CA2047861A1 - Sustained release formulations - Google Patents
Sustained release formulationsInfo
- Publication number
- CA2047861A1 CA2047861A1 CA002047861A CA2047861A CA2047861A1 CA 2047861 A1 CA2047861 A1 CA 2047861A1 CA 002047861 A CA002047861 A CA 002047861A CA 2047861 A CA2047861 A CA 2047861A CA 2047861 A1 CA2047861 A1 CA 2047861A1
- Authority
- CA
- Canada
- Prior art keywords
- acid
- sustained release
- pharmaceutical composition
- release pharmaceutical
- food grade
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Abstract
Abstract Semi-enteric controlled release formulations are comprised of a biological active agent such as an antibiotic that is blended with a water-soluble bulking agent, the mix then coated onto an inert core. The coated active core is further coated with a mixture comprised of an acrylic copolymer, bulking agent and pH dependent food acid. These different coating components possess different solubility characteristics which result in a gradual release of the active in both the stomach and small intestine that provides an increased bioavailability of the active drug.
DA8R9009.DOC 7/11/90 #29-1
DA8R9009.DOC 7/11/90 #29-1
Description
- 2 ~
Field_of_the Invention_ The present invention relates to pharmaceutical preparations and the controlled, sustained release thereof. In particular, the pre~ent invention concerns the ~ustain~d r~lease of an antibiotic such as doxycycline hyclate over a period of time after oral administration so that the drug is completely absorbed into the patient's system. The pharmaceutical composition comprises a coated, inert sphere or pellet that initially begins a partial breakdown and absorption of the drug in the stomach with complete release and ab~orption in the small intestine.
Backqround of the Invention Many pharmaceutical delivery systems are known in the art which are designed to either delay the,release of the drug until the system reaches a particular region of the digestive tract or they are designed to gradually release the drug immediately after oral administration. Enteric formulations are designed to prevent any release of the drug for bioavailability until the delivery ~ystem reaches the intestine. The~e are generally designed for those pharmaceuticals that cause stomach irritation or distress.
Normally, pharmaceuticals that are highly soluble irrespective of the pH of the surrounding environment can be~
formulated into su~tained relea~e delivery sy~tems relatively easily. The delayed relea~e properties can be attained by several methods. On the one hand, the drug can be embedded into a matrix of other excipient~ which are relatively water insoluble and henc0, dissolve slowly so as to release the drug to the digesti~e ~ys~em 310wly. Another method is to shape the drug and e~cipient~ into granules or pellets a~ an active cora which are then coated with a substance that dis~olve~ slowly. Usually, DA8R9009.DOC 7/11/90 ~29-1 -- 3 - ~f ~
these methods produce a delivery syste~ that di~solves either entirely in the stom~ch or intestirle but not both -The other drawback with many of these sustained release delivery systems known in the art is the fact that not all of the drug becomes bioavailable during its passa~e through the digestive tract and it eventually becomes lo~t and expelled through the feces. Attempts have been made to get around these problem~ by mixing the drug with an excipient and then either forming a core mate~ial compri~ed of the drug e~cipient mixture or by coa~inq an inert core such as a non-p~reil seed with the drug/excipient mi~ture followed by a coating of the entire pellet with a thin polymer film.
A major problem in the coating of the core granules by the methods of the prior art i~ the need to dissolve the coatiny material~ in organic solvents prior to~their application. These solvents are not only exp~nsive but dangerous in that they are highly explosive. They also pose health and environmental problems in that most ara highly toxic.
U.S. Patent No. 4,138,475 to McAinish et al disclose~ a sustained release ~Eormulatlon for propranolol or pharmaceutically acceptable salts thereof whereby the drug is mixed with non-water swellable microcy~talline cellulose and formed into spheroids.
These are then coalted with a heavy film of hydroxypropyl methyl cellulose (HPMC) and or a plastlcizer which prevents any release of the drug in the ~tomach. Needless to say, not all of the drug becomes bioavailab:Le in the small intestine either.
U.S. Patent No. 4,837,030 to Valorose et al discloses a sustained release delivery system for tetra~ycline compounds deRigned to release a minor amount of the drug slowly in the human stomach and then rapidly release the remainder in the small intestine. This i~ aceomplished by mixing the drug with one or more of a number o~ exeipientC, such as microcrystalline DA8R9009.DOC 7/11/90 ~29-1 - 4 ~ "
cellulose, polyvinylpyrrolidone ~PVP), carboxymethyl cellul.ose, etc., and a binder such a~ gelatin whi.ch is then either extruded into a spherical pellet or coated about a non-pareil seed. The pharmaceutical core pellet may then be coated with a thin polymer or left bare; in either case it is only 60-90% released in the course of its passage ~fter ninety (90) minutes.
U.S. Patent No. 4,832,958 to Baudier et al re~eals a ~al~nic form of prolonged release ver~pamil and its salts by mixing the drug with a wetting agent such as fatty acid esters, lecithin, sucrose, mannitol or sorbitol and then spheronizing or granulating the mixture into micro-granule~. These are then coated with a microporou~ membrane comprised of a polymer such as Eudragit~ E30D, (Rohm Pharma GmbH, Weiterstadt, West Germany~, HPMC phthalate and other wetting agents, plasticizers and the like. The formulation~ are designed to withstand adverse environmental conditions during ~torag~ such as high temperature~. The formulation i~ enteric by nature and the drug does not become bioavailable until the system reaches the small intestine.
U.S. Patent No~. 4,795,644 and 4,418,183 to Zentner disclose delivery systems for the controlled release of drug~ that i~ not p~-dependent through the modulation of the release of a core drug through a microporous wall coating using charged, insoluble resins that bear an electrostatic charge that i~ identical to that of the drug. The charged resin is water insoluble and non-diffusibl2 through the microporous wall while the active drug i~ diffu~ible and water soluble. The charged resins may be either anionic or cationic in nature, and include polystyrene, epoxy-amine phenolic or methacrylic backbone3 and release the drug through the microporou3 wall accordin~ to the osmotic pre~sure, not the pH of th~ external environment. This allegedly allow~ for the tailoring of a whole range of release rates a~cording to the type of drug used.
DA8R9009.DOC 7/11/90 #29-1 U.S. Patent No. ~,438,091 to Gru~er et al discloses a composition for the delayed release of bromhexine comprised of a mixture of the bronchodialator with an acid such as fumaric or tartaric acid which is compressed into a spherical tabl~t and coated with lac~uers that are insoluble in gastric juices and soluble in intestin~l juice~. These comprise copolymers of acrylic acid and m~thacylic acid esters. Whereas the drug is generally insoluble at the higher pH values of the intestine and would ~e absorbed too guickly at the lower acidic pH conditions of the stomach, the acidic matrix prevents quick dissolution early and yet promotes the drugs bioavailability further downstream in the digestive tract.
European Patent Appln. No. 0,035,780 to Sekigawa et al disclose~ a proce~s for the preparation of enterosoluble drugs by coating a solid doYage form of the drug with hydroxypropyl methylcellulose phthalate or acidic succinyl and acetyl esters of HPMC. Triethylcitrate i~ a~ded a~ a plastici~er which aid~ in the binding of the coating material to the core pellet. The coating then resiC~ts dis301ution in the stomach but completely dis~olves in the ~mall intestine.
- European Pate~nt Appln. No 0,273,005 to Ventoura~ discloses a water dispersible tablet compri~ed of an active pharmaceutical core material,a pEI dependent di~integrant such a~ crospovldone (N-vinyl-2 pyrro].idone) or croscarmelloYe and a water-swellable agent such a~ guar gum, alginateY, dextran and the like. Once contacted by moisture in the human oral cavity, the ~wellabLe material absorb~ water and becom~s gel-like, aiding passage through the oral cavity and throat. Onc~ the delivery sy~tem reaches the acidic pH of the ~tomach, the di~integrant breaks -- apart immediately, releasing the drug for complete bioavailability.
None of the aforementioned formulationY however, are truly semi-enteric formulation3 whereby the active pharmaceutical is DA8R9009.DOC 7/11/90 #29-1 6 ~ rj~
dispersed slowly and continually from the early stages of the digestive tract throu~hout its passage in the stomach and small intestine so as to become 100% bioavailable. Moreover, none of the prior art references and formulations provide for the gradual and controlled release o an active pharmaceutical whose bioavailability is evenly distributed over time.
It is an object of the present invention to provide a controlled, semi-enteric formulation of an active pharmaceutical that is slowly and continually dissolved and absorbed throughout its passage through both the gastric and intestinal portions of the digestive system. More specifically it is an object of the present invention to provide an antibiotic formulation that is quasi-enteric in nature, i.e., that is partially bioavailable in both the ~tomach and the small intestine so as to insure 100%
bioavailability in both. In particular, it is an object of the present invention to provide a semi-ent~ric formulation for an antibiotic which becomes bioavailable throughout its passage in the digestive tract.
Summary of the Invention Semi-enteric sustained release pharmaceutical compositions provide for the controlled release o a biological active material such as an antibiotic in both the stomach and small intestine for incr~eased bioavailability. The semi-enteric release is made po~ible by initially mixing the active drug`~with a water soluble bulking agent. This mixture is uniformly coated about an inert cor~ material such as a non-pareil seed. This is then further coated with a blend of a methacrylic acid copolymer, a water soluble bulking agent and a food grade acid whose solubility is pH dependent.
Since the RH condition~ of the stomach and small intestine differ, the coating material~ become soluble at different points in the dige~tive tract. The water soluble bulking agent will DA8R9009.DOC 7/11/90 ~29-1 - 7 - ~ ~J ~
beqin to break down in the hydrous environment of the stomash resulting in the partial release of some of the active core. The copolymar a~d the pH dependent food acid do not dissolve until the pharmaceutical composition enters the more basic environment of the small intestine. Hence, a controlled sustained release of the biological active is achieved throughout both the stomach and intestine thereby resulting in increased bioavailability of the~
drug.
Detailed DescriPtion of the Invention The drug delivery system of the present invention utilizes a unique combination of coating materials that result in a controlled, semi-enteric formulation of the drug that releases throughout the digestive system to insure 100% bioavailability of the active agent. The controlled sustained release of the drug i~ due to different solu~ility characteristics of the coating materials which dissolve or break down in different parts of the digestive tract resulting in a gradual, partial release of the drug over time.
The drug is initially mixed with a water soluble bulking agent to form an active matrix that is then uniformly coated about an inert, non-pareil ~ugar seed. This core i~ then coated with a mixture of materials that ultimately control release of the drug to the system. The major coating constituent is a methacrylic acid copolymer co~mercially lcnown as Eudragit~ L30D, a film fo~ming polymer in an aqueous solid dispersion made by Rohm Pharma Gmbh, Weiterstadt, West Germany. In the past, Eudragit~ L30D was employed to prepare fully enteric pharmaceutical formulation~. Drugs that are coated with this polymer are not relea~ed to the system under the pH conditions existing in the ~tomach but rather are released when the polymer dissolves under the pH conditions of the inte~tine. In the pre~ent invention, the release characteristic~ of the Eudragit DA8R9009.DOC 7/11/90 #29-l - 8 ~ "
L30D polymer are modified so that a semi-enteric ormulation is developed.
In order to modify the dissoluti~n characteristics of Eudragit~ L30D, a water sol~ble bulking agent such as a sugar alcohol is mixed with the film forming polymer. Suitable sugar alcohols useful in the practice of the p~esen-t invention include mannitol, sorbitol, lactitol and the like. Mannitol is the preferred bulking agent in that it will dissolve and break down in a~y hydrous environment, irrespecti~e of the pH. Another constituent of the coating i5 a pH- dependent acid such as fumaric acid which will only dissolve and break down in environment~ with a pH of greater than 3.5. Other suitable food grade acids include malic acid, citric acid, tartaric acid, ascorbic acid and mixtures thereof. Fumaric acid ha~ a very low solubility in water and hence its dissolution will only be triggered by the basic conditions exis~ing in the intestine.
The incorporation of the water soluble bulking agent and the pH dependent acid into the Eudragit~ polymer coatins allows for a controlled drug release to be attained in pH regions where there is usually no drug release. This i5 especially useful for those drugs that irritate the stomach since they do permit some release so as to insure 100% bioavailability without releasing all the drug so as to cause gastric distress. As the bulking agent initially dis~olve~ in the hydrous acidic environment of the stomach, small holes appear in the otherwise uniform, intact~
coating. The pharmaceutical is gradually released through these holes until the delivery system finally reache~ the small intestine where the more basic conditions dissolve and break down both the pH dependent food grade acid and the methacrylic acid copol~ner coat. With the systems entry into the mora basic environment of the gastroi~testi~al tract i.e., ~bove 3.5, the pH
dependent food acid portion ~ill dissolve and more holes or spots will appear in the methacryl:ic acid copolymer coat releasing more drug to the sy~tem at a ~reater rate for ab~orption. Finally, DA8R9009.DOC 7/11/90 #29-1 after several minute~ of exposure o the methacrylic acid coat to the basic environment of the small intestine, the methacrylic acid copolymer coating break~ down altogether releasing all of the remaining active drug to the system for absorption. The polymer portion of the matrix coating starts to dissolve at pH
6Ø
Other excipient~ are added to the polymer coating in minor amounts in order to ~tabilize the composition and to help bind the sy~tem together. Plasticizers such as triethyl citrate are added in amount~ of up to about 1.5% in order to aid in the flowability of the coating mixture so as to insure maximum uniformity and integrity of the coating. An anti-adherent such a~ kaolin or talc in amount~ of up to about 3.0% i9 also added as an inert aid in tha stability of coating proces~. Binder~ such as hydroxypropylcellulose in amoùnts of from about 0.01 to about 4.0 may al~o be added to hold the variou~ constituents togethe~.
Whereas the delivery ~y~tem of the present invention could be tailored to provide a ~emi-enteric carrier for nearly any active pharmaceutical of choice, the ~y~tem has proven most effective in the delivery of antibiotic~ such a3 do~ycycline hyclate, minocycline, oxytetracycline, chlortetracycline, demechlorcycline, methycycline their pharmaceutical salts and mixture3 thereof. In a preferred embodiment of the present invention, the pharmaceutical employed is doxycyclina hyclate, an antibiotic with the following ~tructure:
~3C H ~ N N(C8332 ~f CONH2 Thi3 bacteriostactic compound i~ effective against a wide variety of gram-negative and gram-positive ~pecies and i~ useful ~A8R9009.DOC 7/11/90 #~9-1 ,"
in the treatment of Rocky Mountain Spotted Fever, venereal disease etc. The drug can be incorporated into the deli~tery ~ystem in amounts of from about 20% to about 65% w/~, preferably 55~~60% w/w.
The foLlowing example~ are provided to more fully describe and delineate that which is considered to be the invention.
While it is understood th~t minor variation~ and/or alterations in the materials or process parameters may be practiced, it i5 therefore recognized that said examples are for illustration only and should not be con~trued as limiting the spirit and scope of the invention as later recited in the claims Example 1 Doxycycline hyclate core~ were prepared by a powder layeri~g technique usin~ the CF Granulator manufactured by Freund -Chemical Ltd, Tokyo, Japan. One ~1) kg. ~f the drug was pas~ed through a Fitzmill NOOO screen. 110 ~m. of mannitol and 1 gm. of ~llicon dioxide (SiO2) were blended together then pa~ed through a U.S. ~tandard mesh no~ 100 screen.
This blend wa~ then mixed with the milled drug. The final blend wa~ then layered onto 500 gm. of ~ugar spheres (mesh ~ize 20-25) using hydroxypropylcellulose 8% w/w solution as a binder. ~le layering granulator condition~ were: 1.0 bar atomization; rotor at 160 rpm; a powder delivery rate of 10 rpm; a ~pray rate of 8 ml./min at 24C ml/min; product temp.
24C. The cores were then dried in an oven at 45C
overnight.
The active antibiotic cores were coated using a Glatt GPCG3 machine Glatt Air Technique~, Inc., New Jersey. The coating sy~tem employed consisted of: Eudragit~ L30D (30% w/w) 41% w/w;
triethyl citrate 1.3% w/w; kaolin 2.4yO w/w; mannitol 1% w/w;
fumaric acid 0.25% w/w water q.s. to 100% w/w. 500 qm. of doxycycline hyclate cores were coated to 6% coating level~ The coated pellet~ were dried in the machine for 45 min at ~n inlet temp. of 45 C. a~d product temp. 340C-DA8R9009.DOC 7/11/90 #2g-1
Field_of_the Invention_ The present invention relates to pharmaceutical preparations and the controlled, sustained release thereof. In particular, the pre~ent invention concerns the ~ustain~d r~lease of an antibiotic such as doxycycline hyclate over a period of time after oral administration so that the drug is completely absorbed into the patient's system. The pharmaceutical composition comprises a coated, inert sphere or pellet that initially begins a partial breakdown and absorption of the drug in the stomach with complete release and ab~orption in the small intestine.
Backqround of the Invention Many pharmaceutical delivery systems are known in the art which are designed to either delay the,release of the drug until the system reaches a particular region of the digestive tract or they are designed to gradually release the drug immediately after oral administration. Enteric formulations are designed to prevent any release of the drug for bioavailability until the delivery ~ystem reaches the intestine. The~e are generally designed for those pharmaceuticals that cause stomach irritation or distress.
Normally, pharmaceuticals that are highly soluble irrespective of the pH of the surrounding environment can be~
formulated into su~tained relea~e delivery sy~tems relatively easily. The delayed relea~e properties can be attained by several methods. On the one hand, the drug can be embedded into a matrix of other excipient~ which are relatively water insoluble and henc0, dissolve slowly so as to release the drug to the digesti~e ~ys~em 310wly. Another method is to shape the drug and e~cipient~ into granules or pellets a~ an active cora which are then coated with a substance that dis~olve~ slowly. Usually, DA8R9009.DOC 7/11/90 ~29-1 -- 3 - ~f ~
these methods produce a delivery syste~ that di~solves either entirely in the stom~ch or intestirle but not both -The other drawback with many of these sustained release delivery systems known in the art is the fact that not all of the drug becomes bioavailable during its passa~e through the digestive tract and it eventually becomes lo~t and expelled through the feces. Attempts have been made to get around these problem~ by mixing the drug with an excipient and then either forming a core mate~ial compri~ed of the drug e~cipient mixture or by coa~inq an inert core such as a non-p~reil seed with the drug/excipient mi~ture followed by a coating of the entire pellet with a thin polymer film.
A major problem in the coating of the core granules by the methods of the prior art i~ the need to dissolve the coatiny material~ in organic solvents prior to~their application. These solvents are not only exp~nsive but dangerous in that they are highly explosive. They also pose health and environmental problems in that most ara highly toxic.
U.S. Patent No. 4,138,475 to McAinish et al disclose~ a sustained release ~Eormulatlon for propranolol or pharmaceutically acceptable salts thereof whereby the drug is mixed with non-water swellable microcy~talline cellulose and formed into spheroids.
These are then coalted with a heavy film of hydroxypropyl methyl cellulose (HPMC) and or a plastlcizer which prevents any release of the drug in the ~tomach. Needless to say, not all of the drug becomes bioavailab:Le in the small intestine either.
U.S. Patent No. 4,837,030 to Valorose et al discloses a sustained release delivery system for tetra~ycline compounds deRigned to release a minor amount of the drug slowly in the human stomach and then rapidly release the remainder in the small intestine. This i~ aceomplished by mixing the drug with one or more of a number o~ exeipientC, such as microcrystalline DA8R9009.DOC 7/11/90 ~29-1 - 4 ~ "
cellulose, polyvinylpyrrolidone ~PVP), carboxymethyl cellul.ose, etc., and a binder such a~ gelatin whi.ch is then either extruded into a spherical pellet or coated about a non-pareil seed. The pharmaceutical core pellet may then be coated with a thin polymer or left bare; in either case it is only 60-90% released in the course of its passage ~fter ninety (90) minutes.
U.S. Patent No. 4,832,958 to Baudier et al re~eals a ~al~nic form of prolonged release ver~pamil and its salts by mixing the drug with a wetting agent such as fatty acid esters, lecithin, sucrose, mannitol or sorbitol and then spheronizing or granulating the mixture into micro-granule~. These are then coated with a microporou~ membrane comprised of a polymer such as Eudragit~ E30D, (Rohm Pharma GmbH, Weiterstadt, West Germany~, HPMC phthalate and other wetting agents, plasticizers and the like. The formulation~ are designed to withstand adverse environmental conditions during ~torag~ such as high temperature~. The formulation i~ enteric by nature and the drug does not become bioavailable until the system reaches the small intestine.
U.S. Patent No~. 4,795,644 and 4,418,183 to Zentner disclose delivery systems for the controlled release of drug~ that i~ not p~-dependent through the modulation of the release of a core drug through a microporous wall coating using charged, insoluble resins that bear an electrostatic charge that i~ identical to that of the drug. The charged resin is water insoluble and non-diffusibl2 through the microporous wall while the active drug i~ diffu~ible and water soluble. The charged resins may be either anionic or cationic in nature, and include polystyrene, epoxy-amine phenolic or methacrylic backbone3 and release the drug through the microporou3 wall accordin~ to the osmotic pre~sure, not the pH of th~ external environment. This allegedly allow~ for the tailoring of a whole range of release rates a~cording to the type of drug used.
DA8R9009.DOC 7/11/90 #29-1 U.S. Patent No. ~,438,091 to Gru~er et al discloses a composition for the delayed release of bromhexine comprised of a mixture of the bronchodialator with an acid such as fumaric or tartaric acid which is compressed into a spherical tabl~t and coated with lac~uers that are insoluble in gastric juices and soluble in intestin~l juice~. These comprise copolymers of acrylic acid and m~thacylic acid esters. Whereas the drug is generally insoluble at the higher pH values of the intestine and would ~e absorbed too guickly at the lower acidic pH conditions of the stomach, the acidic matrix prevents quick dissolution early and yet promotes the drugs bioavailability further downstream in the digestive tract.
European Patent Appln. No. 0,035,780 to Sekigawa et al disclose~ a proce~s for the preparation of enterosoluble drugs by coating a solid doYage form of the drug with hydroxypropyl methylcellulose phthalate or acidic succinyl and acetyl esters of HPMC. Triethylcitrate i~ a~ded a~ a plastici~er which aid~ in the binding of the coating material to the core pellet. The coating then resiC~ts dis301ution in the stomach but completely dis~olves in the ~mall intestine.
- European Pate~nt Appln. No 0,273,005 to Ventoura~ discloses a water dispersible tablet compri~ed of an active pharmaceutical core material,a pEI dependent di~integrant such a~ crospovldone (N-vinyl-2 pyrro].idone) or croscarmelloYe and a water-swellable agent such a~ guar gum, alginateY, dextran and the like. Once contacted by moisture in the human oral cavity, the ~wellabLe material absorb~ water and becom~s gel-like, aiding passage through the oral cavity and throat. Onc~ the delivery sy~tem reaches the acidic pH of the ~tomach, the di~integrant breaks -- apart immediately, releasing the drug for complete bioavailability.
None of the aforementioned formulationY however, are truly semi-enteric formulation3 whereby the active pharmaceutical is DA8R9009.DOC 7/11/90 #29-1 6 ~ rj~
dispersed slowly and continually from the early stages of the digestive tract throu~hout its passage in the stomach and small intestine so as to become 100% bioavailable. Moreover, none of the prior art references and formulations provide for the gradual and controlled release o an active pharmaceutical whose bioavailability is evenly distributed over time.
It is an object of the present invention to provide a controlled, semi-enteric formulation of an active pharmaceutical that is slowly and continually dissolved and absorbed throughout its passage through both the gastric and intestinal portions of the digestive system. More specifically it is an object of the present invention to provide an antibiotic formulation that is quasi-enteric in nature, i.e., that is partially bioavailable in both the ~tomach and the small intestine so as to insure 100%
bioavailability in both. In particular, it is an object of the present invention to provide a semi-ent~ric formulation for an antibiotic which becomes bioavailable throughout its passage in the digestive tract.
Summary of the Invention Semi-enteric sustained release pharmaceutical compositions provide for the controlled release o a biological active material such as an antibiotic in both the stomach and small intestine for incr~eased bioavailability. The semi-enteric release is made po~ible by initially mixing the active drug`~with a water soluble bulking agent. This mixture is uniformly coated about an inert cor~ material such as a non-pareil seed. This is then further coated with a blend of a methacrylic acid copolymer, a water soluble bulking agent and a food grade acid whose solubility is pH dependent.
Since the RH condition~ of the stomach and small intestine differ, the coating material~ become soluble at different points in the dige~tive tract. The water soluble bulking agent will DA8R9009.DOC 7/11/90 ~29-1 - 7 - ~ ~J ~
beqin to break down in the hydrous environment of the stomash resulting in the partial release of some of the active core. The copolymar a~d the pH dependent food acid do not dissolve until the pharmaceutical composition enters the more basic environment of the small intestine. Hence, a controlled sustained release of the biological active is achieved throughout both the stomach and intestine thereby resulting in increased bioavailability of the~
drug.
Detailed DescriPtion of the Invention The drug delivery system of the present invention utilizes a unique combination of coating materials that result in a controlled, semi-enteric formulation of the drug that releases throughout the digestive system to insure 100% bioavailability of the active agent. The controlled sustained release of the drug i~ due to different solu~ility characteristics of the coating materials which dissolve or break down in different parts of the digestive tract resulting in a gradual, partial release of the drug over time.
The drug is initially mixed with a water soluble bulking agent to form an active matrix that is then uniformly coated about an inert, non-pareil ~ugar seed. This core i~ then coated with a mixture of materials that ultimately control release of the drug to the system. The major coating constituent is a methacrylic acid copolymer co~mercially lcnown as Eudragit~ L30D, a film fo~ming polymer in an aqueous solid dispersion made by Rohm Pharma Gmbh, Weiterstadt, West Germany. In the past, Eudragit~ L30D was employed to prepare fully enteric pharmaceutical formulation~. Drugs that are coated with this polymer are not relea~ed to the system under the pH conditions existing in the ~tomach but rather are released when the polymer dissolves under the pH conditions of the inte~tine. In the pre~ent invention, the release characteristic~ of the Eudragit DA8R9009.DOC 7/11/90 #29-l - 8 ~ "
L30D polymer are modified so that a semi-enteric ormulation is developed.
In order to modify the dissoluti~n characteristics of Eudragit~ L30D, a water sol~ble bulking agent such as a sugar alcohol is mixed with the film forming polymer. Suitable sugar alcohols useful in the practice of the p~esen-t invention include mannitol, sorbitol, lactitol and the like. Mannitol is the preferred bulking agent in that it will dissolve and break down in a~y hydrous environment, irrespecti~e of the pH. Another constituent of the coating i5 a pH- dependent acid such as fumaric acid which will only dissolve and break down in environment~ with a pH of greater than 3.5. Other suitable food grade acids include malic acid, citric acid, tartaric acid, ascorbic acid and mixtures thereof. Fumaric acid ha~ a very low solubility in water and hence its dissolution will only be triggered by the basic conditions exis~ing in the intestine.
The incorporation of the water soluble bulking agent and the pH dependent acid into the Eudragit~ polymer coatins allows for a controlled drug release to be attained in pH regions where there is usually no drug release. This i5 especially useful for those drugs that irritate the stomach since they do permit some release so as to insure 100% bioavailability without releasing all the drug so as to cause gastric distress. As the bulking agent initially dis~olve~ in the hydrous acidic environment of the stomach, small holes appear in the otherwise uniform, intact~
coating. The pharmaceutical is gradually released through these holes until the delivery system finally reache~ the small intestine where the more basic conditions dissolve and break down both the pH dependent food grade acid and the methacrylic acid copol~ner coat. With the systems entry into the mora basic environment of the gastroi~testi~al tract i.e., ~bove 3.5, the pH
dependent food acid portion ~ill dissolve and more holes or spots will appear in the methacryl:ic acid copolymer coat releasing more drug to the sy~tem at a ~reater rate for ab~orption. Finally, DA8R9009.DOC 7/11/90 #29-1 after several minute~ of exposure o the methacrylic acid coat to the basic environment of the small intestine, the methacrylic acid copolymer coating break~ down altogether releasing all of the remaining active drug to the system for absorption. The polymer portion of the matrix coating starts to dissolve at pH
6Ø
Other excipient~ are added to the polymer coating in minor amounts in order to ~tabilize the composition and to help bind the sy~tem together. Plasticizers such as triethyl citrate are added in amount~ of up to about 1.5% in order to aid in the flowability of the coating mixture so as to insure maximum uniformity and integrity of the coating. An anti-adherent such a~ kaolin or talc in amount~ of up to about 3.0% i9 also added as an inert aid in tha stability of coating proces~. Binder~ such as hydroxypropylcellulose in amoùnts of from about 0.01 to about 4.0 may al~o be added to hold the variou~ constituents togethe~.
Whereas the delivery ~y~tem of the present invention could be tailored to provide a ~emi-enteric carrier for nearly any active pharmaceutical of choice, the ~y~tem has proven most effective in the delivery of antibiotic~ such a3 do~ycycline hyclate, minocycline, oxytetracycline, chlortetracycline, demechlorcycline, methycycline their pharmaceutical salts and mixture3 thereof. In a preferred embodiment of the present invention, the pharmaceutical employed is doxycyclina hyclate, an antibiotic with the following ~tructure:
~3C H ~ N N(C8332 ~f CONH2 Thi3 bacteriostactic compound i~ effective against a wide variety of gram-negative and gram-positive ~pecies and i~ useful ~A8R9009.DOC 7/11/90 #~9-1 ,"
in the treatment of Rocky Mountain Spotted Fever, venereal disease etc. The drug can be incorporated into the deli~tery ~ystem in amounts of from about 20% to about 65% w/~, preferably 55~~60% w/w.
The foLlowing example~ are provided to more fully describe and delineate that which is considered to be the invention.
While it is understood th~t minor variation~ and/or alterations in the materials or process parameters may be practiced, it i5 therefore recognized that said examples are for illustration only and should not be con~trued as limiting the spirit and scope of the invention as later recited in the claims Example 1 Doxycycline hyclate core~ were prepared by a powder layeri~g technique usin~ the CF Granulator manufactured by Freund -Chemical Ltd, Tokyo, Japan. One ~1) kg. ~f the drug was pas~ed through a Fitzmill NOOO screen. 110 ~m. of mannitol and 1 gm. of ~llicon dioxide (SiO2) were blended together then pa~ed through a U.S. ~tandard mesh no~ 100 screen.
This blend wa~ then mixed with the milled drug. The final blend wa~ then layered onto 500 gm. of ~ugar spheres (mesh ~ize 20-25) using hydroxypropylcellulose 8% w/w solution as a binder. ~le layering granulator condition~ were: 1.0 bar atomization; rotor at 160 rpm; a powder delivery rate of 10 rpm; a ~pray rate of 8 ml./min at 24C ml/min; product temp.
24C. The cores were then dried in an oven at 45C
overnight.
The active antibiotic cores were coated using a Glatt GPCG3 machine Glatt Air Technique~, Inc., New Jersey. The coating sy~tem employed consisted of: Eudragit~ L30D (30% w/w) 41% w/w;
triethyl citrate 1.3% w/w; kaolin 2.4yO w/w; mannitol 1% w/w;
fumaric acid 0.25% w/w water q.s. to 100% w/w. 500 qm. of doxycycline hyclate cores were coated to 6% coating level~ The coated pellet~ were dried in the machine for 45 min at ~n inlet temp. of 45 C. a~d product temp. 340C-DA8R9009.DOC 7/11/90 #2g-1
Claims (18)
1) A process for the preparation of a biologically active material as a semi-enteric, sustained release formulation comprising the steps of:
a) mixing said active into an aqueous solution with a water soluble bulking agent and a flowability agent.
b) drying said mixture as a layer or film about an inert core material.
c) coating said layered core with a second aqueous solution consisting of a water insoluble polymer, a water soluble sugar alcohol, a food grade acid and a plasticizer d) curing said coated active cores so as to effect a substantially hard shell thereon.
a) mixing said active into an aqueous solution with a water soluble bulking agent and a flowability agent.
b) drying said mixture as a layer or film about an inert core material.
c) coating said layered core with a second aqueous solution consisting of a water insoluble polymer, a water soluble sugar alcohol, a food grade acid and a plasticizer d) curing said coated active cores so as to effect a substantially hard shell thereon.
2) The process of claim 1 wherein said biologically active material is selected from the group consisting of doxycycline hyclate, minocycline, oxytetracycline, chlortetracycline, demechlorcyline, methacycline and pharmaceutically acceptable mixtures thereof.
3) The process of claim 2 wherein said water insoluble polymer is selected from the group consisting of a methacrylic acid copolymer.
4) The process of claim 3 wherein said bulking agent is a sugar alcohol.
5) The process of claim 4 wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol, lactitol, and mixtures thereof.
DA8R9009.DOC 7/11/90 #29-1
DA8R9009.DOC 7/11/90 #29-1
6) The process of claim 5 wherein the solubility of said food grade acid is pH dependent.
7) The process of claim 6 wherein said food grade acid is soluble in solutions with a pH of approximately 3.5 and above.
8) The process of claim 7 wherein said food grade acid is selected from the group consisting of fumaric acid, malic acid, citric acid, tartaric acid, ascorbic acid and mixtures thereof.
9) A semi-enteric, sustained release pharmaceutical composition comprised of a biologically active material coated by a mixture of a water soluble bulking agent, a water insoluble polymer and food grade acid
10) The sustained release pharmaceutical composition of claim 9 wherein said biologically active material is selected from the group consisting of doxycycline hyclate, minocycline, oxytetracycline, chlortetracycline, demechlorcycline, metacycline and pharmaceutically acceptable mixtures thereof.
11) The sustained release pharmaceutical composition of claim 10 wherein said water soluble bulking agent is a sugar alcohol.
12) The sustained release pharmaceutical composition of claim 11 wherein said sugar alcohol is selected from the group consisting of mannitol, sorbital, lactitol and mixtures thereof.
13) The sustained release pharmaceutical composition of claim 12 wherein said water insoluble polymer is selected from the group consisting of methacrylic acid copolymer.
DA8R9009.DOC 7/11/90 #29-1
DA8R9009.DOC 7/11/90 #29-1
14) The sustained release pharmaceutical composition of claim 13 wherein said food grade acid has a water solubility that is pH-dependent.
15) The sustained release pharmaceutical composition of claim 14 wherein said food grade acid is soluble in solutions with a pH of approximately 3.5 and above.
16) The sustained release pharmaceutical composition of claim 15 wherein said food grade acid is selected from the groups consisting of fumaric acid, malic acid, citric acid, tartaric acid, ascorbic acid and mixtures thereof.
17) The pharmaceutical composition of claim 16 where said biologically active material is selected from the group consisting of doxycycline hyclate, minocycline, oxytetracycline, chlortetracycline, demechlorcycline, methacrycline and pharmaceutically acceptable mixtures thereof.
18) A semi-enteric, sustained release pharmaceutical composition comprised of an inner biologically active core and an outer inert coating characterized by a two-tiered solubility profile in the human digestive tract such that initial dissolution begins in the stomach with complete dissolution and absorption of the composition in the intestine.
DA8R9009.DOC 7/11/90 #29-1
DA8R9009.DOC 7/11/90 #29-1
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/559,221 US5188836A (en) | 1990-07-27 | 1990-07-27 | Sustained release formulations |
| US559,221 | 1990-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2047861A1 true CA2047861A1 (en) | 1992-01-28 |
Family
ID=24232777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002047861A Abandoned CA2047861A1 (en) | 1990-07-27 | 1991-07-25 | Sustained release formulations |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5188836A (en) |
| EP (1) | EP0470047A1 (en) |
| JP (1) | JPH04234313A (en) |
| AU (1) | AU8131191A (en) |
| CA (1) | CA2047861A1 (en) |
| IE (1) | IE912644A1 (en) |
| PT (1) | PT98446A (en) |
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| EP0452862B1 (en) * | 1990-04-18 | 1995-07-19 | Asahi Kasei Kogyo Kabushiki Kaisha | Spherical seed cores, spherical granules and process for production thereof |
| FR2692146B1 (en) * | 1992-06-16 | 1995-06-02 | Ethypharm Sa | Stable compositions of gastro-protected omeprazole microgranules and process for obtaining them. |
| US5376384A (en) * | 1992-12-23 | 1994-12-27 | Kinaform Technology, Inc. | Delayed, sustained-release pharmaceutical preparation |
| DE4332394A1 (en) * | 1993-09-23 | 1995-03-30 | Falk Pharma Gmbh | Controlled release budesonide pellets and method of making the same |
| US5633000A (en) * | 1994-06-23 | 1997-05-27 | Axxia Technologies | Subcutaneous implant |
| ES2087823B1 (en) * | 1994-07-13 | 1997-02-16 | Estudes Et Richerches Pharma E | FORMULATION OF GASTRORESISTENT MICROGRANULES OF OMEPRAZOLE AND ITS MANUFACTURING PROCEDURE. |
| CA2160423A1 (en) * | 1994-11-02 | 1996-05-03 | Hemant N. Joshi | Salts of nefazodone having improved dissolution rates |
| US5573783A (en) * | 1995-02-13 | 1996-11-12 | Nano Systems L.L.C. | Redispersible nanoparticulate film matrices with protective overcoats |
| DE29502547U1 (en) * | 1995-02-16 | 1995-03-30 | Roehm Gmbh | Thermoplastic coating and binding agent for pharmaceutical forms |
| TW592730B (en) | 1998-05-15 | 2004-06-21 | Chugai Pharmaceutical Co Ltd | Controlled release formulations |
| US6312728B1 (en) | 1998-07-07 | 2001-11-06 | Cascade Development, Inc. | Sustained release pharmaceutical preparation |
| US5968554A (en) * | 1998-07-07 | 1999-10-19 | Cascade Development, Inc. A Subsidiary Of Cardinal Health, Inc. | Sustained release pharmaceutical preparation |
| EP0978275A1 (en) * | 1998-08-05 | 2000-02-09 | Pharma Pass SA, Les Scientifiques | Solid pharmaceutical dosage form with controlled drug release |
| US6793934B1 (en) | 1999-12-08 | 2004-09-21 | Shire Laboratories, Inc. | Solid oral dosage form |
| KR100402053B1 (en) * | 2000-09-28 | 2003-10-17 | 한국화학연구원 | Controlled Released Implant Antibiotics |
| JP2004525955A (en) * | 2001-04-05 | 2004-08-26 | コッラジェネックス ファーマシューチカルス インコーポレイテッド | Controlled transmission of tetracycline compounds and tetracycline derivatives |
| AU2003213876B2 (en) * | 2002-04-12 | 2006-10-12 | Mayne Pharma International Pty Ltd | An improved modified release preparation |
| US6958161B2 (en) * | 2002-04-12 | 2005-10-25 | F H Faulding & Co Limited | Modified release coated drug preparation |
| AUPS167602A0 (en) * | 2002-04-12 | 2002-05-16 | F.H. Faulding & Co. Limited | An improved modified release preparation |
| US20040096498A1 (en) * | 2002-04-29 | 2004-05-20 | Alvin Kershman | Oral pharmaceutical delivery system with improved sustained release |
| EP1565167B1 (en) * | 2002-11-07 | 2016-06-22 | Advanced Bionutrition Corporation | Nutraceuticals and method of feeding aquatic animals |
| WO2004091483A2 (en) | 2003-04-07 | 2004-10-28 | Shire Laboratories, Inc. | Once daily formulations of tetracyclines |
| WO2004112746A1 (en) * | 2003-06-26 | 2004-12-29 | Korea Research Institute Of Chemical Technology | Controlled release-drug delivery system for oral administration |
| NZ544826A (en) * | 2003-07-25 | 2008-07-31 | Warner Chilcott Co Inc | A doxycycline metal complex in a solid dosage form |
| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| NZ556582A (en) * | 2005-01-21 | 2010-12-24 | Warner Chilcott Co Llc | A tetracycline metal complex in a solid dosage form |
| US7544373B2 (en) * | 2007-04-02 | 2009-06-09 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
| US8722650B1 (en) | 2005-06-24 | 2014-05-13 | Medicis Pharmaceutical Corporation | Extended-release minocycline dosage forms |
| US20080242642A1 (en) | 2007-04-02 | 2008-10-02 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
| US7919483B2 (en) * | 2005-06-24 | 2011-04-05 | Medicis Pharmaceutical Corporation | Method for the treatment of acne |
| US8252776B2 (en) | 2007-04-02 | 2012-08-28 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
| US9192615B2 (en) | 2008-08-06 | 2015-11-24 | Medicis Pharmaceutical Corporation | Method for the treatment of acne and certain dosage forms thereof |
| US7541347B2 (en) * | 2007-04-02 | 2009-06-02 | Medicis Pharmaceutical Coropration | Minocycline oral dosage forms for the treatment of acne |
| US20080241235A1 (en) * | 2007-04-02 | 2008-10-02 | Medicis Pharmaceutical Corporation | Minocycline oral dosage forms for the treatment of acne |
| EP2298324A1 (en) * | 2006-01-24 | 2011-03-23 | Paratek Pharmaceuticals, Inc. | Methods of increasing oral bioavailability of tetracyclines |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| US20080241197A1 (en) * | 2007-04-02 | 2008-10-02 | Medicis Pharmaceutical Corporation | Minocycline dosage forms for the treatment of acne |
| DK2152250T3 (en) * | 2007-05-07 | 2019-12-09 | Evonik Degussa Gmbh | FIXED DOSAGE FORMS CONCERNING AN ENTERIC COATING, WITH ACCELERATED PHARMACEUTICAL RELEASE |
| US9561241B1 (en) | 2011-06-28 | 2017-02-07 | Medicis Pharmaceutical Corporation | Gastroretentive dosage forms for minocycline |
| US10398705B2 (en) * | 2012-03-15 | 2019-09-03 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
| CN113197846A (en) | 2013-07-19 | 2021-08-03 | 勃林格殷格翰动物保健有限公司 | Liquid aqueous pharmaceutical composition containing preserved etherified cyclodextrin derivatives |
| AU2014359427B2 (en) | 2013-12-04 | 2017-04-20 | Boehringer Ingelheim Vetmedica Gmbh | Improved pharmaceutical compositions of pimobendan |
| US20170182070A1 (en) | 2014-10-08 | 2017-06-29 | Mayne Pharma International Pty Ltd. | Controlled Release Doxycycline |
| WO2016079590A1 (en) | 2014-11-19 | 2016-05-26 | Dr. Reddy's Laboratories Ltd. | Modified release doxycycline composition |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
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|---|---|---|---|---|
| US3993072A (en) * | 1974-08-28 | 1976-11-23 | Alza Corporation | Microporous drug delivery device |
| DD146547A5 (en) * | 1978-07-15 | 1981-02-18 | Boehringer Sohn Ingelheim | MEDICINAL RETARDANT SHAPE WITH UNFORGETTABLE POROESEN DIFFUSION SHELLS |
| CA1266827A (en) * | 1984-06-20 | 1990-03-20 | Merck & Co., Inc. | Controlled porosity osmotic pump |
| GB8707416D0 (en) * | 1987-03-27 | 1987-04-29 | Wellcome Found | Pharmaceutical formulations |
| US5026559A (en) * | 1989-04-03 | 1991-06-25 | Kinaform Technology, Inc. | Sustained-release pharmaceutical preparation |
-
1990
- 1990-07-27 US US07/559,221 patent/US5188836A/en not_active Expired - Fee Related
-
1991
- 1991-07-19 EP EP91810586A patent/EP0470047A1/en active Pending
- 1991-07-24 AU AU81311/91A patent/AU8131191A/en not_active Abandoned
- 1991-07-25 CA CA002047861A patent/CA2047861A1/en not_active Abandoned
- 1991-07-25 PT PT98446A patent/PT98446A/en not_active Application Discontinuation
- 1991-07-26 JP JP3187281A patent/JPH04234313A/en active Pending
- 1991-07-26 IE IE264491A patent/IE912644A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE912644A1 (en) | 1992-01-29 |
| PT98446A (en) | 1992-06-30 |
| JPH04234313A (en) | 1992-08-24 |
| AU8131191A (en) | 1992-01-30 |
| EP0470047A1 (en) | 1992-02-05 |
| US5188836A (en) | 1993-02-23 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |