mixture was heated with stirring while allowing the re-sulting ethanol to distill at 120, 130 and 140C for 4, 2.5 and 2 hours respectively. The pressure was then reduced to 0.5 mm while heating to 190C for 20 minutes. The polymerization was continued ln vacuo at 190 and 210C for 4 and 13 hours, respec-tively. The polymer was recovered and characterized as follows:
Polymer Characterization ~inh in CHC13 = 0.45 DSC (10C/min): Tm = 77.5C
In vitro hydrolysis data: Melt extruded filaments had a weight loss of 1, 11, 38 and 62 percent after 6, 17, 44 and 177 days, respectively.
110~0~2 EX~IPLE 6 Poly(dodecamethylene oxalate) Distilled diethyl oxalate (14.6 g, 0.100 mole) was mixed with 1,12-dodecanediol (20.8 g, 0.103 mole) and stannous octoate catalyst (0.33 M in toluene - 0.061 ml, 0.02 mmole) under a dry nitrogen atmosphere in a glass reactor equipped for magnetic stirring. The prepolymer was formed after heating thè
mixture at 120C for 3 hours and 160C for 2 hours under nitro-gen at 1 atmosphere while allowing the formed ethanol to distill.
The mixture was then heated for 6 hours in vacuo (0.1 mm Hg) at 200C and then 210C for 2 hours. ~he postpolymerization of the polymer melt was completed after heating at 200C for 5 addi-tional hours. The polymer was cooled at room temperature and recovered.
Polymer Characterization ~inh in CHC13 = 0.57 DSC (20C/min): Tm = 31C
Poly(hexadecamethylene oxalate) Using a similar system to that used for Example 6, di-ethyl oxalate ~8.0 g, 0.055 mole), 1,16-hexadecanediol (14.6 g, 0.057 mole) and stannous octoate catalyst (0.33 ~ in toluene -0.033 ml, 0.01 mmole) were mixed under an atmosphere o dry nitrogen in a glass reactor equipped for ~agnetic stirring. The 110~042 prepolymer was formed after heating the mixture at 120C for 3 hours and then at 160C for 2 hours under nitrogen at 1 atmo-sphere while allowing the formed ethanol to distill. The mix-ture was then heated in vacuo at 0.1 mm Hg and at 200, 210 and 230C for 2, 2 and 3 hours, respectively. The postpolymerization of the stirred polymer melt was completed after heating at 200C
for 4 additional hours. The polymer was cooled and recovered.
Polymer Characterization ~inh in CHC13 = 0.45 DSC (20C/min): Tm = 95C, Tg = 40C
While the preceding examples have been directed to the preparation of specific homopolymers of poly(alkylene oxalates), these examples are for purposes of illustration only and are not limiting of the invention. Copolymers of C3 to C16 alkylene oxalate with up to about S0 percent by weight of one or more other monomers copolymerizable therewith to produce nontoxic and absorbable polymers, and physical mixtures of such homopolymers and copolymers, are likewise included within the present inven-tion. For example, mixtures of poly(alkylene oxalate) with polymers of lactide and/or glycolide are useful in the prepara-tion of compositions wherein the rate of absorption can be con-trolled by varying the relative proportions or the constituents.
.
Polymers of the present invention are adversely affected by moisture and are accordingly preferably prepared and stored -~ in a substantially moisture free environment and in hermetically sealed packages. Polymers which have been dried under vacuum at elevated temperatures and subsequently stored under vacuum or in . .
-~ a dry nitrogen en~ironment are found to be quite storage stable.
.
Preparation and Administration of `~ PolYmer-Drug Compositions ~
The drug and the polymer can be mixed, and the intimacy of mixing, particle size, and particle shape of the formulation ; ~ ,, .
~ ~can be varied, by any of a number of known methods. Intimacy of ~.-mixing, particle size, and particle shape of the formulations of the invention will depend~to some extent on the intended use.
- ~High homogeneity can be obtained by~mixing the components in the , molten~state, cooling, and grinding the resulting solid.- A
formulation so obtained is suitable for injection as 0.1 ~ to 1000 p particles suspended in saline solution or a pharmaceuti-cally acceptable oil. In some cases particles with cores of pure drug coated with various thic~nesses ~f polymer can be preferred . ~
for de}ayed~and/or sustained release. Relatively large pellets 10 mm) may be preferred for re~Jersible implantation in animals by surgery or by injection as projectiles. For this use adequate homogeneity can usually be realized by grlnding or milling the drug and the polymer together be~ore forming pellets under pres-sure. Known techniques of encapsulation,including microencapsu-lation, can be used to mix the polymer and the drug. The .
11~QQ42 formulations of this invention provide a slow, steady release of drug in contradistinction to conventional preparations which generally produce a rapid surge followed by a fairly quick decline in drug effect.
Polymer-drug mixtures of the invention may contain pharmaceutically acceptable inert additives such as plasticizers.
Typical plasticizers are Carbowax ~ polyethylene glycols, glycer-ides and ethylcellulose.
The relative proportions of the drug and poly(alkylene oxalate) polymer can be varied over a wide range depending on the desired effect. Since the drug will be released over an ex-tended period of time, the quantity of drug may be greater than the conventional single dose and the polymer must not break down or become absorbed by the body so rapidly as to release undue quantities of drug. The polymer-drug composition may range from 1 percent of drug and 99 percent of the polymer to 99 percent of drug and 1 percent of the polymer. Preferred compositions include 1 part of drug and from 4 to 20 parts of polymer.
These formulations can be injected as fluid suspensions by syringe into subcutaneous cellular tissue or muscular tissue, or implanted in pellet form subcutaneously or intramuscularly.
Liquid vehicles useful for suspensions of the drug-polymer formulation include water or aqueous solutions such as normal sodium chloride solution or sodium carboxymethyl cellulose in water. Oils such as sesame oil or peanut oil containing, if desired, dissolved adjuvants such as benzyl alcohol, may also be used to prepare suspensions of the polymer-drug formulation.
11000~2 ~ L}~ 2 Drug compounds of the classes mentioned earlier ma~ be coated, embedded, or intimately mixed in or with a matrix of one or a combination of different chain-length biodegradable poly-mers to give a drug-polymer mixture which will provide a control-led sustained release of the drug compound over a period of 8 hours to 2 months or longer when administered parenterally.
Coating, embedding or intimately mixing the drug com-pound with the polymer can be accomplished in the following ways:
(A) Coating the discrete drug particles or drug-particle aggregates, agglomerates or flocs by:
(1) Spray drying: Finely divided drug particles are suspended in a solvent system in which the drug is not soluble containing the dissolved polymer and other agents, e.g., extenders, plasticizers, dyes, etc., in the drug/
polymer ratio from 1/99 to 99/1, followed by spray dry-ing. For example: Drug particles 0.2 to 10 microns in size and equal to the weight of polymer used are sus-pended in a solvent solution of polymer in such a con-centration so as to give a liquid viscosity suitable for atomizing. The drug-polymer mixture is spray-dried using conventional methods of atomizing, e.g., centrifugal wheel, pressure, and two-fluid nozzle using appropriate drying conditions and temperatures that do not exceed the softening point of the polymer and do not exceed the melting point or decomposition point of the drug. Sol vents useful in preparing solutions of the pol-ymers of --1~--the present invention include, but are not limited to, hexafluoroisopropyl alcohol, hexafluoroacetone, trichloro-ethane, tetrachloroethane, trifluoroacetone, toluene, di-- chloroethane, chloroform, and methylene chloride.
(2) Pan coating or fluid-bed coating: Place granules or pellets, 5 microns to 20 mm, preferably between 0.25 and 10 mm diameter, in a rotating coating pan or fluid-bed drier, and apply polymer (dissolved in a carrier to a suitable viscosity for spraying) by spraying until a suitable coating quantity has been deposited to give the required release-rate characteristics. For example:
granules of drug are prepared b-~ extrusion of a wet granu-lation or other suitable methods known to the art, and dried. 16-to-4Q Mesh granules are placed in a rotating coating pan and a solution of polymer, dissolved in a suit-able nonaqueous volatile solvent, is sprayed onto the mov-ing granules with a continuous fine spray under conditions known to the art, until a coating giving the desired re-lease rate has been applied. The granules are then dried.
(3) Microencapsulation: Suspend drug particles, granules or pellets (.1 to 2000 microns diameter) in a solvent system in which the drug is not soluble, and which contains the polymer in solution. Add an agent incompatible with the polymer-solvent system, such as an incompatible polymer, a nonsolvent for the polymer, or a salt, or vary conditions such as temperature and pressure~ One ox a combination of the above will pre-cipitate the polymer, coating the drug particles, granules or pellets.~ For example: 0.5 to 25 micron drug particles are suspended in a low viscosity solution of the polymer in a suitable solvent in which the drug is not soluble. A miscible solvent in which the polymer is not soluble, such as hexane, is then added slowly to precipitate the polymer. The coated particles are fil-tered and washed with hexane and allowed to dry. The lQ powder is stored for use in the suitable dosage form.
(B) Embedding The polymer or polymer mixture is melted and a nonheat-labile drug is suspended and thoroughly dispersed in the melt. The melt is congealed by spraying, or in a mass and ground into small particles to give a polymer matrix with the drug embedded. ~or example: the poly(alkylene oxalate) polymer is melted and 0.5-to-400-micron (preferably 0.5 to 25 micron) drug particles are suspend-ed and thoroughly dispersed in the molten polymer in a concentration necessary to give the desired release rate patterns. The polymer is solidified by cooling and ground into small pieces 1 to 200 microns in size.
(C) Intimate mixin~
The drug and polymer are dissolved in a common solvent and the solvent is removed in some suitable way ET~-432 ~lOQQ4Z
(spray-drying, flash-evaporation, etc.). For example:
the drug and polymer are dissolved in the solvent in a 1:1 ratio and to a concentration of 2~. The solvent is flash-evaporated and the resulting film is scraped from the flask and powdered.
The above sustained-release powder, granular or pellet forms may be included in the following type formulations:
(1) Suspensions: Active ingredients of low solubility which have been embedded in or coated with the polymer and are in a finely divided state, 200 microns diameter or less, preferably S0 microns or less, may be sus-pended in a suitable pharmaceutical vehicle for injec-tion. This vehicle may also contain suspending and thickening agents, e.g., methyl cellulose, and preserva-tives. These ingredients are combined to give a stable suspension which will release the active ingredient over the time period desired.
(2) Emulsions: Active inqredients insoluble in oil in fine powder form, preferably 10 microns or less, are tnoroughly dispersed in a suitable oil, which is, in turn, emulsi~ied in an external aqueous phase (oil in water) using suitable emulsifying agents, e.g., tri-ethanolamine oleate, polyoxyethylene sorbitan monooleate, acacia, gelatin, etc. The aqueous ?hase may also con-tain agents such as ?rotective colloids and 2reserva-tives, ~ormulated to give a stable emulsion which will ET~-432 ~10QQ42 provide a controlled release of the active ingredient over the time period desired.
(3) Aqueous suspensions: The acti~e ingredient em-bedded and/or coated with the polymer in a particle S size no greater tllan 200 microns and preferably no grea~er than 50 microns is suspended in an aqueous solu-tion which may contain thickening agents, e.g., carboxy-methylcellulose; preservatives, e.g., phenol; suspending agents, e.g., oolyvinylpyrrolidone; surface active agents; buffers and dextrose or saline to adjust for isotonicity.
(4) ~onaqueous suspensions: Lhe active ingredient em-bedded and/or coated with the polymer in a particle size usually no greater than 200 microns and preferably no greater than 50 microns is suspended in a suitable oil, etc. The suspension may contain presérvatives, e.g., chlorbutanol or methylparaben ana ?ropylparaben mixtures, and suspendlng agents such as aluminum l~ono-stearate.
In both the aqueous and nonaqueous preparations, the final product is sterilized by ~eat, radiation, ethylene oxide or other suitable means prior to use.
The use of absorbable polymer-drug formulations in the controlled administration of fertility controL agents over ~100Q42 extended periods of time is well-known. U.S. Patent No.
3,773,919, for example, describes the combination of poly-L-lactide polymers with endocrine agents such as 17 ~-estradiol;
2q, 17a-diethynyl-A-nor-S~-androstane-2p,17~-diol; 17~-estra-S diol; 6,6-difluoro-17d-ethynyl-17~-hydroxyestr-4-en-3-one;
and 17~-hydroxyestr-4-en-3-one adamantane-l'-methanolcarbonate.
The poly(alkylene oxalate) polymers of the present invention are effectively substituted for the poly-L-lactide polymers of U.S.
Patent No. 3,?73,919 to obtain an alternative polymer-drug com-position of similar effect.
Claims (12)
1. In a pharmaceutical depot composition for parenteral administration of effective amounts of a drug released slowly over an extended period of time which comprises a combination of a) from 1 to 99 percent by weight of composition of a drug in an effective depot amount greater than the single dose amount, and b) a solid, absorbable polymer which is nonreactive toward body tissue and which undergoes biodegrada-tion in the presence of body fluids into products which are metabolized or excreted by the body with-out adverse body reaction, the improvement comprising employing as said absorbable polymer a poly(alkylene oxalate) having the formula wherein R is a C3 to C16 alkylene and n is the degree of poly-merization resulting in a polymer inherent viscosity of at least 0.20 determined at 25°C on a 0.1 g/dl solution of polymer in CHCl3 or hexafluoroisopropanol.
2. The composition of Claim 1 wherein R is a C4 to C10 alkylene.
3. The composition of Claim 1 wherein the ratio of drug to polymer is from 1:4 to 1:20 by weight.
4. The composition of Claim 1 wherein the drug is an endocrine agent.
5. The composition of Claim 4 wherein the drug is a fertility control agent.
6. The composition of Claim 1 in the form of injectable particles dispersed in normal saline or a pharmaceutically ac-ceptable oil.
7. The composition of Claim 6 wherein the injectable particles range in size from about 0.1 to 200 microns.
8. The composition of Claim 1 in the form of pellets for implantation.
9. The composition of Claim 1 wherein the polymer is a mixture of a poly(alkylene oxalate) and at least one other ab-sorbable polymer.
10. The composition of Claim 9 wherein the other ab-sorbable polymer is selected from the group consisting of homo-polymers and copolymers of lactide and glycolide.
11. The composition of Claim 1 wherein the absorb-able polymer is a copolymer of C3 to C16 alkylene oxalate and at least one other monomer copolymerizable therewith and resulting in an absorbable copolymer.
12. The composition of Claim 11 wherein said other monomer is selected from the group consisting of lactide and glycolide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US837,076 | 1977-09-28 | ||
| US05/837,076 US4186189A (en) | 1977-09-28 | 1977-09-28 | Absorbable pharmaceutical compositions based on poly(alkylene oxalates) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1100042A true CA1100042A (en) | 1981-04-28 |
Family
ID=25273452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA304,044A Expired CA1100042A (en) | 1977-09-28 | 1978-05-25 | Absorbable pharmaceutical compositions based on poly(alkylene oxalates) |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4186189A (en) |
| JP (1) | JPS5452721A (en) |
| AU (1) | AU518227B2 (en) |
| CA (1) | CA1100042A (en) |
| DE (1) | DE2842089A1 (en) |
| FR (1) | FR2404436A1 (en) |
| GB (1) | GB1592829A (en) |
| ZA (1) | ZA785491B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4130639A (en) * | 1977-09-28 | 1978-12-19 | Ethicon, Inc. | Absorbable pharmaceutical compositions based on isomorphic copolyoxalates |
| US4650665A (en) * | 1985-02-08 | 1987-03-17 | Ethicon, Inc. | Controlled release of pharmacologically active agents from an absorbable biologically compatible putty-like composition |
| US4568536A (en) * | 1985-02-08 | 1986-02-04 | Ethicon, Inc. | Controlled release of pharmacologically active agents from an absorbable biologically compatible putty-like composition |
| US5187150A (en) * | 1987-10-14 | 1993-02-16 | Debiopharm S.A. | Polyester-based composition for the controlled release of polypeptide medicinal substances |
| CH672887A5 (en) * | 1987-10-14 | 1990-01-15 | Debiopharm Sa | |
| PH30995A (en) * | 1989-07-07 | 1997-12-23 | Novartis Inc | Sustained release formulations of water soluble peptides. |
| US5538739A (en) * | 1989-07-07 | 1996-07-23 | Sandoz Ltd. | Sustained release formulations of water soluble peptides |
| CA2133756C (en) * | 1992-04-06 | 2000-02-22 | Robert A. Ersek | Treatment of urological and gastric fluid reflux disorders by injection of micro particles |
| DE69924749T2 (en) | 1998-11-20 | 2006-04-27 | The University Of Connecticut, Farmington | Generically integrated implantable potentiostat remote sensing device for electrochemical probes |
| US20030099682A1 (en) * | 1998-11-20 | 2003-05-29 | Francis Moussy | Apparatus and method for control of tissue/implant interactions |
| DE10315640A1 (en) * | 2003-04-04 | 2004-10-14 | Ignatov, Konstantin | Process for the controlled release of components into a solution |
| US20060286138A1 (en) * | 2003-04-10 | 2006-12-21 | Malshe Vinod C | Novel biodegradable aliphatic polyesters and pharmaceutical compositions and applications thereof |
| US20050271727A1 (en) * | 2004-06-07 | 2005-12-08 | Callisyn Pharmaceuticals, Inc. | Biodegradable and biocompatible crosslinked polymer hydrogel prepared from PVA and/or PEG macromer mixtures |
| EP1781264B1 (en) * | 2004-08-04 | 2013-07-24 | Evonik Corporation | Methods for manufacturing delivery devices and devices thereof |
| EP2222281B1 (en) | 2007-12-20 | 2018-12-05 | Evonik Corporation | Process for preparing microparticles having a low residual solvent volume |
| US20090181068A1 (en) | 2008-01-14 | 2009-07-16 | Dunn Richard L | Low Viscosity Liquid Polymeric Delivery System |
| BR112012006443A2 (en) * | 2009-09-22 | 2017-07-25 | Evonik Degussa Corp | implant devices that feature variable loading configurations of bioactive agents |
| ES2675307T3 (en) | 2011-12-22 | 2018-07-10 | Centre Hospitalier Universitaire Vaudois (Chuv) | Selective plasma activation for medical implants and wound healing devices |
| US9717583B2 (en) | 2014-03-13 | 2017-08-01 | Cell and Molecular Tissue Engineering, LLC | Sensors, cannulas, collars and coated surgical mesh, and corresponding systems and methods |
| CA2935016C (en) * | 2013-12-24 | 2019-11-05 | Toyo Seikan Group Holdings, Ltd. | Polyoxalates and a process for the production thereof |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2012267A (en) * | 1929-08-01 | 1935-08-27 | Du Pont | Alkylene ester of polybasic acids |
| US2071251A (en) * | 1931-07-03 | 1937-02-16 | Du Pont | Fiber and method of producing it |
| US2071250A (en) * | 1931-07-03 | 1937-02-16 | Du Pont | Linear condensation polymers |
| US2111762A (en) * | 1936-01-06 | 1938-03-22 | Ellis Foster Co | Resinous compositions from oxalic acid and polyhydric alcohols and process of makingsame |
| BE582184A (en) * | 1958-09-04 | |||
| US3773919A (en) * | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| US3755558A (en) * | 1971-02-23 | 1973-08-28 | Du Pont | Polylactide drug mixtures for topical application atelet aggregation |
| FR2208687B1 (en) * | 1972-12-01 | 1976-07-23 | Rhone Poulenc Sa | |
| AR205997A1 (en) * | 1973-11-21 | 1976-06-23 | American Cyanamid Co | NORMALLY SOLID BIODEGRADABLE AND HYDROLYZABLE POLYESTER RESIN |
| US3997512A (en) * | 1973-11-21 | 1976-12-14 | American Cyanamid Company | High molecular weight polyester resin, the method of making the same |
| US3978203A (en) * | 1974-07-12 | 1976-08-31 | Dynatech Corporation | Sustained release of pharmaceuticals from polyester matrices |
| US4105034A (en) * | 1977-06-10 | 1978-08-08 | Ethicon, Inc. | Poly(alkylene oxalate) absorbable coating for sutures |
| US4130639A (en) * | 1977-09-28 | 1978-12-19 | Ethicon, Inc. | Absorbable pharmaceutical compositions based on isomorphic copolyoxalates |
-
1977
- 1977-09-28 US US05/837,076 patent/US4186189A/en not_active Expired - Lifetime
-
1978
- 1978-05-25 GB GB22606/78A patent/GB1592829A/en not_active Expired
- 1978-05-25 CA CA304,044A patent/CA1100042A/en not_active Expired
- 1978-06-02 AU AU36834/78A patent/AU518227B2/en not_active Expired
- 1978-07-18 JP JP8684878A patent/JPS5452721A/en active Pending
- 1978-09-27 ZA ZA785491A patent/ZA785491B/en unknown
- 1978-09-27 DE DE19782842089 patent/DE2842089A1/en not_active Withdrawn
- 1978-09-27 FR FR7827665A patent/FR2404436A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| AU3683478A (en) | 1979-12-06 |
| JPS5452721A (en) | 1979-04-25 |
| FR2404436A1 (en) | 1979-04-27 |
| ZA785491B (en) | 1980-05-28 |
| AU518227B2 (en) | 1981-09-17 |
| FR2404436B1 (en) | 1983-05-27 |
| GB1592829A (en) | 1981-07-08 |
| DE2842089A1 (en) | 1979-04-05 |
| US4186189A (en) | 1980-01-29 |
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