CA1288344C - Drug delivery system - Google Patents
Drug delivery systemInfo
- Publication number
- CA1288344C CA1288344C CA000528750A CA528750A CA1288344C CA 1288344 C CA1288344 C CA 1288344C CA 000528750 A CA000528750 A CA 000528750A CA 528750 A CA528750 A CA 528750A CA 1288344 C CA1288344 C CA 1288344C
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- CA
- Canada
- Prior art keywords
- cross
- weight
- polymer
- mixture
- active ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Abstract
ABSTRACT
DRUG DELIVERY SYSTEM
A controlled release formulation comprising an adsorbate of a mixture of a pharmaceutically useful active ingredient and an inactive substance adsorbed on a cross-linked polymer. The inactive substance is selected to modify the dissolution of the active ingredient from the cross-linked polymer in vivo.
DRUG DELIVERY SYSTEM
A controlled release formulation comprising an adsorbate of a mixture of a pharmaceutically useful active ingredient and an inactive substance adsorbed on a cross-linked polymer. The inactive substance is selected to modify the dissolution of the active ingredient from the cross-linked polymer in vivo.
Description
334~
DRUG DELIVERY S~!STEM
BACKGROIJND OF T}IE INVENTION
This invention relates to a method for the manufacture of adsorbates for use in drug delivery systems and to the adsorbates and drug formulations thereby obtained.
It is frequently desirable to delay the release of an active substance from a pharmaceutical formulation ln vivo. For example, it may be desirable to delay release of the active substance within the body so that the active substance is released at a particular target site. Various coated tablets are available which are resistant to gastric juices but which are readily soluble in the higher pH environment of the small intestine. Various controlled absorption pharmacautical formulations are also available which have a particular dissolution pattern, resulting in a controlled absorption of the active substance and, therefore, more ef~ective medication~ For example, controlled absorption pellets of the latter type for oral administration are described in the U.S. Patent Nos.
4,663,150 (issued May 5, 1987), 4,716,040 (issued December 29, 1987), 4,721,619 (issued January 26, 1988), 4,820,521 (issued April 11, 1989) and 4,826,688 (issued ~5 May 2, 1989) and EP-A-0 123 470.
The use of many active substances in therapy is complicated by solubility problems. In the case of some insoluble Arugs like nifedipine co-precipitates thereof with certain polymers are known, said co-precipitates .~
~ ~ 3 ~ 133~
having been formed into tablets by conventional tabletting procedures. Such co--precipitates however normally require a pol~mer to active drug ratio exceeding 3:1 in order to be effective in producing products characterised by high bioavailability with prompt peak blood levels.
Pharmaceutical formulations based on an adsorbate of a drug within a cross-linked polymer, such as cross-povidone, are also known. Furthermore, solid, rapidly absorbable medicament formulations comprising a dihydropyridine, polyvinylpyrrolidone with an average molecular weight of 15,000 to 50,000 and cross-linked insoluble polyvinylpyrrolidone are known from EP-A-0 167 909.
It is an object of the present invention to provide an improved drug delivery system wherein the bioavailability of an otherwise poorly bioavailable active substance is enhanced and effective controlled and sustained release formulations thereof can be produced.
SU~ARY OF THE INVENTION
According to one a~t, the ~vention provides a controlled release ~ormulation comprising an adsorbate of a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 to 10 parts by weight of an inactive substance adsorbed on a cross-linXed polymer in a ratio of 1 part by weight of said mixture to 0.5 - 20 parts by weight of cross-linked polymer, said inactive substance being selected to modi~`y the dissolution o~ the active drug from the cross-linked polymer in vivo, with the proviso that the active ingr2dient is not a dihydropyridine when the inactive substance is polyvinylpyrrolidone with an average molecular weight in the range 15,000 to 50,000 and the cross-linked polymer is cross-linked polyvinylpyrrolidone.
~ ~383~
- 3a -According to another aspect, the invention provides a sustained release drug delivery syste.m comprising a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 - 10 parts by weight of inactive substance, wherein 1 part by weight of said mixture is adsorbed on 0.5-20 parts by weight of a cross-linked polymer, wherein said inactive substance is selected to modify the dissolution of the active drug from the cross-linked polymer in vivo, and said active ingredient is in substantially amorphous form, the resultant adsorbate being granulated and blended with a polymer or mixture of polymers to yield a long-acting controlled release matrix system.
The invention also relates to processes for forming such products.
..,?~,., 33~
DETAILED DESCRIPTION OF THE INVENTION
The existence of the drug (active ingredient) in the pore spaces of the cross-linked polymer can be confirmed by x-ray diffraction studies. In the case of certain water-insoluble drugs, the formation o the adsorbate results in an amorphous state which can be verified by x-ray diffraction and, in addition, differential scanning calorimetery.
The inactive substance i5 preferably present in the adsorbate in an amount of 0.5 - 3 parts by weight relative to 1 part by weight of the active ingredient.
Furthexmore, the formulation preferably contains 1 part by weight of said mixture relative to 1 10 parts by weight of cross-linked polymer.
The invention also provides a process for preparing a controlled release formulation as defined above, which comprises dissolving the active ingredient and the inactive substance in a common solvent, mixing the solution thereby obtained with a given quantity of the cross-linked polymer so as to permit adsorption of said active ingredient and said inactive s~bstance to said cross-linked polymer and removing the solvent.
The solvent used is any pharmaceutically suitable co-solvent for the active drug and the inactive substance.
The solvent is suitably selected from water, alcohols, ketones, halo~enated aliphatic compounds, haloyenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.
Espacially preferred solvents include water, hexane, heptane, methanol, ethanol, isopropyl alcohol, acetone, methylethyl ketone, methylisobutyl ketone, mathylene chloride, chloroform, carbon tetrachloride, toluene, xylene and tetrahydro~uran.
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The inackive substance is chosen to modi~y the di~solution o~ the active drug from the cross-linked polymer such that a water soluble inactive substance will serve to enhance the rate of active drug leaching from the cross-linked polymer. Conversely, a water insoluble material would serve to impede the rate of active ingredient leaching ~rom the cross-linked polymer.
The inactive substancs is also chosen to modi~y the crystalline properties of the active ingredient both in 10 the controlled release formulation as prepared and in vivo after administration of the formulation.
An especially preferred cross-linked polymer is cross-povidone (Polplasdone XL (GAF), Kollidon CL (BASF) Polplasdone XL and Kollidon CL are Trade Marks) Others 15 include cross-linXed carboxymethylcellulose and cross-linked methylcellulose.
Any drug, subject to the above proviso, is suitable for use as active ingredient in the for~ulation according to the present invention. However, preferred drugs 20 include ibuprofen, acylovir, 5-amino-salicyclic acid, dextromethorphan, propranolol, theophylline, methyldopa, pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxicam, diclofenac, indomethacin, a~oxycillin, pivampicillin, bacampicillin, 25 dicloxacillin, erythromycin, linco~ycin, co-dergocrine mesylate, doxycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, nicardipine/ 4-~2, 1, 3-bensoxadiasol-4-yl)-2, 6-dimethyl-1, 4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl 30 ester, atenolol, lorazempam, glibenclamide, salbutamol, spironolactone, chlorpheniramine maleate, carboxamine maleake, potassium chloride and metoprolol tartrate.
~.%~33~
Especially preferred active ingredients include chlorphaniramine maleate, diclofenac, theophylline, felodipi:ne, nifedipine, nicardipine, nitrendipine, 4-(2, 1, 3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3~isopropyloxycarbonyl-pyridine- 5-carboxylic acid methyl ester, co-dergocrine mesylats, oxendolone, azidothymidine (AZT) and spironolactone.
The choica of inactive substance for use in controlliny the dissolution of the adsorbed active drug according to the present invention is determined by the particular pharmacological properties desired. For example, a water insoluble inactive substance may be used to delay the release of a highly water soluble drug.
Examples of inactive substances include inert polymers such as, for example, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkyl-c211uloses such as methyl- and ethylcellulose, shellac, polymers sold under the trademark ~udragit, polyethy:Lene glycol, sodium alginate, galactomannone or carboxypolymethylene or mixtures thereof.
Eudragit polymers are polymeric lacquer substances based on acrylates and/or methacrylates.
Especially suitable Eudragi~s for use as inactive substances in the system according to the invention include co-polymers of acrylic and methacrylic acid esters of varying permeability to the active ingredient and aqueous media.
Other suitable inactive substances for use in the system a~cording to the invention include sugars and many organic acids, such as adipic acid, ascorbic acid, citric acid, fumaric acid, mal~ic acid, succinic acid or tartaric acid.
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The choice of inactive substance is generally made by reference to the solubility of the active substance and will usually have its own solubility inversely proportional to that of the active drug. Therefore, water insoluble, polymeric materials have use in conjunction with highly water-soluble active drugs.
The invention also provides a sustained release drug delivery system comprising a controlled release formulation as defined above, suitably granulated and blended with a polymer or mixture o~ polymers which gels in the presence of water, and optionally other ingredients. The blend thereby obtained can be tabletted or encapsulated according to conventional methods, thereby yielding a long acting controlled release matrix system which also exhibits improved drug absorption.
~ Suitable polymers for blending with the controlled release formulation for subsequent tabletting or encapsulation are any one of the inert polymers cited above, which include both water soluble and water insoluble polymers. An especially suitable group of polymers is the polymers sold under the Trade Mark Methocel. If one wishes to delay release of the active ingredient in vivo in capsule or tablet ~orm a combination of a water soluble and a water insoluble polymer or a mixture of such polymers will be used, with the ratio o~ the water soluble to water insoluble polymer being varied to give the desired rate of release.
Similarly, in the case of polymers/copolymers of varying permeability the permeabililty characteristic of the polymers/copolymers will be chosen to give the desired rate of release.
The adsorbates according to the present invention result in improved controlled drug delivery relative to known active drug adsorbates in cross linked polymers, ~1.2~3~33~
since the adsorbate~ according to the present invention yield a matrix system exhibiting both delayed or sustained releaae o~ active drug and improved absorption of said active drug in vivo when granulated and blended with pharmaceutically acceptable polymers.
The invention will be further illustrated with reference to the following Examples.
Polyvinylpyrrolidone K-30 (~rade Mark) (2 kg) was dissolved in isopropylalcohol (10 kg). Nifedipine (1 kg) was then added to this solution and allowed to dissolve.
The solution thereby obtained was then adsorbed onto cross-linked carboxymethylcellulose (4 kg) and the - solvent evaporated. The resulting powder was then passed through an oscillating granulator to obtain a finer particle size. X ray di~raction and differential scanning calorimetry studie~ were performed on the powder and demonstrated that the nifedipine was in an amorphous form. The powder (30%~ wa~ then tabletted with the following lngredients.
Methocel XlOO~V (Trade Mark) 8.0 Avicel pX101 (Trade Mark) 61.5%
Magnesium stearate 0.5~
to obtain a tablet containing 20 mg of active ingredient.
An x-ray diffraction pattern o~ the tablet was obtained which demonstrated the amorphous nature of the nifedipine had been retained.
In the above Example, the ratio o~ nifedipine, polyvinylpyrrolidone and cros~-linked carboxymethylcellulose may be altered within the limits which retain the amorphous nature o~ the drug. This also applies in the case o~ the subsequent Examples.
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Furthermore, the MethocPl used may be Methocel K4M, K15M, KlOOM, or E, J, F grades depending on the release characteristics desired.
The gel forming polymer may be used in an amount of 3 - 50% with proportional changes in the percentage of adsorbate u ed. This also applies in the case of the subsequent Examples~
Polyvinylpyrrolidone K-30 (Trade Mark~ (2 kg) was dissolved in isopropyl alcohol (lO kg). Nicardipine (lkg) was then added to this solution and allowed to dissolve.
The solution thereby obtained was then adsorbed onto a cross-linked carboxymethylcellulose (Croscarmellulose -Trade Mark) (4 kg) and the solvent evaporated. The resulting powder was passed through an oscillating granulator to obtain a finer particle size. The powder (60~) was then tabletted with the following ingredients:
Methocel KlOOM (Trade Mark) 8.0~
Avicel pHlO1 (Trade Mark) 31.5%
Magnesium stearate 0.5~
to obtain a tablet containing 60 mg of active ingredient.
The procedure of Example 1 was repeated except that the nifedipine was replaced by an egual amount (1 kg) of (4- (2 r 1,3-benzoxadiazol-4-yl)-2, 6-dimethyl-1, 4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester to obtain tablets containing 10 mg mg of active ingredient.
Spironolactone ~1 kg) and polyvinylpyrrolidone K-30 (~ kg) were dissolved in a common solvent ethanol (lOkg).
Cross-povidone (4 kg) was added to the solution of spironolactone and polyvinylpyrrolidone so as to permit adsorption of the spironolactone and polyvinylpyrrolidone to the cros~-povidone. The solvent was then removed by heating. The ability of the spironolactone to be dissolved out of the cross-povidone is enhanced by the ready solubility of the polyvinylpyrrolidone in water. A
given ~uantity (50%~ of the adsorbate was granulated and blended with hydroxypropylmethylcellulose t50%). The blend thereby obtained was filled into soft gelatine capsules so as to obtain capsules containing (50 mg) of spironolactone.
83~
.... .~
Anhydrous theophylline (0.5 kg) and citric acid (1 kg) were dissolved in isopropyl alcohol tlO kg) and adsorbed on cross-povidone (2 kg) in the manner described in Example 1. A given quantity (50~) of the adsorbate thereby obtained was granulated and blended with Eudragit RL (50%). The blend was then filled into hard gelatine capsules (422 mg) so as to obtain capsules containing 300 mg of anhydrous theophylline. The presence of the citric acid was found to enhance the solubility of the anhydrous th~ophylline at pH values in excess of 7 and was suitable for use in a long acting or sustained release drug formulation.
Chlorpheniramine maleate (O.5%) and ethylcellulose (1 kg) which is insoluble in water and thereby inactive in an aqueous environment were dissolved in isopropyl alcohol (10 kg) and adsorbed onto cross-povidone (2 kg) in the manner described in Example 1. The powder (30%) was then tabletted with the following ingredients:
Methocel K15M (Trade Mark) 8.0%
Avicel pHlOl (Trade MarX) 61.5%
Magnesium stearate 0.5%
to obtain a tablet containing 10 mg of chlorpheniramine maleate r~
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Polyvinylpyrrolidone (K-30) (0.75 kg) was dissolved in methylene chloride (12 kg) nifedipine (1 kg) was then added to this solution and allowed to dissolve~ The solution thereby obtained was then adsorbed onto cross-linked carboxymethylcsllulose (3 kg) and the solvent evaporated. The resulting powder was then passed through an oscillating granulator to obtain a fine particle siz~. X-ray diffraction and differential scanning calorimetry studies showed that the drug was in amorphous form in this adsorbate. The powder (30%) was then tabletted with the following ingredients:
Methocel K100 LV (Trade Mark) 10%
Avicel pH101 (Trade Mark) 59.5%
Magnesium stearate 0.5%
to obtain a tablet containing 20 mg active ingredient.
Similar x-ray diffraction and differential scanning calorimetry studies showed this product to be amorphous.
The procedure employed was similar to that in Example 7 except that the amount of polyvinylpyrrolidone (K~30) used was 0.5 kg and also included was polyethylene glycol 6000 (1 kg).
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334~*
The procedure employed was similar to that in Example 8 except that the polyethylsne glycol was replaced by methylcellulose (0.75 kg).
The procedure employed was similar to that in Example 7 except that methylcellulose (0.75 kg) was used instead of polyvinylpyrrolidone 0.75 kg.
The procedure employed was simllar to that in Example 8 except that polyvinylpyrrolidone ~0.5 kg) was replaced by methylcellulose (0.5 kg~.
The procedure used was simi.lar to that employed in Example 7 except the polyvinylpyrrolidone (O.75 kg) was replaced by polyethylene glycol 6000 (1.5 kg).
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Polyvinylpyrrolidone K-25 (Trade Mark) (O.50 kg) was di~solved in isopropyl alcohol (10 kg). Diclofenac (lkg) was added to this solution and allowed to dissolve.
The solutlon thereby obtained was then adsorbed onto cross-linked polyvinylpyrrolidone (2.5 kg) and the solvent evaporated. The resulting powder (60%) was treated as in Example 1 and tabletted with the following ingredients-Methocel KlOOLV (Trade Mark) 16.5%
Avicel pH101 (Trade Mar~) 23.0%
Calcium stearate 0.5%
to obtain a tablet containing 100 mg active ingredient.
Methocel A4M (Trade Mark) (0.15 kg) was dissolved in dichloromethane (10 kg). Oxendolona (1 kg) was added to the solution and di~solved. The resulting solution was adsorbed onto cross-povidone (4 kg) and treated as per Example 1.
The resulting powder (80~) was tabletted with the following ingredients:
Methocel KlOOLV (Trade Mark) 1.5%
~vicel pH 10% (Trade Mark) 13.0%
Magnasium stearate 0.5%
to obtain a tablet contain~ng 100 mg active ingredient.
334~
Example 1 was repeated except the nifedipine formulation (50%) was tabletted with the following ingredients.
Sodium alginate 15.0~
Pregelatinized starch N.F. 33.5%
Talc 1.5%
Example 2 was repeated except the nicardipina formulation (50%) was tabletted with the ~ollowing ingredients:
Lactose U.S.P. 10.0%
Eudragit R.S. 10.0%
Eudragit R.L. 29.25%
Calcium stearate 0.75%
Example 6 was repeated except the chlorpheniramine maleate formulation (40~) was tabletted with the following ingredients.
Dibasic calcium phosphate 15.0%
dihydrate N.F.
Ethylcellulose 100 cps 15.0%
Polyethyleneglycol 6000 5.0%
Hydroxyethylcallulose 29.0%
Calcium ~tearate 1.0~
' '',; .' ,
DRUG DELIVERY S~!STEM
BACKGROIJND OF T}IE INVENTION
This invention relates to a method for the manufacture of adsorbates for use in drug delivery systems and to the adsorbates and drug formulations thereby obtained.
It is frequently desirable to delay the release of an active substance from a pharmaceutical formulation ln vivo. For example, it may be desirable to delay release of the active substance within the body so that the active substance is released at a particular target site. Various coated tablets are available which are resistant to gastric juices but which are readily soluble in the higher pH environment of the small intestine. Various controlled absorption pharmacautical formulations are also available which have a particular dissolution pattern, resulting in a controlled absorption of the active substance and, therefore, more ef~ective medication~ For example, controlled absorption pellets of the latter type for oral administration are described in the U.S. Patent Nos.
4,663,150 (issued May 5, 1987), 4,716,040 (issued December 29, 1987), 4,721,619 (issued January 26, 1988), 4,820,521 (issued April 11, 1989) and 4,826,688 (issued ~5 May 2, 1989) and EP-A-0 123 470.
The use of many active substances in therapy is complicated by solubility problems. In the case of some insoluble Arugs like nifedipine co-precipitates thereof with certain polymers are known, said co-precipitates .~
~ ~ 3 ~ 133~
having been formed into tablets by conventional tabletting procedures. Such co--precipitates however normally require a pol~mer to active drug ratio exceeding 3:1 in order to be effective in producing products characterised by high bioavailability with prompt peak blood levels.
Pharmaceutical formulations based on an adsorbate of a drug within a cross-linked polymer, such as cross-povidone, are also known. Furthermore, solid, rapidly absorbable medicament formulations comprising a dihydropyridine, polyvinylpyrrolidone with an average molecular weight of 15,000 to 50,000 and cross-linked insoluble polyvinylpyrrolidone are known from EP-A-0 167 909.
It is an object of the present invention to provide an improved drug delivery system wherein the bioavailability of an otherwise poorly bioavailable active substance is enhanced and effective controlled and sustained release formulations thereof can be produced.
SU~ARY OF THE INVENTION
According to one a~t, the ~vention provides a controlled release ~ormulation comprising an adsorbate of a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 to 10 parts by weight of an inactive substance adsorbed on a cross-linXed polymer in a ratio of 1 part by weight of said mixture to 0.5 - 20 parts by weight of cross-linked polymer, said inactive substance being selected to modi~`y the dissolution o~ the active drug from the cross-linked polymer in vivo, with the proviso that the active ingr2dient is not a dihydropyridine when the inactive substance is polyvinylpyrrolidone with an average molecular weight in the range 15,000 to 50,000 and the cross-linked polymer is cross-linked polyvinylpyrrolidone.
~ ~383~
- 3a -According to another aspect, the invention provides a sustained release drug delivery syste.m comprising a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 - 10 parts by weight of inactive substance, wherein 1 part by weight of said mixture is adsorbed on 0.5-20 parts by weight of a cross-linked polymer, wherein said inactive substance is selected to modify the dissolution of the active drug from the cross-linked polymer in vivo, and said active ingredient is in substantially amorphous form, the resultant adsorbate being granulated and blended with a polymer or mixture of polymers to yield a long-acting controlled release matrix system.
The invention also relates to processes for forming such products.
..,?~,., 33~
DETAILED DESCRIPTION OF THE INVENTION
The existence of the drug (active ingredient) in the pore spaces of the cross-linked polymer can be confirmed by x-ray diffraction studies. In the case of certain water-insoluble drugs, the formation o the adsorbate results in an amorphous state which can be verified by x-ray diffraction and, in addition, differential scanning calorimetery.
The inactive substance i5 preferably present in the adsorbate in an amount of 0.5 - 3 parts by weight relative to 1 part by weight of the active ingredient.
Furthexmore, the formulation preferably contains 1 part by weight of said mixture relative to 1 10 parts by weight of cross-linked polymer.
The invention also provides a process for preparing a controlled release formulation as defined above, which comprises dissolving the active ingredient and the inactive substance in a common solvent, mixing the solution thereby obtained with a given quantity of the cross-linked polymer so as to permit adsorption of said active ingredient and said inactive s~bstance to said cross-linked polymer and removing the solvent.
The solvent used is any pharmaceutically suitable co-solvent for the active drug and the inactive substance.
The solvent is suitably selected from water, alcohols, ketones, halo~enated aliphatic compounds, haloyenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.
Espacially preferred solvents include water, hexane, heptane, methanol, ethanol, isopropyl alcohol, acetone, methylethyl ketone, methylisobutyl ketone, mathylene chloride, chloroform, carbon tetrachloride, toluene, xylene and tetrahydro~uran.
,~' "~ .
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The inackive substance is chosen to modi~y the di~solution o~ the active drug from the cross-linked polymer such that a water soluble inactive substance will serve to enhance the rate of active drug leaching from the cross-linked polymer. Conversely, a water insoluble material would serve to impede the rate of active ingredient leaching ~rom the cross-linked polymer.
The inactive substancs is also chosen to modi~y the crystalline properties of the active ingredient both in 10 the controlled release formulation as prepared and in vivo after administration of the formulation.
An especially preferred cross-linked polymer is cross-povidone (Polplasdone XL (GAF), Kollidon CL (BASF) Polplasdone XL and Kollidon CL are Trade Marks) Others 15 include cross-linXed carboxymethylcellulose and cross-linked methylcellulose.
Any drug, subject to the above proviso, is suitable for use as active ingredient in the for~ulation according to the present invention. However, preferred drugs 20 include ibuprofen, acylovir, 5-amino-salicyclic acid, dextromethorphan, propranolol, theophylline, methyldopa, pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxicam, diclofenac, indomethacin, a~oxycillin, pivampicillin, bacampicillin, 25 dicloxacillin, erythromycin, linco~ycin, co-dergocrine mesylate, doxycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, nicardipine/ 4-~2, 1, 3-bensoxadiasol-4-yl)-2, 6-dimethyl-1, 4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl 30 ester, atenolol, lorazempam, glibenclamide, salbutamol, spironolactone, chlorpheniramine maleate, carboxamine maleake, potassium chloride and metoprolol tartrate.
~.%~33~
Especially preferred active ingredients include chlorphaniramine maleate, diclofenac, theophylline, felodipi:ne, nifedipine, nicardipine, nitrendipine, 4-(2, 1, 3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3~isopropyloxycarbonyl-pyridine- 5-carboxylic acid methyl ester, co-dergocrine mesylats, oxendolone, azidothymidine (AZT) and spironolactone.
The choica of inactive substance for use in controlliny the dissolution of the adsorbed active drug according to the present invention is determined by the particular pharmacological properties desired. For example, a water insoluble inactive substance may be used to delay the release of a highly water soluble drug.
Examples of inactive substances include inert polymers such as, for example, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkyl-c211uloses such as methyl- and ethylcellulose, shellac, polymers sold under the trademark ~udragit, polyethy:Lene glycol, sodium alginate, galactomannone or carboxypolymethylene or mixtures thereof.
Eudragit polymers are polymeric lacquer substances based on acrylates and/or methacrylates.
Especially suitable Eudragi~s for use as inactive substances in the system according to the invention include co-polymers of acrylic and methacrylic acid esters of varying permeability to the active ingredient and aqueous media.
Other suitable inactive substances for use in the system a~cording to the invention include sugars and many organic acids, such as adipic acid, ascorbic acid, citric acid, fumaric acid, mal~ic acid, succinic acid or tartaric acid.
A
gl 2~3~33~4~
The choice of inactive substance is generally made by reference to the solubility of the active substance and will usually have its own solubility inversely proportional to that of the active drug. Therefore, water insoluble, polymeric materials have use in conjunction with highly water-soluble active drugs.
The invention also provides a sustained release drug delivery system comprising a controlled release formulation as defined above, suitably granulated and blended with a polymer or mixture o~ polymers which gels in the presence of water, and optionally other ingredients. The blend thereby obtained can be tabletted or encapsulated according to conventional methods, thereby yielding a long acting controlled release matrix system which also exhibits improved drug absorption.
~ Suitable polymers for blending with the controlled release formulation for subsequent tabletting or encapsulation are any one of the inert polymers cited above, which include both water soluble and water insoluble polymers. An especially suitable group of polymers is the polymers sold under the Trade Mark Methocel. If one wishes to delay release of the active ingredient in vivo in capsule or tablet ~orm a combination of a water soluble and a water insoluble polymer or a mixture of such polymers will be used, with the ratio o~ the water soluble to water insoluble polymer being varied to give the desired rate of release.
Similarly, in the case of polymers/copolymers of varying permeability the permeabililty characteristic of the polymers/copolymers will be chosen to give the desired rate of release.
The adsorbates according to the present invention result in improved controlled drug delivery relative to known active drug adsorbates in cross linked polymers, ~1.2~3~33~
since the adsorbate~ according to the present invention yield a matrix system exhibiting both delayed or sustained releaae o~ active drug and improved absorption of said active drug in vivo when granulated and blended with pharmaceutically acceptable polymers.
The invention will be further illustrated with reference to the following Examples.
Polyvinylpyrrolidone K-30 (~rade Mark) (2 kg) was dissolved in isopropylalcohol (10 kg). Nifedipine (1 kg) was then added to this solution and allowed to dissolve.
The solution thereby obtained was then adsorbed onto cross-linked carboxymethylcellulose (4 kg) and the - solvent evaporated. The resulting powder was then passed through an oscillating granulator to obtain a finer particle size. X ray di~raction and differential scanning calorimetry studie~ were performed on the powder and demonstrated that the nifedipine was in an amorphous form. The powder (30%~ wa~ then tabletted with the following lngredients.
Methocel XlOO~V (Trade Mark) 8.0 Avicel pX101 (Trade Mark) 61.5%
Magnesium stearate 0.5~
to obtain a tablet containing 20 mg of active ingredient.
An x-ray diffraction pattern o~ the tablet was obtained which demonstrated the amorphous nature of the nifedipine had been retained.
In the above Example, the ratio o~ nifedipine, polyvinylpyrrolidone and cros~-linked carboxymethylcellulose may be altered within the limits which retain the amorphous nature o~ the drug. This also applies in the case o~ the subsequent Examples.
., g.2~
_ 9 ~
Furthermore, the MethocPl used may be Methocel K4M, K15M, KlOOM, or E, J, F grades depending on the release characteristics desired.
The gel forming polymer may be used in an amount of 3 - 50% with proportional changes in the percentage of adsorbate u ed. This also applies in the case of the subsequent Examples~
Polyvinylpyrrolidone K-30 (Trade Mark~ (2 kg) was dissolved in isopropyl alcohol (lO kg). Nicardipine (lkg) was then added to this solution and allowed to dissolve.
The solution thereby obtained was then adsorbed onto a cross-linked carboxymethylcellulose (Croscarmellulose -Trade Mark) (4 kg) and the solvent evaporated. The resulting powder was passed through an oscillating granulator to obtain a finer particle size. The powder (60~) was then tabletted with the following ingredients:
Methocel KlOOM (Trade Mark) 8.0~
Avicel pHlO1 (Trade Mark) 31.5%
Magnesium stearate 0.5~
to obtain a tablet containing 60 mg of active ingredient.
The procedure of Example 1 was repeated except that the nifedipine was replaced by an egual amount (1 kg) of (4- (2 r 1,3-benzoxadiazol-4-yl)-2, 6-dimethyl-1, 4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester to obtain tablets containing 10 mg mg of active ingredient.
Spironolactone ~1 kg) and polyvinylpyrrolidone K-30 (~ kg) were dissolved in a common solvent ethanol (lOkg).
Cross-povidone (4 kg) was added to the solution of spironolactone and polyvinylpyrrolidone so as to permit adsorption of the spironolactone and polyvinylpyrrolidone to the cros~-povidone. The solvent was then removed by heating. The ability of the spironolactone to be dissolved out of the cross-povidone is enhanced by the ready solubility of the polyvinylpyrrolidone in water. A
given ~uantity (50%~ of the adsorbate was granulated and blended with hydroxypropylmethylcellulose t50%). The blend thereby obtained was filled into soft gelatine capsules so as to obtain capsules containing (50 mg) of spironolactone.
83~
.... .~
Anhydrous theophylline (0.5 kg) and citric acid (1 kg) were dissolved in isopropyl alcohol tlO kg) and adsorbed on cross-povidone (2 kg) in the manner described in Example 1. A given quantity (50~) of the adsorbate thereby obtained was granulated and blended with Eudragit RL (50%). The blend was then filled into hard gelatine capsules (422 mg) so as to obtain capsules containing 300 mg of anhydrous theophylline. The presence of the citric acid was found to enhance the solubility of the anhydrous th~ophylline at pH values in excess of 7 and was suitable for use in a long acting or sustained release drug formulation.
Chlorpheniramine maleate (O.5%) and ethylcellulose (1 kg) which is insoluble in water and thereby inactive in an aqueous environment were dissolved in isopropyl alcohol (10 kg) and adsorbed onto cross-povidone (2 kg) in the manner described in Example 1. The powder (30%) was then tabletted with the following ingredients:
Methocel K15M (Trade Mark) 8.0%
Avicel pHlOl (Trade MarX) 61.5%
Magnesium stearate 0.5%
to obtain a tablet containing 10 mg of chlorpheniramine maleate r~
, ':' ,:
~, :
Polyvinylpyrrolidone (K-30) (0.75 kg) was dissolved in methylene chloride (12 kg) nifedipine (1 kg) was then added to this solution and allowed to dissolve~ The solution thereby obtained was then adsorbed onto cross-linked carboxymethylcsllulose (3 kg) and the solvent evaporated. The resulting powder was then passed through an oscillating granulator to obtain a fine particle siz~. X-ray diffraction and differential scanning calorimetry studies showed that the drug was in amorphous form in this adsorbate. The powder (30%) was then tabletted with the following ingredients:
Methocel K100 LV (Trade Mark) 10%
Avicel pH101 (Trade Mark) 59.5%
Magnesium stearate 0.5%
to obtain a tablet containing 20 mg active ingredient.
Similar x-ray diffraction and differential scanning calorimetry studies showed this product to be amorphous.
The procedure employed was similar to that in Example 7 except that the amount of polyvinylpyrrolidone (K~30) used was 0.5 kg and also included was polyethylene glycol 6000 (1 kg).
. ..... ; ,.
334~*
The procedure employed was similar to that in Example 8 except that the polyethylsne glycol was replaced by methylcellulose (0.75 kg).
The procedure employed was similar to that in Example 7 except that methylcellulose (0.75 kg) was used instead of polyvinylpyrrolidone 0.75 kg.
The procedure employed was simllar to that in Example 8 except that polyvinylpyrrolidone ~0.5 kg) was replaced by methylcellulose (0.5 kg~.
The procedure used was simi.lar to that employed in Example 7 except the polyvinylpyrrolidone (O.75 kg) was replaced by polyethylene glycol 6000 (1.5 kg).
.. ..
3~
Polyvinylpyrrolidone K-25 (Trade Mark) (O.50 kg) was di~solved in isopropyl alcohol (10 kg). Diclofenac (lkg) was added to this solution and allowed to dissolve.
The solutlon thereby obtained was then adsorbed onto cross-linked polyvinylpyrrolidone (2.5 kg) and the solvent evaporated. The resulting powder (60%) was treated as in Example 1 and tabletted with the following ingredients-Methocel KlOOLV (Trade Mark) 16.5%
Avicel pH101 (Trade Mar~) 23.0%
Calcium stearate 0.5%
to obtain a tablet containing 100 mg active ingredient.
Methocel A4M (Trade Mark) (0.15 kg) was dissolved in dichloromethane (10 kg). Oxendolona (1 kg) was added to the solution and di~solved. The resulting solution was adsorbed onto cross-povidone (4 kg) and treated as per Example 1.
The resulting powder (80~) was tabletted with the following ingredients:
Methocel KlOOLV (Trade Mark) 1.5%
~vicel pH 10% (Trade Mark) 13.0%
Magnasium stearate 0.5%
to obtain a tablet contain~ng 100 mg active ingredient.
334~
Example 1 was repeated except the nifedipine formulation (50%) was tabletted with the following ingredients.
Sodium alginate 15.0~
Pregelatinized starch N.F. 33.5%
Talc 1.5%
Example 2 was repeated except the nicardipina formulation (50%) was tabletted with the ~ollowing ingredients:
Lactose U.S.P. 10.0%
Eudragit R.S. 10.0%
Eudragit R.L. 29.25%
Calcium stearate 0.75%
Example 6 was repeated except the chlorpheniramine maleate formulation (40~) was tabletted with the following ingredients.
Dibasic calcium phosphate 15.0%
dihydrate N.F.
Ethylcellulose 100 cps 15.0%
Polyethyleneglycol 6000 5.0%
Hydroxyethylcallulose 29.0%
Calcium ~tearate 1.0~
' '',; .' ,
Claims (24)
1. A controlled release formulation comprising an adsorbate of a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 to 10 parts by weight of an inactive substance adsorbed on a cross-linked polymer in a ratio of 1 part by weight of said mixture to 0.5 - 20 parts by weight of cross-linked polymer, said inactive substance being selected to modify the dissolution of the active drug from the cross-linked polymer in vivo, with the proviso that the active ingredient is not a dihydropyridine when the inactive substance is polyvinylpyrrolidone with an average molecular weight in the range 15,000 to 50,000 and the cross-linked polymer is cross-linked polyvinylpyrrolidone.
2. A controlled release formulation according to claim 1, wherein the inactive substance is present in an amount of 0.5 - 3 parts by weight relative to 1 part by weight of the active ingredient.
3. A controlled release formulation according to claim 1, which contains 1 part by weight of said mixture relative to 1 - 10 parts by weight of cross-linked polymer.
4. A controlled release formulation according to claim 1, wherein the cross-linked polymer is a cross-linked polyvinylpyrrolidone, carboxymethylcellulose or methylcellulose.
5. A controlled release formulation according to claim 1, wherein the inactive substance is a substance whose solubility in aqueous media is inversely proportional to that of the active ingredient.
6. A controlled release formulation according to claim 1, wherein the inactive substance is a natural or synthetic, inert, pharmaceutically acceptable polymer.
7. A controlled release formulation according to claim 6, wherein the polymer is selected from the group consisting of substituted or unsubstituted alkylcelluloses, copolymers of acrylic and methacrylic acid esters, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, galactomannone, carboxypolymethylene and shellac or mixtures thereof.
8. A controlled release formulation according to claim 7, wherein the polymer is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcalluluse or sodium carboxymethylcellulose.
9. A controlled release formulation according to claim 1, wherein the inactive substance is an organic acid selected from the group consisting of adipic acid, ascorbic acid, citric acid, fumaric acid, maleic acid, succinic acid or tartaric acid.
10. A controlled release formulation according to claim 1, wherein the inactive substance is a sugar.
11. A controlled release formulation according to claim 1, wherein the active ingredient is selected from the group consisting of diclofenac, theophylline, felodipine, nifedipine, nicardipine, nitrendipine, 4-(2,1,3-benzoxadiazol-4-yl)-2, 6-dimethyl-1,4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester, co-dergocrine mesylate, oxendolone, azidothymidine, spironolactone and chlorpheniramine maleate.
12. A controlled release drug delivery system which comprises an adsorbate adsorbed on a cross-linked polymer as defined in claim 1.
13. A controlled release drug delivery system according to claim 12, which is in the form of capsules or tablets.
14. A sustained release drug delivery system comprising a mixture of 1 part by weight of a pharmaceutically useful active ingredient and from 0.1 - 10 parts by weight of inactive substance, wherein 1 part by weight of said mixture is adsorbed on 0.5-20 parts by weight of a cross-linked polymer, wherein said inactive substance is selected to modify the dissolution of the active drug from the cross-linked polymer in vivo, and said active in-gredient is in substantially amorphous form, the resultant adsor-bate being granulated and blended with a polymer or mixture of polymers to yield a long-acting controlled release matrix system.
15. A sustained release drug delivery system according to Claim 14, wherein the polymer or mixture of polymers gels in the presence of water.
16. A sustained release drug delivery system according to Claim 15, wherein the polymer which gels in the presence of water is selected from the group consisting of polyvinyl alcohol, poly-vinylpyrrolidone hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkylcelluloses, copolymers of acrylic and methacrylic acid esters, shellac, polyethylene glycol, sodium alginate, galactomannone or carboxypolymethylene or a mixture thereof.
17. A sustained release drug delivery system according to Claim 16, wherein the polymer which gels in the presence of water is selected from the group consisting of methylcellulose, ethyl-cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or a copolymer of acrylic and methacrylic acid esters or a mixture thereof.
18. A sustained release drug delivery system according to Claim 16, wherein said gel forming polymer is present in an effective amount between 3 to 50% by weight of the system.
19. A sustained release drug delivery system according to Claim 14, wherein the active ingredient is a dihydropyridine, the inactive substance is a polyvinylpyrrolidone, polyethylene glycol or methylcellulose or a mixture thereof, and the cross-linked polymer is a cross-linked polyvinylpyrrolidone, carboxymethylcellulose or methylcellulose.
20. A sustained release drug delivery system according to Claim 19, wherein the inactive substance is present in an amount of 0.5 - 3 parts by weight relative to 1 part by weight of the active ingredient.
21. A sustained release drug delivery system according to Claim 19, which contains 1 part by weight of said mixture relative to 1-10 parts by weight of cross-linked polymer.
22. A process for preparing a sustained release formulation according to Claim 14, which comprises dissolving the active ingredient and the inactive substance in a pharmaceutically suitable solvent in which both substances are soluble, mixing the solution thereby obtained with a given quantity of the cross-linked polymer so as to permit adsorption of said active ingredient and said inactive substance to said cross-linked polymer, removing the solvent and granulating and blending the resulting product with said polymer or mixture of polymers.
23. A process according to Claim 22, wherein the solvent used is any pharmaceutically suitable co-solvent for the active ingredient and the inactive substance.
24. A process according to Claim 22, wherein the solvent is selected from the group consisting of water, alcohols, ketones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds or cyclic ethers or a mixture thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE30686A IE63321B1 (en) | 1986-02-03 | 1986-02-03 | Drug delivery system |
| IE306/86 | 1987-01-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1288344C true CA1288344C (en) | 1991-09-03 |
Family
ID=11010197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000528750A Expired - Lifetime CA1288344C (en) | 1986-02-03 | 1987-02-02 | Drug delivery system |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US4973469A (en) |
| EP (1) | EP0232155B1 (en) |
| JP (1) | JP2527432B2 (en) |
| AU (1) | AU598514B2 (en) |
| CA (1) | CA1288344C (en) |
| DE (1) | DE3750619T2 (en) |
| DK (1) | DK173082B1 (en) |
| ES (1) | ES2060593T3 (en) |
| IE (1) | IE63321B1 (en) |
| NZ (1) | NZ219139A (en) |
| PH (1) | PH24331A (en) |
| ZA (1) | ZA87737B (en) |
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-
1986
- 1986-02-03 IE IE30686A patent/IE63321B1/en not_active IP Right Cessation
-
1987
- 1987-01-28 PH PH34776A patent/PH24331A/en unknown
- 1987-02-02 ES ES87300886T patent/ES2060593T3/en not_active Expired - Lifetime
- 1987-02-02 EP EP87300886A patent/EP0232155B1/en not_active Expired - Lifetime
- 1987-02-02 NZ NZ219139A patent/NZ219139A/en unknown
- 1987-02-02 AU AU68206/87A patent/AU598514B2/en not_active Expired
- 1987-02-02 DK DK198700527A patent/DK173082B1/en not_active IP Right Cessation
- 1987-02-02 ZA ZA87737A patent/ZA87737B/en unknown
- 1987-02-02 JP JP62022274A patent/JP2527432B2/en not_active Expired - Lifetime
- 1987-02-02 CA CA000528750A patent/CA1288344C/en not_active Expired - Lifetime
- 1987-02-02 DE DE3750619T patent/DE3750619T2/en not_active Expired - Lifetime
-
1989
- 1989-08-17 US US07/395,184 patent/US4973469A/en not_active Expired - Lifetime
- 1989-08-17 US US07/395,670 patent/US5128142A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62195322A (en) | 1987-08-28 |
| DK52787D0 (en) | 1987-02-02 |
| EP0232155B1 (en) | 1994-10-05 |
| US4973469A (en) | 1990-11-27 |
| US5128142A (en) | 1992-07-07 |
| JP2527432B2 (en) | 1996-08-21 |
| ES2060593T3 (en) | 1994-12-01 |
| IE860306L (en) | 1987-08-03 |
| DK173082B1 (en) | 1999-12-27 |
| PH24331A (en) | 1990-05-29 |
| DE3750619T2 (en) | 1995-04-20 |
| AU6820687A (en) | 1987-08-06 |
| DK52787A (en) | 1987-08-04 |
| DE3750619D1 (en) | 1994-11-10 |
| IE63321B1 (en) | 1995-04-05 |
| AU598514B2 (en) | 1990-06-28 |
| NZ219139A (en) | 1989-02-24 |
| EP0232155A3 (en) | 1988-09-28 |
| EP0232155A2 (en) | 1987-08-12 |
| ZA87737B (en) | 1987-09-30 |
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| MKEX | Expiry |