CA1225030A - Crosslinked, porous polymers for controlled drug delivery - Google Patents
Crosslinked, porous polymers for controlled drug deliveryInfo
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- CA1225030A CA1225030A CA000460855A CA460855A CA1225030A CA 1225030 A CA1225030 A CA 1225030A CA 000460855 A CA000460855 A CA 000460855A CA 460855 A CA460855 A CA 460855A CA 1225030 A CA1225030 A CA 1225030A
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- 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Abstract
CROSSLINKED, POROUS POLYMERS FOR CONTROLLED DRUG DELIVERY
ABSTRACT OF THE DISCLOSURE
A controlled-release, drug-delivery composition which comprises (A) a crosslinked copolymer, capable of swelling in ethanol to give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer con-taining no more than 20% by weight of water, where the swelling ratio (% ethanol: % water) is 2:1 to 22:1, which comprises the copolymerization product of (a) 50 to 99% by weight of said copolymer of a water-insoluble monoolefinic monomer or (a) with 0 to 45% by weight of total monomers of a water-soluble mono-olefinic monomer, with (b) 50 to 1% by weight, but no more than 20 mol % of a divinyl or polyvinyl crosslinking agent; and (B) an effective amount of a pharmaceutical medicament is useful for the controlled and prolonged release of drugs when taken orally.
ABSTRACT OF THE DISCLOSURE
A controlled-release, drug-delivery composition which comprises (A) a crosslinked copolymer, capable of swelling in ethanol to give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer con-taining no more than 20% by weight of water, where the swelling ratio (% ethanol: % water) is 2:1 to 22:1, which comprises the copolymerization product of (a) 50 to 99% by weight of said copolymer of a water-insoluble monoolefinic monomer or (a) with 0 to 45% by weight of total monomers of a water-soluble mono-olefinic monomer, with (b) 50 to 1% by weight, but no more than 20 mol % of a divinyl or polyvinyl crosslinking agent; and (B) an effective amount of a pharmaceutical medicament is useful for the controlled and prolonged release of drugs when taken orally.
Description
1~2~1~3C~
Case ~-14544/CGV 1047/+
CROSS LINKED, POROUS POLYMERS FOR CONTROLLED DRUG DELIVERY
In the pharmaceutical industry much work has been devoted during recent years to improving the effectiveness, safety and practicality of orally administered drugs. This invention is specifically directed toward the goal of prolonging the release of an orally taken drug over a period of several hours. Such a prolonged release has the following advantages: peak blood levels of the drug, which sometimes represent toxic levels, are avoided since not all the drug it released into the stomach at the same time; secondly, drug concern-tractions in the blood are maintained for a longer time within the therapeutic range, thereby increasing the overall effectiveness of the drug and reducing the overall dose-size necessary for treatment;
thirdly, drugs which would have to be taken in conventional form several times daily for the treatment of chronic diseases, can be administered in once- or twice-a-day dose forms, which are safer and more convenient for the patient.
Conventional dose forms of orally taken drugs are tablets or pills in which the drug is compounded with a water soluble gum or polyp saccharine which quickly dissolves or disintegrates in the stomach.
An extension of this technology are tablet coatings and multiple coatings around tablets which retard the disintegration and disk solution speed. Material and synthetic polymers with different molecular weight and water solubilities are used for this purpose.
U.S. Patent No. 3,432,592 describes an advanced formulation of this sort, which consists of inJection-molded water soluble polymers, like polyvinyl alcohol), containing drugs dispersed therein.
Case ~-14544/CGV 1047/+
CROSS LINKED, POROUS POLYMERS FOR CONTROLLED DRUG DELIVERY
In the pharmaceutical industry much work has been devoted during recent years to improving the effectiveness, safety and practicality of orally administered drugs. This invention is specifically directed toward the goal of prolonging the release of an orally taken drug over a period of several hours. Such a prolonged release has the following advantages: peak blood levels of the drug, which sometimes represent toxic levels, are avoided since not all the drug it released into the stomach at the same time; secondly, drug concern-tractions in the blood are maintained for a longer time within the therapeutic range, thereby increasing the overall effectiveness of the drug and reducing the overall dose-size necessary for treatment;
thirdly, drugs which would have to be taken in conventional form several times daily for the treatment of chronic diseases, can be administered in once- or twice-a-day dose forms, which are safer and more convenient for the patient.
Conventional dose forms of orally taken drugs are tablets or pills in which the drug is compounded with a water soluble gum or polyp saccharine which quickly dissolves or disintegrates in the stomach.
An extension of this technology are tablet coatings and multiple coatings around tablets which retard the disintegration and disk solution speed. Material and synthetic polymers with different molecular weight and water solubilities are used for this purpose.
U.S. Patent No. 3,432,592 describes an advanced formulation of this sort, which consists of inJection-molded water soluble polymers, like polyvinyl alcohol), containing drugs dispersed therein.
- 2 - I
None of these methods works satisfactorily. Tablet disintegration is fast and poorly reproducible since it us to a large degree a function of physical motion in the stomach. Therefore,, polymeric dosage-fo DO were developed in which the drug-release is diffusion-controlled, independent of physical variables other than polymer compositions and morphology. In these dosage forms the polymer is passed through the body without degradation.
Examples of such a monolithic dose form with uniform drug concern-tractions are described in Australian Patent No. 16202, and in U.S. Patent No. 3,390,050, wherein hydrophilic polynler beads are synthesized in the presence of a drug. U.S. Patent No. 4,267,138 describes an oral dose form in which the release of an active ingredient is controlled by a coating surrounding drug containing particles, which are compressed into tablets. The coatings are complicated mixtures of plasticized synthetic polymers and water.
U.S. Patent No. 3,538,214 also describes coated tablets, in which the coating acts as a porous membrane, letting water pass through to dissolve the enclosed drug, which in turn diffuses to the outside.
Porous membranes are obtained and their porosity is controlled by addition of auxiliary, water-soluble substances to the coating material which are loaded out prior to drug-diffusion. Similar membrane enclosed oral dose forms are described in U.S. Patent Nos. 3,854,480, 3,993,072 and 4,244,941.
When used in combination with water-soluble drugs, the above mentioned membrane devices all have the drawback of uncontrollable expansions and breaking due to osmotic pressure build up. This problem was overcome by applying the osmotic pump principle, as described in J. Harm. Sat. 64, 1981 (1975). This consists of a Semite Doable membrane, which lets only water diffuse into the tablet to dissolve the drug, which in turn is pumped out through _ 3 _ 03~
a pinhole in the membrane. Although this method works well with moderately soluble drugs, it is less applicable to highly water-soluble ingredients because the osmotic pressure quickly become too high as the drug-reservoir is dissolved. As in all membrane devices, constant release is achieved only as long as an undissolved drug reservoir is present in the core. Another disadvantage of the osmotic pump is the high level drug concentration existing at the exit hole which can lead to irritation of the stomach wall.
The above mentioned monolithic polymer-drug compositions of U.S.
Patent No. 3,390,050 and Australian Relent No. 16202 do not have these disadvantages. In U.S. 3,390,050 no final polymer purification can be carried out since the drug is incorporated during synthesis.
Australian Patent No. 16202 describes the use of a water syllable poly(2-hydroxyethyl methacrylate) or copolymers of 2-hydroxyethyl methacrylate to imbibe drugs from an aqueous solution. The dried polymer-drug composite forms a controlled oral release device. A
similar approach, but using water-swellable polymers (hydrogels) which are themselves two-phase polymers and which exhibit a much wider range of swelling in water and organic solvents is described in U.S. Patent Nos. 4,192,827 and 4,136,250. Although in all these polymers certain drugs can be imbibed in sufficient amounts to make the manufacture of practical dosage forms possible, their relatively high degree of swelling in water (30 to 80%) is con-comitantly accompanied by a relatively low degree of swelling in organic solvents. Typically the ratio of % swelling in ethanol to % swelling in water for these hydrogels lies in the range ox L/l to 2/1.
Furthermore, in these hydrogen drug-carriers, as a high degree of swelling in water is accompanied by a high degree of swelling in organic solvents, concomitantly a low degree of swelling in water is accompanied by a similarly low degree of swelling in organic liquids like ethanol. This limited swelling ability of the hydrogels limits the amount of drug which can be imbibed into them from a drug solution, be it aqueous or organic in nature. If the polymer swells to a larger degree in a suitable organic solvent than in water, then higher drug-loadings can be achieved by loading from, for instance, ethanol/drug solutions than from aqueous solutions provided the drug is soluble in ethanol. The use of organic solvents to imbibe hydrogels with a drug for later release has also been described in U.S. 4,192,827.
It is an object of this invention to produce a controlled-release, drug delivery composition comprising an effective amount of a forum ceutical medicament in a polymer substrate which can swell in polar organic solvents to a much greater degree than conventional polymers used for drug-delivery and which therefore can be imbibed with active ingredients to a correspondingly high concentration while at the same time exhibiting only a moderate degree of swelling in water.
The ability of a polymer to absorb a large amount of water has always been considered a necessity for a polymeric orally used drug-delivery matrix. Uydrogels have therefore been the only materials previously used for this purpose. Drug diffusion through hydrophobic polymers is normally too slow to be of practical use in an oral drug-delivery. It is consistent with this explanation that hydrophobic polymer-medicament compositions have been used only as body implants where drug-delivery over several weeks or even months is desired and where the overall dose size is very low, as is the case, for instance, with steroids.
~2~25~
It has now very unexpectedly been discovered that polymers can be synthesized in aqueous suspension or in bulk which can swell in organic solvents such as ethanol to a much greater extent than conventional hydrogels, being capable of absorbing from 40 to 90%
by weight of ethanol and typically showing a ratio of swelling to ethanol: % water) of 3:1 to 9:1. Therefore these beads can be loaded from a drug solution in an organic solvent with a soluble drug to correspondingly much higher drug levels than can convention hydrogel-type polymeric drug-carriersO At the same time it has been discovered that even if the amount of water absorbed by the novel polymers is lower than that of conventional hydrogels, namely lying in the range of 2-20% by weight of water, they still satisfy the requirement of releasing imbibed drugs completely within one to six hours.
It is a further object of this invention to prepare copolymers which exhibit unexpectedly high degrees of swelling in organic solvents while their degree of swelling in water is only moderate or low. Therefore, they can imbibe large amounts of medicaments or other active ingredients from organic solutions, yet are ideally suited for the controlled and prolonged release of such active ingredients into an aqueous environment as an oral dosage in form of beads.
The instant invention pertains to a controlled-release, drug-delivery composition which comprises (A) a cross linked copolymer, capable of swelling in ethanol Jo give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer con-twining no more than 20% by weight of water, where the swelling ratio I% ethanol: % water) is 2:1 to 22:1, which copolymer is the copolymerization product of (a) 50 to 99% by weight of said copolymer of (a) a water-insoluble monoolefinic monomer, or mixture of said monomers, or a water-in-soluble monoolefinic monomer, or mixture of said monomers with 0 to 45% by weight of total monomers of (by) a water-soluble moo-olefinic monomer, or mixture of said water-soluble monomers, with (by 50 to 1% by weight of said copolymer of a Donnelly or polyvinyl cross linking agent having a molecular weight of 100 to 10,000, but where (b) is not more than 20 mow % of component I
(B) an effective amount of a pharmaceutical medicament.
Preferably the cross linked copolymer has a swelling ratio (% ethanol:
% water) of 3:1 to 15:1; most preferably 4:1 to 8:1.
In order to assure that the instant copolymers have high sealability in ethanol coupled with moderate sealability in water, it is preferable that at least a third by weight of the water-insoluble monomer of component (a) is a monomer with an alkyd group of 4 to 21 carbon atoms.
A preferred embodiment of the instant invention is a composition wherein the copolymer (A) is the copolymerization product of 75-98 by weight of component (a) and 25-2% by weight of component (b).
Another preferred embodiment of the instant invention is a compost-lion wherein component (a) comprises 70-95% by weight of water-in-soluble monomer (a) and 30-5% by weight of water-soluble monomer (by).
A particularly preferred embodiment is a composition wherein component (a) is 75-0% by weight of methyl acrylate, methyl methacrylate or mixture thereof, and 25-100% by weight of a C4-C10 alkyd acrylate or methacrylate, or mixture thereof.
~51~3~
The vinyl monomers (a) used to prepare the cross linked copolymers of the present invention can conveniently be divided into water-insoluble (a) and water-soluble (by) monomers. The water-insoluble comonomers include for employ: the acrylic- and methacrylic esters and asides of mandrake linear or branched alcohols with from 1 to 20 carbon atoms, and which alcohols may be aliphatic, cycle-aliphatic, or aromatic in nature. Examples are: methyl-, ethyl-, propel-, isopropyl-, n-, is-, and tertiary bottle-, Huxley-, ponytail-, 2-ethylhexyl-, n-octyl-, 1,1,3,3-trimethylbutyl, decal-, tridecyl-, hexadecyl-, Cyril-, cyclohexyl-, isobornyl-, dicyclopentadienyl-, methyl-, dicyclopentadienylethyl-; phenol-, bouncily-, methoxyethyl;
ethoxyethyl-, furfuryl-, glycidyl-, acrylate or methacrylate as well as the corresponding amine; and acrylonitrile.
Vinyl esters, such as: vinyl acetate, vinyl preappoint, vinyl buoyancy-ate.
Vinyl ethers such as: methyl-, propel-, bottle-, methoxyethyl-vinyl ether. Fumarate, Malta and itaconate divesters of the mandrake alcohol-residues mentioned above; styrenes ~-methylstyrene.
The monomers may be used alone or in combination with each other.
It is preferred that at least half of the water-insoluble monomers are monomers containing alkyd groups with at least 4 carbon atoms, such as bottle acrylate or methacrylate; 2-ethylhexyl acrylate or methacrylate; n-octyl acrylate or methacrylate; di-n-butyl fumarate;
bouncily methacrylate; vinyl bitterroot; 1,1,3,3-tetramethylbutyl-acrylamide- and methacrylamide.
Preferred water-insoluble comonomers are methyl methacrylate, n-butyl acrylate, n-butylmethacrylate, 2-ethylhexyl acrylate, n-octyl acrylate and n-octyl methacrylate, glycidyl methacrylate and vinyl acetate or mixtures thereof.
- 8 - ~25~3~
Compositions where 10-60% by weight of component (a is n-buty acrylate or 2-ethylhexyl acrylate are especially preferred.
The water-soluble monomer, (by), are preferably acrylic and/or methacrylic acid or the water-soluble derivatives thereof, such as hydroxyalkyl esters where alkyd is 2 to 4 carbon atoms, ego 2-hydroxyethyl, 3-hydroxypropyl, 2 hydroxypropyl or 2~3-dihydroxy-propel esters; also ethoxylated and polyethoxylated hydroxyalkyl esters such as esters of alcohols of the formula H0-C H -0-(CH2CH2-0) -H
where m represents 2 to 5 and n represents 1 to 20, or esters of analogous alcohols, wherein a part of the ethylene oxide units is replaced by propylene oxide units.
Also suitable are 3-(dimethylamino)-2-hydroxypropyl esters and asides.
Another class of suitable derivatives of such acids are their water-soluble asides, such as unsubstituted asides and asides substituted by lower hydroxyalkyl, lower oxaalkyl or lower dialkylaminoalkyl groups where alkyd it to 4 carbon atoms such as N-(hydroxymethyl)-acrylamide and -methacrylamide. N-(3-hydropropyl)acrylamide, No hydroxyethyl)methacrylamide and N-~l,l-dimethyl-2-(hydroxymethyl)-3-oxabutyl]acrylamide; water soluble hydrazine derivatives such as dimethyl-2-hydroxypropylamine methacrylimide and the corresponding derivatives of acrylic acid.
Also useful, in combination with comonomers, are the lower hydroxy~
alkyd malefic esters and vinyl ethers where alkyd is 2 to 4 carbon atoms, for instance, di-(hydroxyalkyl) Maltese, such as d;(2-hydroxy-ethyl) Malta, and ethoxylated hydroxyalkyl Maltese, hydroxyalkyl monomaleates, such as 2-hydroxyethyl monomaleate and alkoxylated hydroxyalkyl monomaleate together with vinyl ethers, vinyl esters, styrenes or generally any monomer which will easily copolymerize with ~25~33g~
_ 9 _ Maltese or fumarates; hydroxyalkyl vinyl ethers, such as 2-hydroxy-ethyl vinyl ether, 4-hydroxybutyl vinyl ether together with Maltese, forts, or generally all monomers which will easily copolymerize with vinyl ethers Other water-soluble comonomers useful in this invention are:
alkyd ethers of polyethoxylate hydroxyalkyl esters of acrylic and methacrylic acid, such as esters of alcohols of the formula H~-CmHm-O-(CH2~H2 on SHEA
where m = 2 to 5 and n = 4 to 20.
Dialkylaminoalkyl esters and asides, such as 2-(dimethylamino)ethyl or 2-(diethylamino)ethyl acrylate and methacrylate, as well as the corresponding asides; asides substituted by lower oxaalkyl or lower dialkylaminoal~yl groups, such as N-(l,l-dimethyl-3-oxa-butyl)acrylamide; water-soluble hydrazine derivatives, such as trialkylamine methacrylimide, e.g., triethylamine-methacrylimide and the corresponding derivatives of acrylic acid. Monoolefinic sulfonic acids and their salts, such as sodium ethylene sulfonate, sodium styrenes sulfonate and 2-acrylamido 2-methylpropanesulfonic acid; or monoole~inic derivatives of heterocyclic nitrogen-containing monomers, such as N-vinylpyrrole, N-vinylsuccinimide, l-vinyl-2-pyrrolidone, l-vinylimidazole, l-vinylindole, 2-vinylimidazole, 4(5)-vinylimidazole, 2-vinyl-1-methylimidaæole, 5-vinylpyrazoline,
None of these methods works satisfactorily. Tablet disintegration is fast and poorly reproducible since it us to a large degree a function of physical motion in the stomach. Therefore,, polymeric dosage-fo DO were developed in which the drug-release is diffusion-controlled, independent of physical variables other than polymer compositions and morphology. In these dosage forms the polymer is passed through the body without degradation.
Examples of such a monolithic dose form with uniform drug concern-tractions are described in Australian Patent No. 16202, and in U.S. Patent No. 3,390,050, wherein hydrophilic polynler beads are synthesized in the presence of a drug. U.S. Patent No. 4,267,138 describes an oral dose form in which the release of an active ingredient is controlled by a coating surrounding drug containing particles, which are compressed into tablets. The coatings are complicated mixtures of plasticized synthetic polymers and water.
U.S. Patent No. 3,538,214 also describes coated tablets, in which the coating acts as a porous membrane, letting water pass through to dissolve the enclosed drug, which in turn diffuses to the outside.
Porous membranes are obtained and their porosity is controlled by addition of auxiliary, water-soluble substances to the coating material which are loaded out prior to drug-diffusion. Similar membrane enclosed oral dose forms are described in U.S. Patent Nos. 3,854,480, 3,993,072 and 4,244,941.
When used in combination with water-soluble drugs, the above mentioned membrane devices all have the drawback of uncontrollable expansions and breaking due to osmotic pressure build up. This problem was overcome by applying the osmotic pump principle, as described in J. Harm. Sat. 64, 1981 (1975). This consists of a Semite Doable membrane, which lets only water diffuse into the tablet to dissolve the drug, which in turn is pumped out through _ 3 _ 03~
a pinhole in the membrane. Although this method works well with moderately soluble drugs, it is less applicable to highly water-soluble ingredients because the osmotic pressure quickly become too high as the drug-reservoir is dissolved. As in all membrane devices, constant release is achieved only as long as an undissolved drug reservoir is present in the core. Another disadvantage of the osmotic pump is the high level drug concentration existing at the exit hole which can lead to irritation of the stomach wall.
The above mentioned monolithic polymer-drug compositions of U.S.
Patent No. 3,390,050 and Australian Relent No. 16202 do not have these disadvantages. In U.S. 3,390,050 no final polymer purification can be carried out since the drug is incorporated during synthesis.
Australian Patent No. 16202 describes the use of a water syllable poly(2-hydroxyethyl methacrylate) or copolymers of 2-hydroxyethyl methacrylate to imbibe drugs from an aqueous solution. The dried polymer-drug composite forms a controlled oral release device. A
similar approach, but using water-swellable polymers (hydrogels) which are themselves two-phase polymers and which exhibit a much wider range of swelling in water and organic solvents is described in U.S. Patent Nos. 4,192,827 and 4,136,250. Although in all these polymers certain drugs can be imbibed in sufficient amounts to make the manufacture of practical dosage forms possible, their relatively high degree of swelling in water (30 to 80%) is con-comitantly accompanied by a relatively low degree of swelling in organic solvents. Typically the ratio of % swelling in ethanol to % swelling in water for these hydrogels lies in the range ox L/l to 2/1.
Furthermore, in these hydrogen drug-carriers, as a high degree of swelling in water is accompanied by a high degree of swelling in organic solvents, concomitantly a low degree of swelling in water is accompanied by a similarly low degree of swelling in organic liquids like ethanol. This limited swelling ability of the hydrogels limits the amount of drug which can be imbibed into them from a drug solution, be it aqueous or organic in nature. If the polymer swells to a larger degree in a suitable organic solvent than in water, then higher drug-loadings can be achieved by loading from, for instance, ethanol/drug solutions than from aqueous solutions provided the drug is soluble in ethanol. The use of organic solvents to imbibe hydrogels with a drug for later release has also been described in U.S. 4,192,827.
It is an object of this invention to produce a controlled-release, drug delivery composition comprising an effective amount of a forum ceutical medicament in a polymer substrate which can swell in polar organic solvents to a much greater degree than conventional polymers used for drug-delivery and which therefore can be imbibed with active ingredients to a correspondingly high concentration while at the same time exhibiting only a moderate degree of swelling in water.
The ability of a polymer to absorb a large amount of water has always been considered a necessity for a polymeric orally used drug-delivery matrix. Uydrogels have therefore been the only materials previously used for this purpose. Drug diffusion through hydrophobic polymers is normally too slow to be of practical use in an oral drug-delivery. It is consistent with this explanation that hydrophobic polymer-medicament compositions have been used only as body implants where drug-delivery over several weeks or even months is desired and where the overall dose size is very low, as is the case, for instance, with steroids.
~2~25~
It has now very unexpectedly been discovered that polymers can be synthesized in aqueous suspension or in bulk which can swell in organic solvents such as ethanol to a much greater extent than conventional hydrogels, being capable of absorbing from 40 to 90%
by weight of ethanol and typically showing a ratio of swelling to ethanol: % water) of 3:1 to 9:1. Therefore these beads can be loaded from a drug solution in an organic solvent with a soluble drug to correspondingly much higher drug levels than can convention hydrogel-type polymeric drug-carriersO At the same time it has been discovered that even if the amount of water absorbed by the novel polymers is lower than that of conventional hydrogels, namely lying in the range of 2-20% by weight of water, they still satisfy the requirement of releasing imbibed drugs completely within one to six hours.
It is a further object of this invention to prepare copolymers which exhibit unexpectedly high degrees of swelling in organic solvents while their degree of swelling in water is only moderate or low. Therefore, they can imbibe large amounts of medicaments or other active ingredients from organic solutions, yet are ideally suited for the controlled and prolonged release of such active ingredients into an aqueous environment as an oral dosage in form of beads.
The instant invention pertains to a controlled-release, drug-delivery composition which comprises (A) a cross linked copolymer, capable of swelling in ethanol Jo give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer con-twining no more than 20% by weight of water, where the swelling ratio I% ethanol: % water) is 2:1 to 22:1, which copolymer is the copolymerization product of (a) 50 to 99% by weight of said copolymer of (a) a water-insoluble monoolefinic monomer, or mixture of said monomers, or a water-in-soluble monoolefinic monomer, or mixture of said monomers with 0 to 45% by weight of total monomers of (by) a water-soluble moo-olefinic monomer, or mixture of said water-soluble monomers, with (by 50 to 1% by weight of said copolymer of a Donnelly or polyvinyl cross linking agent having a molecular weight of 100 to 10,000, but where (b) is not more than 20 mow % of component I
(B) an effective amount of a pharmaceutical medicament.
Preferably the cross linked copolymer has a swelling ratio (% ethanol:
% water) of 3:1 to 15:1; most preferably 4:1 to 8:1.
In order to assure that the instant copolymers have high sealability in ethanol coupled with moderate sealability in water, it is preferable that at least a third by weight of the water-insoluble monomer of component (a) is a monomer with an alkyd group of 4 to 21 carbon atoms.
A preferred embodiment of the instant invention is a composition wherein the copolymer (A) is the copolymerization product of 75-98 by weight of component (a) and 25-2% by weight of component (b).
Another preferred embodiment of the instant invention is a compost-lion wherein component (a) comprises 70-95% by weight of water-in-soluble monomer (a) and 30-5% by weight of water-soluble monomer (by).
A particularly preferred embodiment is a composition wherein component (a) is 75-0% by weight of methyl acrylate, methyl methacrylate or mixture thereof, and 25-100% by weight of a C4-C10 alkyd acrylate or methacrylate, or mixture thereof.
~51~3~
The vinyl monomers (a) used to prepare the cross linked copolymers of the present invention can conveniently be divided into water-insoluble (a) and water-soluble (by) monomers. The water-insoluble comonomers include for employ: the acrylic- and methacrylic esters and asides of mandrake linear or branched alcohols with from 1 to 20 carbon atoms, and which alcohols may be aliphatic, cycle-aliphatic, or aromatic in nature. Examples are: methyl-, ethyl-, propel-, isopropyl-, n-, is-, and tertiary bottle-, Huxley-, ponytail-, 2-ethylhexyl-, n-octyl-, 1,1,3,3-trimethylbutyl, decal-, tridecyl-, hexadecyl-, Cyril-, cyclohexyl-, isobornyl-, dicyclopentadienyl-, methyl-, dicyclopentadienylethyl-; phenol-, bouncily-, methoxyethyl;
ethoxyethyl-, furfuryl-, glycidyl-, acrylate or methacrylate as well as the corresponding amine; and acrylonitrile.
Vinyl esters, such as: vinyl acetate, vinyl preappoint, vinyl buoyancy-ate.
Vinyl ethers such as: methyl-, propel-, bottle-, methoxyethyl-vinyl ether. Fumarate, Malta and itaconate divesters of the mandrake alcohol-residues mentioned above; styrenes ~-methylstyrene.
The monomers may be used alone or in combination with each other.
It is preferred that at least half of the water-insoluble monomers are monomers containing alkyd groups with at least 4 carbon atoms, such as bottle acrylate or methacrylate; 2-ethylhexyl acrylate or methacrylate; n-octyl acrylate or methacrylate; di-n-butyl fumarate;
bouncily methacrylate; vinyl bitterroot; 1,1,3,3-tetramethylbutyl-acrylamide- and methacrylamide.
Preferred water-insoluble comonomers are methyl methacrylate, n-butyl acrylate, n-butylmethacrylate, 2-ethylhexyl acrylate, n-octyl acrylate and n-octyl methacrylate, glycidyl methacrylate and vinyl acetate or mixtures thereof.
- 8 - ~25~3~
Compositions where 10-60% by weight of component (a is n-buty acrylate or 2-ethylhexyl acrylate are especially preferred.
The water-soluble monomer, (by), are preferably acrylic and/or methacrylic acid or the water-soluble derivatives thereof, such as hydroxyalkyl esters where alkyd is 2 to 4 carbon atoms, ego 2-hydroxyethyl, 3-hydroxypropyl, 2 hydroxypropyl or 2~3-dihydroxy-propel esters; also ethoxylated and polyethoxylated hydroxyalkyl esters such as esters of alcohols of the formula H0-C H -0-(CH2CH2-0) -H
where m represents 2 to 5 and n represents 1 to 20, or esters of analogous alcohols, wherein a part of the ethylene oxide units is replaced by propylene oxide units.
Also suitable are 3-(dimethylamino)-2-hydroxypropyl esters and asides.
Another class of suitable derivatives of such acids are their water-soluble asides, such as unsubstituted asides and asides substituted by lower hydroxyalkyl, lower oxaalkyl or lower dialkylaminoalkyl groups where alkyd it to 4 carbon atoms such as N-(hydroxymethyl)-acrylamide and -methacrylamide. N-(3-hydropropyl)acrylamide, No hydroxyethyl)methacrylamide and N-~l,l-dimethyl-2-(hydroxymethyl)-3-oxabutyl]acrylamide; water soluble hydrazine derivatives such as dimethyl-2-hydroxypropylamine methacrylimide and the corresponding derivatives of acrylic acid.
Also useful, in combination with comonomers, are the lower hydroxy~
alkyd malefic esters and vinyl ethers where alkyd is 2 to 4 carbon atoms, for instance, di-(hydroxyalkyl) Maltese, such as d;(2-hydroxy-ethyl) Malta, and ethoxylated hydroxyalkyl Maltese, hydroxyalkyl monomaleates, such as 2-hydroxyethyl monomaleate and alkoxylated hydroxyalkyl monomaleate together with vinyl ethers, vinyl esters, styrenes or generally any monomer which will easily copolymerize with ~25~33g~
_ 9 _ Maltese or fumarates; hydroxyalkyl vinyl ethers, such as 2-hydroxy-ethyl vinyl ether, 4-hydroxybutyl vinyl ether together with Maltese, forts, or generally all monomers which will easily copolymerize with vinyl ethers Other water-soluble comonomers useful in this invention are:
alkyd ethers of polyethoxylate hydroxyalkyl esters of acrylic and methacrylic acid, such as esters of alcohols of the formula H~-CmHm-O-(CH2~H2 on SHEA
where m = 2 to 5 and n = 4 to 20.
Dialkylaminoalkyl esters and asides, such as 2-(dimethylamino)ethyl or 2-(diethylamino)ethyl acrylate and methacrylate, as well as the corresponding asides; asides substituted by lower oxaalkyl or lower dialkylaminoal~yl groups, such as N-(l,l-dimethyl-3-oxa-butyl)acrylamide; water-soluble hydrazine derivatives, such as trialkylamine methacrylimide, e.g., triethylamine-methacrylimide and the corresponding derivatives of acrylic acid. Monoolefinic sulfonic acids and their salts, such as sodium ethylene sulfonate, sodium styrenes sulfonate and 2-acrylamido 2-methylpropanesulfonic acid; or monoole~inic derivatives of heterocyclic nitrogen-containing monomers, such as N-vinylpyrrole, N-vinylsuccinimide, l-vinyl-2-pyrrolidone, l-vinylimidazole, l-vinylindole, 2-vinylimidazole, 4(5)-vinylimidazole, 2-vinyl-1-methylimidaæole, 5-vinylpyrazoline,
3-methyl-5-isopropenylpyrazole, 5-methylenehydantoin, 3-vinyl-2-oxa-zolidone, 3-methacrylyl-2-oxazolidone, 3-methacrylyl-5-methyl-2-oxa-zolidone, 3-vinyl-5-methyl-2-oxazolidone, 2- and 4-vinylpyridine, 5-vinyl-2-methylpyridine, 2-vinylpyridine-1-oxide, 3-isopropenyl-pardon, 2- and 4-vinylpiperidine, 2- and 4-vinylquinoline, 2,4-dimethyl-6-vinyl-a-triazine and 4-acrylylmorpholine.
Preferred among the water-soluble monomers are N-vinyl-2-pyrrolidone, 2-vinylpyridine, 4-vinylpyridine, 2-(dimethylamino)ethyl methacrylate, N-methacrylamide, N,N-dimethylacrylamide, acrylic acid and moth-acrylic acid or mixtures thereof.
Most preferred water-soluble comonomers are: 2-hydroxyethyl acrylate and methacrylate, acrylic- and methacrylic acid; 2-dimethylamino-ethyl methycrylate; ~,N-dimethylacrylamide and N-vinyl-2-pyrrolidone.
Examples for the divinely or polyvinyl cross linking agent tub) are the insoluble dip or polyacrylates and methacrylates of dills and polyols, such as linear or branched aliphatic dills like ethylene glycol, 1,2-propylene glycol, 1,6-hexanediol, 1,4-butanediol, 1,4 butenediol, 1,4-butynediol; diethylene glycol; dipropylene glycol, di-pentylene glycol; polyethylene oxide glycol; polypropylene-oxide glycol, polytetramethylene-oxide glycol; polyethylene oxide co-propylene-oxide) glycol; thiodiethylene glycol; the reaction product of a diisocyanate (aliphatic, cycloaliphatic and aromatic) with twice the equivalent amount of hydroxyalkyl acrylates or methacrylates; the reaction products of isocyanate terminated pro-polymers derived from polyester dills, poly-ether dills or polyp selection dills as shown in the art of polyurethane technology, with from 500-10,00~ MY, with twice the equivalent amount of hydroxyalkyl methacrylates. Other such as dip and polyvinyl-crosslinking agents, including divinely ethers and Delilah compounds are described in U.S. 4,112,827, useful polysiloxane dip and polyvinyl compounds are described in U.S. 4,136,250.
Examples of such cross linking agents include: trimethylolpropane triacrylate, neopentylglycol diacrylate, pentaerythritol and Dupont-erythritol do-, in-, twitter-, punt hexa-acrylates; ethylene glycol and diethylene glycol acrylates, divinely ether; divinylbenzene, allylmethacrylate; Delilah Malta; diallylamine; divinely cellophane;
triallyl sonority.
L;22~3~
Such a cross linking agent is a terminal diolefinic hydrophobic macromer having a molecular weight from about 400 to about 8000, said macromer having the formula HC=C-X-Y-Rl-Y-X-C3CH
wherein Al is a polycondensate chain having a molecular weight from about 200 to 8000, which is the residue of a polypropylene oxide) or poly(tetramethylene oxide) glycol having ether linkages, R2 is hydrogen, methyl or -SHAKER, wherein R4 is hydrogen or an alkyd group with up to 10 carbon atoms;
R3 is hydrogen or COORS, with the proviso that at least one of R2 and R3 is hydrogen;
X is ox, -COO-, or -CONNER- where R5 is hydrogen or alkyd with up to 5 carbon atoms and Y is a direct bond or the radical -R6-Zl-CO-NH-R7-NH-CO-Z2-, wherein R6 is linked to X and represents branched or linear alkaline with up to 7 carbon atoms; Al and Z2 is ox or NR5 and R7 is the diradical of an aliphatic or aromatic diisocyanate, with the proviso that in case X is ox, Y is different from a direct bond and R2 and R3 are hydrogen.
Preferably Al is a polypropylene oxide) or poly(tetramethylene oxide) chain with a molecular weight of about 600 to about 4,000. Preferably the macromer is a polytetramethylene-oxide glycol with a molecular weight of about 600 to about 4000, end capped with Tulane or is foreign diisocyanate and reacted with 2 moles of a hydroxyalkyl acrylate or methacrylate, wherein alkyd has 2 to 4 carbon atoms.
Other preferred cross linking agents include the C2-C~ alkaline dip acrylates or methacrylates, 3-oxapentamethylene diacrylate, 3-oxapentamethylene dimethacrylate and trimethylolpropane in-acrylate, or mixtures thereof.
25~ Al The amount of cross linking agent can vary from 1 to 50~ by weight, but should not contribute more than 20 mow of the total monomer mixture. Preferred cross linking agents are ones with a molecular weight from 500-5,000, containing polyalkylene ether units, especially as described in U.S. 4,192,827.
A particularly preferred embodiment of the instant invention are those compositions where the copolymer (~) is the copolymerization product of 85-~9% of component (a) and 15-1% of component (b), where (a) is 15-50~ by weight of methyl methacrylate, 15-70% by weight of 2-ethylhexyl acrylate, n-butyl acrylate or n-octyl acrylate, 5-15~ by weight of N-vinyl-2-pyrrolidone and 0-25% by weight of 2-hydroxyethyl methacrylate.
The inert delineate present during polymerization can be any organic liquid which will clearly dissolve in the monomer mixture. However, it need not be a solvent for the polymer and can vary in its solvent power from a thermodynamically good solvent for monomers and polymers to a thermodynamically poor solvent for the polymer.
Inert delineates which are thermodynamically good solvents for the monomers, but poor solvents for the copolymer are commonly used in the preparation of macro porous ion-exchange resins which are co-polymers of styrenes and divinylbenzene. The preparation of macro-porous hydrogels according to the same principle is described in DRY 66283 and U.S. 4,184,020. In all cases the objective was to prepare macro porous hydrog~ls for gel chromatography or gas cremate graph, and none have been used in oral drug-delivery applications.
This is understandable since due their high hydrophilicity the release-rate would be impracticably fast.
The use of inert delineates which are thermodynamically good solvents for both the monomers and the resulting copolymers, results in micro-porous polymers of increased distances between cross links (expanded gel structure) comparable to the micro porous, homogeneous structure of polymers prepared in absence of such delineates.
A preferred embodiment of the instant invention pertains to compost-lions prepared with the use of inert delineates which are good solvents for the monomers and which vary from good to poor in solvent power for the copolymers. Thus copolymer with a selected range of micro-porous to macro porous structures can be prepared by choosing the delineate used. The structure desired in turn is dictated by the volubility characteristics of the drug to be imbibed as jell as its dose size.
If the delineate is a good solvent for the polymer, the product is obtained with a network structure which is a microreticular, that is micro porous, in nature. This structure is comparable to the one obtained in the absence of solvent when the polymerization is carried out in bulk, but differs from it by a more extended and open network structure as a result of the good solvent present. If, on the other hand, the delineate is only a solvent for the monomer, but is a non-solvent or precipitant for the polymer, the product is obtained with a macro porous or macroreticular structure which is a 2-phase (gas -polymer) in nature. Although the extremes of both possibilities can be well distinguished from each other, intermediate grades of micro-and macroreticular polymers form a a continuum between them.
The solvent power and the volubility parameter of the delineate are commonly a function of its chemical nature, like the degree of hydrogen bonding, polar- and non-polar interactions, presence of hotter atoms and, generally, of the degree of similarity of the delineate to the monomer which is used. The effect of phase separation ~;22~31~) during polymerization in the presence of an inert delineate is enhanced by an increase in crosslink-density. To choose the right delineates and the right amount of cross linking agent to get a micro- or macro-reticula structure is a task easily performed by anyone slcilled in the art of polymer chemistry and especially the art of making ion-exchange resins.
Another group of delineates which are very poor solvents for the polymer are other polymers. It is well known that two different polymers will essentially not dissolve in each other due to the extremely low heat of mixing. Therefore, while polymeric delineates can dissolve in the monomer mixture, during polymerization phase-separation between both polymers occurs. After extraction of the inert polymeric delineate, a product is obtained with an extended network structure which is likely to be more macroreticular than microreticular in nature. Such polymeric delineates, like poly-alkylene ether glycols or polyesters are especially preferred in the context of this invention.
.
Useful low molecular weight delineates are: ester, such as ethyl acetate; bottle cello solve acetate; bottle acetate; isobutyl acetate;
methyl cello solve acetates; ethers, such as methyl phenol ether;
tetrahydrofuran; alcohols, such as ethanol; isopropanol; n-, is-and tert-butanol; laurel alcohol; octanol; decanol; dodecanol, bottle cello solve ethyl cello solve, bottle alcohol; cyclohexanol. Kittens such as methyl ethyl kitten; methyl iso-butyl kitten; asides, such as dimethylformamide; formamide; acetamide; dimethylacetamide.
Dim ethyl sulfoxide. Sulfolane. N-methyl-2-pyrrolidone. Also useful are hydrocarbons such as hexane, Hutton, cyclohexane or halogenated hydrocarbons like tetrachloroethylene, trichloroethane or in-chloroethylene.
- 15 - æ 3 Preferred inert delineates are polyalkylene ether glycols, such as polyethylene oxide glycol, polypropylene oxide glycol and pylon-butylenenxide glycol, and block-coplymers thereof, octanol, decanol, dodecanol, Hutton, or isobutyl acetate.
Any of the drugs used to treat the body, both topical and systemic, can be incorporated as the active agent in the copolymeric carrier of this invention. 'rug" is used herein in its broadest sense as including any composition of matter that will produce a pharmacy-logical or biological response.
Suitable drugs for use in therapy according to this invention in-elude, without limitations, those listed in U.S. Patent Noah.
Other drugs having the same or different physiological activity as those recited above can be employed in carriers within the scope of the present invention. Suitable mixtures of drugs can, of course, be dispensed with equal facility as with single component systems.
rugs can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, e.g. the hydrochloride, hydrobromide, sulfite, phosphate, nitrate, borate, acetate, Malta, tart rate, salicylate, etc. For acidic drugs, salts of metals, amine, or organic cations (e.g.
qua ternary ammonium) can be employed. Furthermore, simple derivatives of the drugs (such as ethers, esters, asides, etc.) which have desirable retention and release characteristics but which are easily hydrolyzed by body phi enzymes, etc., can be employed.
The amount of drug incorporated in the carrier varies widely depending on the particular drug, the desired therapeutic effect, and the time span for which it takes the drug to be released. Since a variety of carriers in a variety of sizes and shapes are intended to provide I
complete dosage regimes for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the carrier. the lower limit, too, Jill depend on the activity of the drug and the span of its release from the carrier. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be released by the carrier.
Preferred drugs to be incorporated according to the present invention are those designed for long-term treatment so that multiple daily doses can be avoided. For example, anabolicsl e.g. methandrostenolone;
analgesics, e.g. acetylsalicyclic acid, phenylbutazone or methadone;
androgynous, e.g. methyltestoterone; antibiotics, e.g. rifampin;
antidepressants, e.g. imipramine or maprotiline; anti diabetics, e.g. phenformin; anticonvulsives, e.g. carbamazepine; antihistamines, e.g. tripelennamine; antihypertensives, e.g. hydralazine; anti-invectives, e.g. trimethoprim; antiparasitics, e.g. nifurimox;
anti Parkinson agents, e.g. levodopa; antiphlogistics~ e.g. naproxen;
antitussives, e.g. benzonstate; appetite depressants, e.g. mazindol;
bronchodilators, e.g. fenoterol; coronary dilators, e.g. fenalcomine;
corticoids, e.g. dexamethasone; cytostatic, e.g. floxuridine;
diuretics, e.g. hydrochlorothiazide; hypnotics, e.g. glutethimide9 neuroleptics, e.g. reserpine or thioridazine; psycho-analeptics, e.g. methylpenidate; tranquilizers, e.g. depone; uricosutics, e.g. sulfinpyrazone; vasodi~ators, e.g. isoproterenol.
Among the most preferred drugs are oxprenolol- Hal (TRASICOR~ ) diclofenac-sodium (VOLTAREN I), baclofen (Lyres ) metropolol clue (LOPRESSOR I), beta blockers, such as oxprenolol and propanolol;
calcium channel blockers, such as Nifedipine~ and Verapamil~ .
The copolymers of this invention are synthesized by free-radical initiated polymerization, using either redoxcatalyst, proxy compounds or ago compounds; typical initiators include laurel peroxide . .
tert.-butyl peroctoate and azo-biisobutyronitrile. As known to those skilled in the art, many different proxy- and ago compounds are commercially available and can be used. Free radical polymerization can also be Uninitiated in the presence of commonly used W -initiators and sensitizers such as benzophenone, Bunsen, diethoxyacetophenone (DEEP) and related compounds. Electron-beam radiation can be used if the polymer are made in form of films, coating or sheets.
The polymers are synthesized in form of beads by suspension polyp merization process in an aqueous medium. To reduce the volubility of water-soluble comonomers present, the medium is preferably an inorganic salt solution, usually concentrated sodium chloride solution.
As suspending agents can be used either polymeric suspending agents such as polyvinyl pyrrolidone), polyvinyl alcohol) or poly(hydroxy-ethyl cellulose), or inorganic, insoluble salts such as calcium phosphate, calcium oxalate, calcium carbonate, calcium sulfate or magnesium phosphate, or the insoluble hydroxides such as Mg(OH)2, Allah or Tao. A process which can be used to make the polymers of this invention in form of beads is described in U.S. 4,224,427.
After synthesis the polymer beads are thoroughly extracted with ethanol or ethanol/water mixtures or other suitable solvents and dried to constant weight. The polymers of this invention can also be manufactured by bulk polymerization methods in form of sheets, films or shapes.
In form of shapes, rods, films or sheets and coatings the instant co-polymer can also be made by casting and thermally or W-initiated polymerization.
The polymers after synthesis are characterized by their degree of swelling in water and ethanol, by their ability to imbibe an active ingredient and the release of this ingredient into an aqueous en-vironment, as described in detail in the examples.
- 18 - ~2~3~
after drying, the polymer beads are imbibed with a chosen active ingredient such as a drug. As solvent for imbibing the drug, any solvent which will (a) dissolve the drug, (b) swell the polymer, and (c) can be quantitatively removed can be used. These are prefer-ably low boiling solvents like methanol or ethanol, ethylene chloride, acetone or mixtures of such solvents. aqueous alcoholic solutions are also suitable. The best choice of solvents will depend on the volubility of the drug and on the desired level of loading.
In general, however, it will be seen from the accompanying examples, that for many water-soluble drugs, ethanol is also a good solvent and the high ethanol swelling capability of the polymers of this invent lion makes high drug-loadings from ethanol solutions possible and preferred.
Especially high loading are obtained with certain drugs when the polymer-synthesis is carried out in presence of an inert delineate.
To load the copolymer with an active ingredient, the copolymer is equilibrated in a solution of said active ingredient in ethanol, methanol or other organic solvent or a mixture of such solvents which may also contain water. Subsequently the loaded composition is removed, for example by filtration and the solvent is driven off from the composition by drying in heat and/or vacua.
It has further been discovered that especially high drug-loadings can be achieved if the polymerization is carried out in the presence of an inert delineate which results in a final polymer of increased pore size and which copolymer therefore is capable of absorbing even higher amounts of solvent and drug.
Drug loaded compositions, in which the polymer is obtained in the presence of such inert delineates as polypropylene glycol), decanol or dodecanol are thus a preferred embodiment of the present invention.
.
~2~:5~
Despite high drug loadings, beads treated in this manner show a prolonged and delayed release.
Loading zip a polymer bead with enough drug to make a practical dose size is only one requirement for a successful oral dosage form; that the drug be released within a practical time span is another. In many cases it is sufficient advantage over conventional dose-forms to release the drug from a monolithic polymeric matrix since such a system reduces the possibility of drug-abuse. although the release is not constant, but concentration-dependent, it is slowed down enough to eliminate potential toxic overdose effects.
In cases where a more constant release is desired, it has unexpectedly been found that polymer-drug compositions of the present invention in which the polymer contains a major proportion - 30 to 100% of all hydrophobic monomers - of monomeric units bearing alkyd groups of
Preferred among the water-soluble monomers are N-vinyl-2-pyrrolidone, 2-vinylpyridine, 4-vinylpyridine, 2-(dimethylamino)ethyl methacrylate, N-methacrylamide, N,N-dimethylacrylamide, acrylic acid and moth-acrylic acid or mixtures thereof.
Most preferred water-soluble comonomers are: 2-hydroxyethyl acrylate and methacrylate, acrylic- and methacrylic acid; 2-dimethylamino-ethyl methycrylate; ~,N-dimethylacrylamide and N-vinyl-2-pyrrolidone.
Examples for the divinely or polyvinyl cross linking agent tub) are the insoluble dip or polyacrylates and methacrylates of dills and polyols, such as linear or branched aliphatic dills like ethylene glycol, 1,2-propylene glycol, 1,6-hexanediol, 1,4-butanediol, 1,4 butenediol, 1,4-butynediol; diethylene glycol; dipropylene glycol, di-pentylene glycol; polyethylene oxide glycol; polypropylene-oxide glycol, polytetramethylene-oxide glycol; polyethylene oxide co-propylene-oxide) glycol; thiodiethylene glycol; the reaction product of a diisocyanate (aliphatic, cycloaliphatic and aromatic) with twice the equivalent amount of hydroxyalkyl acrylates or methacrylates; the reaction products of isocyanate terminated pro-polymers derived from polyester dills, poly-ether dills or polyp selection dills as shown in the art of polyurethane technology, with from 500-10,00~ MY, with twice the equivalent amount of hydroxyalkyl methacrylates. Other such as dip and polyvinyl-crosslinking agents, including divinely ethers and Delilah compounds are described in U.S. 4,112,827, useful polysiloxane dip and polyvinyl compounds are described in U.S. 4,136,250.
Examples of such cross linking agents include: trimethylolpropane triacrylate, neopentylglycol diacrylate, pentaerythritol and Dupont-erythritol do-, in-, twitter-, punt hexa-acrylates; ethylene glycol and diethylene glycol acrylates, divinely ether; divinylbenzene, allylmethacrylate; Delilah Malta; diallylamine; divinely cellophane;
triallyl sonority.
L;22~3~
Such a cross linking agent is a terminal diolefinic hydrophobic macromer having a molecular weight from about 400 to about 8000, said macromer having the formula HC=C-X-Y-Rl-Y-X-C3CH
wherein Al is a polycondensate chain having a molecular weight from about 200 to 8000, which is the residue of a polypropylene oxide) or poly(tetramethylene oxide) glycol having ether linkages, R2 is hydrogen, methyl or -SHAKER, wherein R4 is hydrogen or an alkyd group with up to 10 carbon atoms;
R3 is hydrogen or COORS, with the proviso that at least one of R2 and R3 is hydrogen;
X is ox, -COO-, or -CONNER- where R5 is hydrogen or alkyd with up to 5 carbon atoms and Y is a direct bond or the radical -R6-Zl-CO-NH-R7-NH-CO-Z2-, wherein R6 is linked to X and represents branched or linear alkaline with up to 7 carbon atoms; Al and Z2 is ox or NR5 and R7 is the diradical of an aliphatic or aromatic diisocyanate, with the proviso that in case X is ox, Y is different from a direct bond and R2 and R3 are hydrogen.
Preferably Al is a polypropylene oxide) or poly(tetramethylene oxide) chain with a molecular weight of about 600 to about 4,000. Preferably the macromer is a polytetramethylene-oxide glycol with a molecular weight of about 600 to about 4000, end capped with Tulane or is foreign diisocyanate and reacted with 2 moles of a hydroxyalkyl acrylate or methacrylate, wherein alkyd has 2 to 4 carbon atoms.
Other preferred cross linking agents include the C2-C~ alkaline dip acrylates or methacrylates, 3-oxapentamethylene diacrylate, 3-oxapentamethylene dimethacrylate and trimethylolpropane in-acrylate, or mixtures thereof.
25~ Al The amount of cross linking agent can vary from 1 to 50~ by weight, but should not contribute more than 20 mow of the total monomer mixture. Preferred cross linking agents are ones with a molecular weight from 500-5,000, containing polyalkylene ether units, especially as described in U.S. 4,192,827.
A particularly preferred embodiment of the instant invention are those compositions where the copolymer (~) is the copolymerization product of 85-~9% of component (a) and 15-1% of component (b), where (a) is 15-50~ by weight of methyl methacrylate, 15-70% by weight of 2-ethylhexyl acrylate, n-butyl acrylate or n-octyl acrylate, 5-15~ by weight of N-vinyl-2-pyrrolidone and 0-25% by weight of 2-hydroxyethyl methacrylate.
The inert delineate present during polymerization can be any organic liquid which will clearly dissolve in the monomer mixture. However, it need not be a solvent for the polymer and can vary in its solvent power from a thermodynamically good solvent for monomers and polymers to a thermodynamically poor solvent for the polymer.
Inert delineates which are thermodynamically good solvents for the monomers, but poor solvents for the copolymer are commonly used in the preparation of macro porous ion-exchange resins which are co-polymers of styrenes and divinylbenzene. The preparation of macro-porous hydrogels according to the same principle is described in DRY 66283 and U.S. 4,184,020. In all cases the objective was to prepare macro porous hydrog~ls for gel chromatography or gas cremate graph, and none have been used in oral drug-delivery applications.
This is understandable since due their high hydrophilicity the release-rate would be impracticably fast.
The use of inert delineates which are thermodynamically good solvents for both the monomers and the resulting copolymers, results in micro-porous polymers of increased distances between cross links (expanded gel structure) comparable to the micro porous, homogeneous structure of polymers prepared in absence of such delineates.
A preferred embodiment of the instant invention pertains to compost-lions prepared with the use of inert delineates which are good solvents for the monomers and which vary from good to poor in solvent power for the copolymers. Thus copolymer with a selected range of micro-porous to macro porous structures can be prepared by choosing the delineate used. The structure desired in turn is dictated by the volubility characteristics of the drug to be imbibed as jell as its dose size.
If the delineate is a good solvent for the polymer, the product is obtained with a network structure which is a microreticular, that is micro porous, in nature. This structure is comparable to the one obtained in the absence of solvent when the polymerization is carried out in bulk, but differs from it by a more extended and open network structure as a result of the good solvent present. If, on the other hand, the delineate is only a solvent for the monomer, but is a non-solvent or precipitant for the polymer, the product is obtained with a macro porous or macroreticular structure which is a 2-phase (gas -polymer) in nature. Although the extremes of both possibilities can be well distinguished from each other, intermediate grades of micro-and macroreticular polymers form a a continuum between them.
The solvent power and the volubility parameter of the delineate are commonly a function of its chemical nature, like the degree of hydrogen bonding, polar- and non-polar interactions, presence of hotter atoms and, generally, of the degree of similarity of the delineate to the monomer which is used. The effect of phase separation ~;22~31~) during polymerization in the presence of an inert delineate is enhanced by an increase in crosslink-density. To choose the right delineates and the right amount of cross linking agent to get a micro- or macro-reticula structure is a task easily performed by anyone slcilled in the art of polymer chemistry and especially the art of making ion-exchange resins.
Another group of delineates which are very poor solvents for the polymer are other polymers. It is well known that two different polymers will essentially not dissolve in each other due to the extremely low heat of mixing. Therefore, while polymeric delineates can dissolve in the monomer mixture, during polymerization phase-separation between both polymers occurs. After extraction of the inert polymeric delineate, a product is obtained with an extended network structure which is likely to be more macroreticular than microreticular in nature. Such polymeric delineates, like poly-alkylene ether glycols or polyesters are especially preferred in the context of this invention.
.
Useful low molecular weight delineates are: ester, such as ethyl acetate; bottle cello solve acetate; bottle acetate; isobutyl acetate;
methyl cello solve acetates; ethers, such as methyl phenol ether;
tetrahydrofuran; alcohols, such as ethanol; isopropanol; n-, is-and tert-butanol; laurel alcohol; octanol; decanol; dodecanol, bottle cello solve ethyl cello solve, bottle alcohol; cyclohexanol. Kittens such as methyl ethyl kitten; methyl iso-butyl kitten; asides, such as dimethylformamide; formamide; acetamide; dimethylacetamide.
Dim ethyl sulfoxide. Sulfolane. N-methyl-2-pyrrolidone. Also useful are hydrocarbons such as hexane, Hutton, cyclohexane or halogenated hydrocarbons like tetrachloroethylene, trichloroethane or in-chloroethylene.
- 15 - æ 3 Preferred inert delineates are polyalkylene ether glycols, such as polyethylene oxide glycol, polypropylene oxide glycol and pylon-butylenenxide glycol, and block-coplymers thereof, octanol, decanol, dodecanol, Hutton, or isobutyl acetate.
Any of the drugs used to treat the body, both topical and systemic, can be incorporated as the active agent in the copolymeric carrier of this invention. 'rug" is used herein in its broadest sense as including any composition of matter that will produce a pharmacy-logical or biological response.
Suitable drugs for use in therapy according to this invention in-elude, without limitations, those listed in U.S. Patent Noah.
Other drugs having the same or different physiological activity as those recited above can be employed in carriers within the scope of the present invention. Suitable mixtures of drugs can, of course, be dispensed with equal facility as with single component systems.
rugs can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, e.g. the hydrochloride, hydrobromide, sulfite, phosphate, nitrate, borate, acetate, Malta, tart rate, salicylate, etc. For acidic drugs, salts of metals, amine, or organic cations (e.g.
qua ternary ammonium) can be employed. Furthermore, simple derivatives of the drugs (such as ethers, esters, asides, etc.) which have desirable retention and release characteristics but which are easily hydrolyzed by body phi enzymes, etc., can be employed.
The amount of drug incorporated in the carrier varies widely depending on the particular drug, the desired therapeutic effect, and the time span for which it takes the drug to be released. Since a variety of carriers in a variety of sizes and shapes are intended to provide I
complete dosage regimes for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the carrier. the lower limit, too, Jill depend on the activity of the drug and the span of its release from the carrier. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be released by the carrier.
Preferred drugs to be incorporated according to the present invention are those designed for long-term treatment so that multiple daily doses can be avoided. For example, anabolicsl e.g. methandrostenolone;
analgesics, e.g. acetylsalicyclic acid, phenylbutazone or methadone;
androgynous, e.g. methyltestoterone; antibiotics, e.g. rifampin;
antidepressants, e.g. imipramine or maprotiline; anti diabetics, e.g. phenformin; anticonvulsives, e.g. carbamazepine; antihistamines, e.g. tripelennamine; antihypertensives, e.g. hydralazine; anti-invectives, e.g. trimethoprim; antiparasitics, e.g. nifurimox;
anti Parkinson agents, e.g. levodopa; antiphlogistics~ e.g. naproxen;
antitussives, e.g. benzonstate; appetite depressants, e.g. mazindol;
bronchodilators, e.g. fenoterol; coronary dilators, e.g. fenalcomine;
corticoids, e.g. dexamethasone; cytostatic, e.g. floxuridine;
diuretics, e.g. hydrochlorothiazide; hypnotics, e.g. glutethimide9 neuroleptics, e.g. reserpine or thioridazine; psycho-analeptics, e.g. methylpenidate; tranquilizers, e.g. depone; uricosutics, e.g. sulfinpyrazone; vasodi~ators, e.g. isoproterenol.
Among the most preferred drugs are oxprenolol- Hal (TRASICOR~ ) diclofenac-sodium (VOLTAREN I), baclofen (Lyres ) metropolol clue (LOPRESSOR I), beta blockers, such as oxprenolol and propanolol;
calcium channel blockers, such as Nifedipine~ and Verapamil~ .
The copolymers of this invention are synthesized by free-radical initiated polymerization, using either redoxcatalyst, proxy compounds or ago compounds; typical initiators include laurel peroxide . .
tert.-butyl peroctoate and azo-biisobutyronitrile. As known to those skilled in the art, many different proxy- and ago compounds are commercially available and can be used. Free radical polymerization can also be Uninitiated in the presence of commonly used W -initiators and sensitizers such as benzophenone, Bunsen, diethoxyacetophenone (DEEP) and related compounds. Electron-beam radiation can be used if the polymer are made in form of films, coating or sheets.
The polymers are synthesized in form of beads by suspension polyp merization process in an aqueous medium. To reduce the volubility of water-soluble comonomers present, the medium is preferably an inorganic salt solution, usually concentrated sodium chloride solution.
As suspending agents can be used either polymeric suspending agents such as polyvinyl pyrrolidone), polyvinyl alcohol) or poly(hydroxy-ethyl cellulose), or inorganic, insoluble salts such as calcium phosphate, calcium oxalate, calcium carbonate, calcium sulfate or magnesium phosphate, or the insoluble hydroxides such as Mg(OH)2, Allah or Tao. A process which can be used to make the polymers of this invention in form of beads is described in U.S. 4,224,427.
After synthesis the polymer beads are thoroughly extracted with ethanol or ethanol/water mixtures or other suitable solvents and dried to constant weight. The polymers of this invention can also be manufactured by bulk polymerization methods in form of sheets, films or shapes.
In form of shapes, rods, films or sheets and coatings the instant co-polymer can also be made by casting and thermally or W-initiated polymerization.
The polymers after synthesis are characterized by their degree of swelling in water and ethanol, by their ability to imbibe an active ingredient and the release of this ingredient into an aqueous en-vironment, as described in detail in the examples.
- 18 - ~2~3~
after drying, the polymer beads are imbibed with a chosen active ingredient such as a drug. As solvent for imbibing the drug, any solvent which will (a) dissolve the drug, (b) swell the polymer, and (c) can be quantitatively removed can be used. These are prefer-ably low boiling solvents like methanol or ethanol, ethylene chloride, acetone or mixtures of such solvents. aqueous alcoholic solutions are also suitable. The best choice of solvents will depend on the volubility of the drug and on the desired level of loading.
In general, however, it will be seen from the accompanying examples, that for many water-soluble drugs, ethanol is also a good solvent and the high ethanol swelling capability of the polymers of this invent lion makes high drug-loadings from ethanol solutions possible and preferred.
Especially high loading are obtained with certain drugs when the polymer-synthesis is carried out in presence of an inert delineate.
To load the copolymer with an active ingredient, the copolymer is equilibrated in a solution of said active ingredient in ethanol, methanol or other organic solvent or a mixture of such solvents which may also contain water. Subsequently the loaded composition is removed, for example by filtration and the solvent is driven off from the composition by drying in heat and/or vacua.
It has further been discovered that especially high drug-loadings can be achieved if the polymerization is carried out in the presence of an inert delineate which results in a final polymer of increased pore size and which copolymer therefore is capable of absorbing even higher amounts of solvent and drug.
Drug loaded compositions, in which the polymer is obtained in the presence of such inert delineates as polypropylene glycol), decanol or dodecanol are thus a preferred embodiment of the present invention.
.
~2~:5~
Despite high drug loadings, beads treated in this manner show a prolonged and delayed release.
Loading zip a polymer bead with enough drug to make a practical dose size is only one requirement for a successful oral dosage form; that the drug be released within a practical time span is another. In many cases it is sufficient advantage over conventional dose-forms to release the drug from a monolithic polymeric matrix since such a system reduces the possibility of drug-abuse. although the release is not constant, but concentration-dependent, it is slowed down enough to eliminate potential toxic overdose effects.
In cases where a more constant release is desired, it has unexpectedly been found that polymer-drug compositions of the present invention in which the polymer contains a major proportion - 30 to 100% of all hydrophobic monomers - of monomeric units bearing alkyd groups of
4-21 carbon atoms are especially well suited for carrying out a 'controlled extraction' process.
In this process, a thin surface region of the drug loaded bead is rendered free of drug by extraction with a few boiling solvent like acetone for a precise time period, followed by rapid drying. Why these polymers show this unexpectedly useful behavior is not well understood, but may be due to a phase-inversion of polymer segments on the bead-surface under the influence of a solvent. Drug-loaded polymers having 30-70% of their total hydrophobic monomer composition derived from C4-C21 alkyd substituted monomers are thus another especially preferred embodiment of this invention.
It has furthermore been found unexpectedly that use of polymeric inert dilettantes during the synthesis of the polymer beads of the instant invention gave after extraction beads with a specifically modified network structure which resulted in unexpectedly good drug-- 20 - ~22~3~
release characteristics, especially the elimination of excessive tailing.
The polymers of this invention are exceptionally well suited as drug carriers for an oral dose-form, especially when their gel-structure is expanded by use of an inert Dylan during synthesis 9 and contain at least 25% by weight of residues derived from a monomer which is an alkyd acrylate and/or alkyd methacrylate having 4 to 10 carbon atoms in the alkyd group.
In form of shapes, for instance rods, the polymers of this invention are also useful as implant able drug carriers, since their blood- and tissue computability is excellent.
In form of films or sheets, the polymers of this invention are useful as drug carriers for transdermal devices or wound treatment and bandages.
In the following examples the degrees of swelling (DO) in water or ethanol are expressed as percent of water or of ethanol in the swollen polymer, namely:
DO in weight of - weight of = swollen polymer dry polymer X 100 water or ethanol (%) weight of swollen polymer Drug concentrations (DC) of drug loaded polymers are likewise ox-pressed in % of drug-loaded polymer.
The swelling ratio for a polymer is defined as the ratio % ethanol:
% water.
- 21 ~2-~3~
In the following examples MAO refers to a difunctional cross linking agent obtained by reaction of 2 mows isophorone diisocyanate with 1 mow poly-n-butyleneox;de dill of 2000 average molecular weight, followed by end-capping with 2 moles 2-hydroxyethyl methacrylate, which is described in Example 1.
The following abbreviations are used:
HEM : 2-hydroxyethyl methacrylate NIP : N-vinyl-2-pyrrolidone MA methyl methacrylate ETA : 2-ethylhexyl acrylate By : bottle acrylate ticket : tert.-octylmethacrylamide t= 1,1,3,3-tetramethylbutyl-methacrylamide) DAM : dimethylacrylamide MAO : macromer (B) as prepared in Example 1 MA : glycidyl methacrylate Example 1: Synthesis of Polymer beads by suspension polymerization A smooth wall, lamely resin flask is equipped with a reflex con-denser, nitrogen-inlet tube, thermometer attached to a thermos regulator, baffle and anchor-type stirrer driven by a variable speed motor. A slow flow of nitrogen is maintained through the reaction flask at all times.
To the flask are charged 360 grams of 20% by weight aqueous sodium chloride solution followed by 12.5 grams (0.0615imoles), of magnesium chloride-hexahydrate. The solution is heated slowly to ~0C with rapid stirring. To this solution is then added drops 123 ml (0.123 moles) of a l-normal sodium hydroxide solution to form a fine, gelatinous precipitate of magnesium hydroxide in the reaction flask - 22 - ~2~3~
after all the sodium hydroxide is added, the stirring speed is reduced to 100 rum and a mixture of 42 g 2-hydroxyethyl methacrylate, 110 g methyl methacrylate and 24 g N-vinylpyrrolidone and 24 g macromer (b) containing dissolved therein 0.2 g of tert.-butyl peroctoate as a free radical polymerization initiator is added.
[The macromer (b) is prepared by dissolving 60 g (cay. 0.024 moles) of a poly(tetramethylene oxide) glycol (average molecular weight of 2,000) end capped with isophorone diisocyanate (= 3-isocyanate-methyl-3,5,5-trimethylcyclohexyl isocyanate) in 40 g (0.31 moles) of 2-hydroxyethyl methacrylate HEM and allowing said mixture to react for 72 hours at room temperature. At the end of this period the disappearance of the terminal isocyanate groups is verified by noting the absence of the characteristic infrared spectral band at 227n cm associated with the -NC0 group.]
The reaction mixture is stirred under nitrogen at 100 rum and at 75C for three hours. The temperature is then raised to 100C for 1 hour after which time the flask is cooled to room temperature.
10 ml of concentrated hydrochloric acid are then added to dissolve the magnesium hydroxide suspending agent. The reaction is then filtered through fine cheesecloth. The isolated product beads are washed with 2,000 ml of water and soaked overnight in 500 ml of ethanol to extract any residual monomer. The beads are then isolated by filtration through a polyester cloth bag which is then sewn closed, and dried in a home clothes dryer. Uniform spherical beads are obtained in a yield of 184 g (92.7%) which have an average diameter of 0.98 mm and exhibit a percent swelling in water of 16% and in ethanol of 38%.
The following examples demonstrate the unique swelling properties (high % ethanol/% water ratio; % ~2 1) of the polymers.
Examples 2-12: Using the procedure of Rx. 1 beads with the following compositions and physical properties were synthesized.
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- 24 - ~2~3~
Example 13: The procedure of Example 2 is repeated, but instead of methyl methacrylate, 27.5% isoborny] methacrylate is used.
Colorless beads are obtained with 0.97 mm average dianleter with a degree of swelling of in ethanol = 58%, in water 8% and with the swelling ratio of 7.2.
Examples 14-15: Following the procedure of Example 1, beads con-twining 21% HEM, 12% MAO cross linking agent and 67% of the listed comonomers are prepared:
Hydrophobic Ethanol Water Comonomer A. Bead % Swelling in Swellillg En. (% Betty) size (mm) Ethanol Water Ratio (%/~) .
14 cyclohexyl (67) 1.20 52 8.7 6.0 methacrylate 15 n-butyl 1.00 70 9.9 7.1 acrylate (67) The following examples show that the polymers obtained with higher alkyd (C4~C10~acrylates and methacrylates exhibit superior ethanol swelling properties (high % ethanol/% water ratio.
Example 16: Following the procedure of Example 1 copolymer beads are synthesized by polymerizing a mixture of 42 g HEM, 66 g MA, 66 g ETA;
24 g NIP and 2 g ethylene dimethacrylate (EGDM) instead of the macromeric cross linking agent MAO. Uniformly spherical beads are ox-twined with an average diameter of 0.72 mm.
Their composition was: HEM : 21%
NIP : 12~
MA : 33%
ETA : 33%
EGDM : 1%
.
- 25 - ~2~3~
The ethanol swelling is 60%, water swelling 11% and the swelling ratio (I ethanol water) = 5.5.
xample 17: Synthesis of polymer beads with expanded gel-structure by polymerization in presence of inert delineates A smooth wall, l,000-ml resin flask is equipped with a reflex con-denser, nitrogen-inlet tube, thermometer attached to a thermoregulator, baffle and anchor-type stirrer driven by a variable speed motor.
A slow flow of nitrogen is maintained through the reaction flask at all times.
To the flask are charged 360 g of a 20% by weight aqueous sodium chloride solution followed by 12.5 g (0.0615 moles), of magnesium chloride-hexahydrate. The solution is heated slowly to 80C with rapid stirring. To this solution is then added drops 123 mow (0.123 moles) of a l-normal sodium hydroxide solution to form a fine, gelatinous precipitate of magnesium hydroxide in the reaction flask.
After all the sodium hydroxide is added, the stirring speed is reduced to 100 rum and a mixture of 42 g HEM, 55 g MA, 55 g ELLA, 24 g NIP, 50 g poly(oxypropylene) glycol, MY 3600, and 24 g macromer (b) containing dissolved therein 0.2 g of tert.-butyl peroctoate as a free radical polymerization initiator is added. (The macromer (b) is prepared as described in Example I
The reaction mixture is stirred under nitrogen at 100 rum and a 75C
for three hours. The temperature is then raised to Luke for 1 hour after winch time the flask is cooled to room temperature. 10 ml of concentrated hydrochloric acid are then added to dissolve the magnesium hydroxide suspending agent. The reaction mixture is then filtered through the cheesecloth. The isolated product beads are washed with 2,000 ml of water end soaked overnight in 500 ml of - 26 - 03~
ethanol to extract any residual monomer and then extracted in a sexuality with refluxing ethanol. The beads are then isolated by filtration through a polyester cloth bag, which is then sewn closed, and dried in a home clothes dryer. Uniform spherical beads are ox-twined in a yield of 177 g (89%~ which an average diameter of 0.74 mm and exhibited a percent swelling in waxer of 12% and in ethanol of 58%.
Examples 18-27: Following the procedure of Example 17, beads with expanded gel-structure are prepared using the inert delineates listed below. All polymers contain 21% HEM, 12% NIP and 12% I cross-linking agent.
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The following example show the preparation and drug-release of oral drug dosage forms by imbibition of the polymers with drug solutions.
: 10 g of dry polymer beads prepared according to Example 2 having an average diameter of 1.1 0.1 mm (-16+18 mesh) are immersed and shaken for 12 hours in a solution of 50 g oxprenolol-Hal in 50 g methanol. The beads are filtered off, rinsed free of drug adhering to the surface with absolute ethanol and dried in vacua at 50C to constant weight (10 hours). The drug content of the beads is determined gravimetrically to be 37.3% oxprenolol-HCl.
In this process, a thin surface region of the drug loaded bead is rendered free of drug by extraction with a few boiling solvent like acetone for a precise time period, followed by rapid drying. Why these polymers show this unexpectedly useful behavior is not well understood, but may be due to a phase-inversion of polymer segments on the bead-surface under the influence of a solvent. Drug-loaded polymers having 30-70% of their total hydrophobic monomer composition derived from C4-C21 alkyd substituted monomers are thus another especially preferred embodiment of this invention.
It has furthermore been found unexpectedly that use of polymeric inert dilettantes during the synthesis of the polymer beads of the instant invention gave after extraction beads with a specifically modified network structure which resulted in unexpectedly good drug-- 20 - ~22~3~
release characteristics, especially the elimination of excessive tailing.
The polymers of this invention are exceptionally well suited as drug carriers for an oral dose-form, especially when their gel-structure is expanded by use of an inert Dylan during synthesis 9 and contain at least 25% by weight of residues derived from a monomer which is an alkyd acrylate and/or alkyd methacrylate having 4 to 10 carbon atoms in the alkyd group.
In form of shapes, for instance rods, the polymers of this invention are also useful as implant able drug carriers, since their blood- and tissue computability is excellent.
In form of films or sheets, the polymers of this invention are useful as drug carriers for transdermal devices or wound treatment and bandages.
In the following examples the degrees of swelling (DO) in water or ethanol are expressed as percent of water or of ethanol in the swollen polymer, namely:
DO in weight of - weight of = swollen polymer dry polymer X 100 water or ethanol (%) weight of swollen polymer Drug concentrations (DC) of drug loaded polymers are likewise ox-pressed in % of drug-loaded polymer.
The swelling ratio for a polymer is defined as the ratio % ethanol:
% water.
- 21 ~2-~3~
In the following examples MAO refers to a difunctional cross linking agent obtained by reaction of 2 mows isophorone diisocyanate with 1 mow poly-n-butyleneox;de dill of 2000 average molecular weight, followed by end-capping with 2 moles 2-hydroxyethyl methacrylate, which is described in Example 1.
The following abbreviations are used:
HEM : 2-hydroxyethyl methacrylate NIP : N-vinyl-2-pyrrolidone MA methyl methacrylate ETA : 2-ethylhexyl acrylate By : bottle acrylate ticket : tert.-octylmethacrylamide t= 1,1,3,3-tetramethylbutyl-methacrylamide) DAM : dimethylacrylamide MAO : macromer (B) as prepared in Example 1 MA : glycidyl methacrylate Example 1: Synthesis of Polymer beads by suspension polymerization A smooth wall, lamely resin flask is equipped with a reflex con-denser, nitrogen-inlet tube, thermometer attached to a thermos regulator, baffle and anchor-type stirrer driven by a variable speed motor. A slow flow of nitrogen is maintained through the reaction flask at all times.
To the flask are charged 360 grams of 20% by weight aqueous sodium chloride solution followed by 12.5 grams (0.0615imoles), of magnesium chloride-hexahydrate. The solution is heated slowly to ~0C with rapid stirring. To this solution is then added drops 123 ml (0.123 moles) of a l-normal sodium hydroxide solution to form a fine, gelatinous precipitate of magnesium hydroxide in the reaction flask - 22 - ~2~3~
after all the sodium hydroxide is added, the stirring speed is reduced to 100 rum and a mixture of 42 g 2-hydroxyethyl methacrylate, 110 g methyl methacrylate and 24 g N-vinylpyrrolidone and 24 g macromer (b) containing dissolved therein 0.2 g of tert.-butyl peroctoate as a free radical polymerization initiator is added.
[The macromer (b) is prepared by dissolving 60 g (cay. 0.024 moles) of a poly(tetramethylene oxide) glycol (average molecular weight of 2,000) end capped with isophorone diisocyanate (= 3-isocyanate-methyl-3,5,5-trimethylcyclohexyl isocyanate) in 40 g (0.31 moles) of 2-hydroxyethyl methacrylate HEM and allowing said mixture to react for 72 hours at room temperature. At the end of this period the disappearance of the terminal isocyanate groups is verified by noting the absence of the characteristic infrared spectral band at 227n cm associated with the -NC0 group.]
The reaction mixture is stirred under nitrogen at 100 rum and at 75C for three hours. The temperature is then raised to 100C for 1 hour after which time the flask is cooled to room temperature.
10 ml of concentrated hydrochloric acid are then added to dissolve the magnesium hydroxide suspending agent. The reaction is then filtered through fine cheesecloth. The isolated product beads are washed with 2,000 ml of water and soaked overnight in 500 ml of ethanol to extract any residual monomer. The beads are then isolated by filtration through a polyester cloth bag which is then sewn closed, and dried in a home clothes dryer. Uniform spherical beads are obtained in a yield of 184 g (92.7%) which have an average diameter of 0.98 mm and exhibit a percent swelling in water of 16% and in ethanol of 38%.
The following examples demonstrate the unique swelling properties (high % ethanol/% water ratio; % ~2 1) of the polymers.
Examples 2-12: Using the procedure of Rx. 1 beads with the following compositions and physical properties were synthesized.
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Example 13: The procedure of Example 2 is repeated, but instead of methyl methacrylate, 27.5% isoborny] methacrylate is used.
Colorless beads are obtained with 0.97 mm average dianleter with a degree of swelling of in ethanol = 58%, in water 8% and with the swelling ratio of 7.2.
Examples 14-15: Following the procedure of Example 1, beads con-twining 21% HEM, 12% MAO cross linking agent and 67% of the listed comonomers are prepared:
Hydrophobic Ethanol Water Comonomer A. Bead % Swelling in Swellillg En. (% Betty) size (mm) Ethanol Water Ratio (%/~) .
14 cyclohexyl (67) 1.20 52 8.7 6.0 methacrylate 15 n-butyl 1.00 70 9.9 7.1 acrylate (67) The following examples show that the polymers obtained with higher alkyd (C4~C10~acrylates and methacrylates exhibit superior ethanol swelling properties (high % ethanol/% water ratio.
Example 16: Following the procedure of Example 1 copolymer beads are synthesized by polymerizing a mixture of 42 g HEM, 66 g MA, 66 g ETA;
24 g NIP and 2 g ethylene dimethacrylate (EGDM) instead of the macromeric cross linking agent MAO. Uniformly spherical beads are ox-twined with an average diameter of 0.72 mm.
Their composition was: HEM : 21%
NIP : 12~
MA : 33%
ETA : 33%
EGDM : 1%
.
- 25 - ~2~3~
The ethanol swelling is 60%, water swelling 11% and the swelling ratio (I ethanol water) = 5.5.
xample 17: Synthesis of polymer beads with expanded gel-structure by polymerization in presence of inert delineates A smooth wall, l,000-ml resin flask is equipped with a reflex con-denser, nitrogen-inlet tube, thermometer attached to a thermoregulator, baffle and anchor-type stirrer driven by a variable speed motor.
A slow flow of nitrogen is maintained through the reaction flask at all times.
To the flask are charged 360 g of a 20% by weight aqueous sodium chloride solution followed by 12.5 g (0.0615 moles), of magnesium chloride-hexahydrate. The solution is heated slowly to 80C with rapid stirring. To this solution is then added drops 123 mow (0.123 moles) of a l-normal sodium hydroxide solution to form a fine, gelatinous precipitate of magnesium hydroxide in the reaction flask.
After all the sodium hydroxide is added, the stirring speed is reduced to 100 rum and a mixture of 42 g HEM, 55 g MA, 55 g ELLA, 24 g NIP, 50 g poly(oxypropylene) glycol, MY 3600, and 24 g macromer (b) containing dissolved therein 0.2 g of tert.-butyl peroctoate as a free radical polymerization initiator is added. (The macromer (b) is prepared as described in Example I
The reaction mixture is stirred under nitrogen at 100 rum and a 75C
for three hours. The temperature is then raised to Luke for 1 hour after winch time the flask is cooled to room temperature. 10 ml of concentrated hydrochloric acid are then added to dissolve the magnesium hydroxide suspending agent. The reaction mixture is then filtered through the cheesecloth. The isolated product beads are washed with 2,000 ml of water end soaked overnight in 500 ml of - 26 - 03~
ethanol to extract any residual monomer and then extracted in a sexuality with refluxing ethanol. The beads are then isolated by filtration through a polyester cloth bag, which is then sewn closed, and dried in a home clothes dryer. Uniform spherical beads are ox-twined in a yield of 177 g (89%~ which an average diameter of 0.74 mm and exhibited a percent swelling in waxer of 12% and in ethanol of 58%.
Examples 18-27: Following the procedure of Example 17, beads with expanded gel-structure are prepared using the inert delineates listed below. All polymers contain 21% HEM, 12% NIP and 12% I cross-linking agent.
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The following example show the preparation and drug-release of oral drug dosage forms by imbibition of the polymers with drug solutions.
: 10 g of dry polymer beads prepared according to Example 2 having an average diameter of 1.1 0.1 mm (-16+18 mesh) are immersed and shaken for 12 hours in a solution of 50 g oxprenolol-Hal in 50 g methanol. The beads are filtered off, rinsed free of drug adhering to the surface with absolute ethanol and dried in vacua at 50C to constant weight (10 hours). The drug content of the beads is determined gravimetrically to be 37.3% oxprenolol-HCl.
5 g of the loaded beads are stirred in 1 liter of distilled water at 37.5QC. The water is circulated through a W -spectrophotometer to measure the rate of drug release. 50% of the drug is released within 35 minutes and 90% is released within 120 minutes Following the same procedure the following polymer-drug compositions are prepared and release rates measured.
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The following two examples demonstrate the usefulness of drug loaded beads of the instant invention for carrying out the controlled-extrac-lion process whereby a much prolonged drug-release can be obtained while still maintaining a high drug content.
Example 58: Two 5 g samples of drug loaded beads from Example 48 are immersed in water for 10 minutes (Treatment A) and for 20 minutes (Treatment B) followed by rapid freeze drying.
The following table shows the resulting drug loadings and times at which 50% and 90% of the drug are released into a stirred volume (1 liter) of water at 37.5C, continuously circulating through an UV-spectrophotometer cell.
Beads of Time to Release Example Drug % (hours) __ _ . . .
48diclofenac sodium 49.2 0.3 1.65 After treatment A 42.3 2.45 6.25 After treatment B 37.4 5.33 9.71 Example 59: 5 g of drug loaded beads of Example 41-are immersed for .
10 min. in acetone, followed by rapid freeze drying in vacua. Drug content is determined and-drug release rates misword as described above, with the following results:
Beads of Doug 7 Example (hours) _ _ , _ _ _ oxprenolol-~CI 50.8 0.2 1.68 After treatment 46.3 1.12 3.27 _ _ ._ _ ..
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examples 60-63:
The following examples show the superiority of beads prepared in the presence of a polymeric inert delineate over beads prepared with a low mol. weight inert delineate in reducing the tailing effect during drug release.
5 g samples of beads prepared according Jo Examples 17, 18 and 22 and loaded according to Examples 28-38 with oxprnolol-HCl and diclofenac, are treated by a controlled-extraction treatment. Their drug release is measured by stirring them in 1 liter distilled water at 37.5C and circulating the water through an UV-spectrophotometer cell. As shown in the table, the polymeric delineate polypropylene oxide (PPM) results in 90% release within 9 hours, whereas low molecular weight dodecanol (DUD) leads to excessive along.
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The following two examples demonstrate the usefulness of drug loaded beads of the instant invention for carrying out the controlled-extrac-lion process whereby a much prolonged drug-release can be obtained while still maintaining a high drug content.
Example 58: Two 5 g samples of drug loaded beads from Example 48 are immersed in water for 10 minutes (Treatment A) and for 20 minutes (Treatment B) followed by rapid freeze drying.
The following table shows the resulting drug loadings and times at which 50% and 90% of the drug are released into a stirred volume (1 liter) of water at 37.5C, continuously circulating through an UV-spectrophotometer cell.
Beads of Time to Release Example Drug % (hours) __ _ . . .
48diclofenac sodium 49.2 0.3 1.65 After treatment A 42.3 2.45 6.25 After treatment B 37.4 5.33 9.71 Example 59: 5 g of drug loaded beads of Example 41-are immersed for .
10 min. in acetone, followed by rapid freeze drying in vacua. Drug content is determined and-drug release rates misword as described above, with the following results:
Beads of Doug 7 Example (hours) _ _ , _ _ _ oxprenolol-~CI 50.8 0.2 1.68 After treatment 46.3 1.12 3.27 _ _ ._ _ ..
~2~i[)3~
examples 60-63:
The following examples show the superiority of beads prepared in the presence of a polymeric inert delineate over beads prepared with a low mol. weight inert delineate in reducing the tailing effect during drug release.
5 g samples of beads prepared according Jo Examples 17, 18 and 22 and loaded according to Examples 28-38 with oxprnolol-HCl and diclofenac, are treated by a controlled-extraction treatment. Their drug release is measured by stirring them in 1 liter distilled water at 37.5C and circulating the water through an UV-spectrophotometer cell. As shown in the table, the polymeric delineate polypropylene oxide (PPM) results in 90% release within 9 hours, whereas low molecular weight dodecanol (DUD) leads to excessive along.
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Claims (16)
1. A process for the production of a controlled-release, drug-delivery composition which comprises equilibrating (A) a crosslinked copolymer, capable of swelling in ethanol to give a swollen copolymer containing at least 40% by weight of ethanol, and capable of swelling in water to give a swollen copolymer con-taining no more than 20% by weight of water, where the swelling ratio (% ethanol: % water) is 2:1 to 22:1, which copolymer is the copolymerization product of (a) 50 to 99% by weight of said copolymer of (aa) a water-insoluble monoolefinic monomer, or mixture of said monomers, or mixture of said monomers with 0 to 45% by weight of total monomers of (bb) a water-soluble monoolefinic monomer, or mixture of said water-soluble monomers, with (b) 50 to 1% by weight of said copolymer of a divinyl or polyvinyl crosslinking agent having a molecular weight of 100 to 10,000, but where (b) is not more than 20 mol% of component (a), and (B) in a solution of a pharmaceutical medicament whose solvent swells said copolymer (A), lodading up said copolymer (A) with an effective amount of said medicament, removing the loaded composition from the solution and subsequently drying it.
2. A process according to claim 1, wherein the used copolymer (A) exhibits a swelling ratio of 3:1 to 15:1.
3. A process according to claim 2, wherein the used copolymer (A) exhibits a swelling ratio of 4:1 to 8:1.
4. A process according to claim 1, wherein the used copolymer (A) at least a third by weight of the water-insoluble monomer of component (a) is a monomer with an alkyl group of 4 to 21 carbon atoms.
5, A process according to claim 1, wherein the used copolymer (A) is the copolymerization product of 75-98% by weight of component (a) and 25-2% by weight of component (b).
6. A process according to claim 1, wherein the used component (a) com-prises 70-95% by weight of water-insoluble monomer (aa) and 30-5%
by weight of water-soluble monomer (bb).
by weight of water-soluble monomer (bb).
7. A process according to claim 1, wherein the used component (a) is 75-0%
by weight of methyl acrylate, methyl methacrylate or mixture thereof, and 25-100% by weight of a C4-C10 alkyl acrylate or methacrylate or mixture thereof.
by weight of methyl acrylate, methyl methacrylate or mixture thereof, and 25-100% by weight of a C4-C10 alkyl acrylate or methacrylate or mixture thereof.
8, A process according to claim 1, wherein the used water-insoluble monomer of component (a) is methyl methacrylate, n-butyl acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate, n-octyl acrylate, n-octyl methacrylate, glycidyl methacrylate, vinyl acetate or mixtures thereof.
9. A process according to claim 1, wherein 10-60% by weight of used component (a) is n-butyl acrylate or 2-ethylhexyl acrylate.
10. A process according to claim 1, wherein the used water-soluble monomer of component (a) is N-vinyl-2-pyrrolidone, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, acrylic acid, methacrylic acid, N,N-dimethylacrylamide, 2-dimethylaminoethyl methacrylate or mixtures thereof.
11. A process according to claim 1, where the used crosslinking agent of component (b) is a terminal diolefinic hydrophobic macromer having a molecular weight from about 400 to about 8000, said monomer having the formula wherein R1 is a polycondensate chain having a molecular weight from about 200 to 8000, which is the residue of a poly(propylene oxide) or poly(tetramethylene oxide) glycol having ether linkages;
R2 is hydrogen, methyl or -CH2COOR4, wherein R4 is hydrogen or an alkyl group with up to 10 carbon atoms;
R3 is hydrogen or COOR4, with the proviso that at least one of R2 and R3 is hydrogen;
X is oxa, -COO-, or -CONR5- where R5 is hydrogen or alkyl with up to 5 carbon atoms and Y is a direct bond or the radical -R6-Z1-CO-NH-R7-NH-CO-Z2-, wherein R6 is linked to X and represents branched or linear alkylene with up to 7 carbon atoms; Z1 and Z2 is oxa or NR5 and R7 is the diradical of an aliphatic or aromatic diisocyanate, with the proviso that in case X is oxa, Y is different from a direct bond and R2 and R3 are hydrogen.
R2 is hydrogen, methyl or -CH2COOR4, wherein R4 is hydrogen or an alkyl group with up to 10 carbon atoms;
R3 is hydrogen or COOR4, with the proviso that at least one of R2 and R3 is hydrogen;
X is oxa, -COO-, or -CONR5- where R5 is hydrogen or alkyl with up to 5 carbon atoms and Y is a direct bond or the radical -R6-Z1-CO-NH-R7-NH-CO-Z2-, wherein R6 is linked to X and represents branched or linear alkylene with up to 7 carbon atoms; Z1 and Z2 is oxa or NR5 and R7 is the diradical of an aliphatic or aromatic diisocyanate, with the proviso that in case X is oxa, Y is different from a direct bond and R2 and R3 are hydrogen.
12. A process according to claim 11, wherein R1 is a polypropylene oxide or polytetramethylene oxide chain with a molecular weight of about 600 to about 4000.
13. A process according to claim 11, wherein said macromer is a polytetramethyleneoxide glycol with a molecular weight of about 600 to about 4000, endcapped with toluene or isophorone diisocyanate and reacted with 2 moles of a hydroxyalkal acrylate or methacrylate, wherein alkyl has 2 to 4 carbon atoms.
14. A process according to claim 1, wherein the used crosslinking agent (b) is a C2-C6 alkylene diacrylate, a C2-C6 alkylene dimeth-acrylate, 3-oxapentamethylene diacrylate, 3-oxapentamethylene dimethacrylate, trimethylolpropane triacrylate or mixtures thereof.
15. A process according to claim 1, where the used copolymer (A) is the copolymerization product of 85-99% of component (a) and 15-1% of component (b) where (a) is 15-55% by weight of methyl methacrylate, 70-15% by weight of 2-ethylhexyl acrylate, n-butyl acrylate or n-octyl acrylate, 15-5% by weight of N-vinyl-2-pyrrolidone and 0-25%
by weight of 2-hydroxyethyl methacrylate.
by weight of 2-hydroxyethyl methacrylate.
16. A process for stabilising an effective amount of pharmaceutical medicament to a controlled-release medicament-delivery composition, which comprises equilibrating a crosslinked copolymer (A) according to claim 1 in a solution of a pharmaceutical medicament, whose solvent swells said copolymer (A), and loading up said copolymer with an effective amount of said medicament, removing the loaded composition from the solution and subsequently drying it.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/523,236 US4548990A (en) | 1983-08-15 | 1983-08-15 | Crosslinked, porous polymers for controlled drug delivery |
| US523,236 | 1983-08-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1225030A true CA1225030A (en) | 1987-08-04 |
Family
ID=24084203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000460855A Expired CA1225030A (en) | 1983-08-15 | 1984-08-13 | Crosslinked, porous polymers for controlled drug delivery |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4548990A (en) |
| EP (1) | EP0140828B1 (en) |
| JP (1) | JPS6067435A (en) |
| AT (1) | ATE60997T1 (en) |
| AU (1) | AU570712B2 (en) |
| CA (1) | CA1225030A (en) |
| DE (1) | DE3484165D1 (en) |
| DK (1) | DK390584A (en) |
| ES (1) | ES8604020A1 (en) |
| FI (1) | FI80283C (en) |
| GR (1) | GR80109B (en) |
| IL (1) | IL72664A (en) |
| NO (1) | NO167360C (en) |
| NZ (1) | NZ209213A (en) |
| PT (1) | PT79054B (en) |
| ZA (1) | ZA846301B (en) |
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-
1983
- 1983-08-15 US US06/523,236 patent/US4548990A/en not_active Expired - Fee Related
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1984
- 1984-08-09 EP EP84810393A patent/EP0140828B1/en not_active Expired - Lifetime
- 1984-08-09 DE DE8484810393T patent/DE3484165D1/en not_active Expired - Lifetime
- 1984-08-09 PT PT79054A patent/PT79054B/en not_active IP Right Cessation
- 1984-08-09 AT AT84810393T patent/ATE60997T1/en not_active IP Right Cessation
- 1984-08-13 GR GR80109A patent/GR80109B/en unknown
- 1984-08-13 FI FI843190A patent/FI80283C/en not_active IP Right Cessation
- 1984-08-13 CA CA000460855A patent/CA1225030A/en not_active Expired
- 1984-08-13 IL IL72664A patent/IL72664A/en unknown
- 1984-08-14 NO NO843237A patent/NO167360C/en unknown
- 1984-08-14 NZ NZ209213A patent/NZ209213A/en unknown
- 1984-08-14 ES ES535129A patent/ES8604020A1/en not_active Expired
- 1984-08-14 ZA ZA846301A patent/ZA846301B/en unknown
- 1984-08-14 AU AU31896/84A patent/AU570712B2/en not_active Ceased
- 1984-08-14 DK DK390584A patent/DK390584A/en not_active Application Discontinuation
- 1984-08-15 JP JP59170319A patent/JPS6067435A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7749203B2 (en) | 2001-07-23 | 2010-07-06 | Boston Scientific Scimed, Inc. | Long-term indwelling medical devices containing slow-releasing antimicrobial agents and having a surfactant surface |
Also Published As
| Publication number | Publication date |
|---|---|
| GR80109B (en) | 1984-12-14 |
| EP0140828A3 (en) | 1987-02-04 |
| EP0140828A2 (en) | 1985-05-08 |
| US4548990A (en) | 1985-10-22 |
| ATE60997T1 (en) | 1991-03-15 |
| ZA846301B (en) | 1985-05-29 |
| EP0140828B1 (en) | 1991-02-27 |
| FI80283B (en) | 1990-01-31 |
| DE3484165D1 (en) | 1991-04-04 |
| DK390584D0 (en) | 1984-08-14 |
| FI843190A0 (en) | 1984-08-13 |
| IL72664A (en) | 1988-03-31 |
| FI843190A (en) | 1985-02-16 |
| NZ209213A (en) | 1986-12-05 |
| DK390584A (en) | 1985-02-16 |
| AU570712B2 (en) | 1988-03-24 |
| JPS6067435A (en) | 1985-04-17 |
| IL72664A0 (en) | 1984-11-30 |
| ES535129A0 (en) | 1986-01-16 |
| NO167360B (en) | 1991-07-22 |
| PT79054B (en) | 1987-06-03 |
| NO167360C (en) | 1991-10-30 |
| NO843237L (en) | 1985-02-18 |
| ES8604020A1 (en) | 1986-01-16 |
| AU3189684A (en) | 1985-02-21 |
| FI80283C (en) | 1990-05-10 |
| PT79054A (en) | 1984-09-01 |
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