The present invention is concerned with a solid slow release oral pharmaceutical dosage unit resistant to amylase which comprises a solid dosage unit made up of an admixture of a therapeutic dosage of an orally effective pharmaceutical product, an optional polysaccharide or polyol, and cross-linked high amylose starch, wherein the cross-linking of the high amylose starch has been carried out with a covalent or non-covalent cross-linking agent with from about 0.1 g to about 30 g of cross-linking agent per 100 g of high amylose starch.
The present invention relates to a slow release pharmaceutical tablet, and more particularly to a slow release pharmaceutical tablet incorporating a covalent or non-covalent cross-linked polymer of a mixture of amylose and amylopectin as the slow release matrix.
The controlled release of biactive molecules has been the subject of extensive research over the last half of the twentieth century. The controlled release of some drugs is of high importance for biopharmaceutical applications. Long acting doses of a variety of drugs are now available, allowing once or twice-a-day dosage regimens where immediate release forms called for multiple and sometimes impractical administrations. Effective slow-release dosage regimens have demonstrated superior patient compliance and hence improved efficacy over multiple immediate release forms.
There are several types of polymers which have already been used as a matrix for the slow-release of drugs. Thus, polymeric materials such as polyvinyl chloride, polyethylene polyamides, ethylcellulose, silicone, poly (hydroxyethyl methacrylate), other acrylic co-polymers, polyvinylacetate-polyvinyl chloride copolymers and other polymers were described as an adequate matrix for tablet preparation (see for example U.S. Pat. No. 3,087,860; U.S. Pat. No. 2,987,445; and Pharm. Acta Helv., 1980, 55, 174-182, Salomon et al.).
Polysaccharides have been used widely in pharmaceutical, chemical, and biochemical drug delivery. This family of natural polymers has been applied to the area of controlled release coatings, matrices, macromolecular carriers and biodegradable carriers. One of the most frequent problems associated with the use of polysaccharides, such as starch, as drug delivery agents is the susceptibility to degradation by intestinal polysaccharidases such a α-amylase. The use of polysaccharides in colonic drug delivery has been reviewed (Critical Reviews™ in Therapeutic Drug Carrier Systems, 13 (3 & 4):185-223 (1996).
Starch is, however, one of the most attractive biopolymers for use as a drug delivery agent since it can be mass produced with a high purity at a very economical price. Recently, in order to apply amylose to the controlled release field, a chemically modified amylose was prepared by cross-linking amylose in the gelatinized state as described in U.S. Pat. No. 5,456,921.
Amylose is a natural substance obtained from starch. It is essentially a linear, non-branched, polymer of glucopyranose units with α-D-(1-4) linkages. In starch, amylose is usually accompanied by amylopectin, which is a branched polyglucose polymer with a significant frequency of branching points based on α-(1-6)-glucosidic bonds. Cross-linked amylose (CLAm) is a novel excipient for the controlled release of drugs in solid drug dosage forms. CLAm is produced by the reaction of amylose with a suitable cross-linking agent in an alkaline medium. Different degrees of cross-linking (CLAx) can be obtained by varying the ratio of cross-linking agent, such as epichlorohydrin, to amylose in the reaction vessel where n indicates the amount (g) of cross-linking agent used for cross-linking 100 g of amylose (i.e., CLAx with×=0, 6, 11, 15 or 30).
CLAm tablets are prepared by direct compression and are highly resistant to mechanical stress in the dry state. When in contact with aqueous fluids, water diffuses into the matrix with subsequent formation of a gel layer. Progressive water sorption leads to significant swelling of the matrix. With degrees of cross-linking below 11, the swollen polymeric matrix does not undergo any erosion in vitro resulting in a dense and homogeneous rubbery matrix. The in vitro medium does not contain any amylase.
Cross-linked amylose (CLAm) has been used as a controlled release (CR) matrix for tablets. However, in certain formulations, tablets were not resistant to amylase, an enzyme responsible for the metabolism of amylose in the human intestine. As a result, tablets containing cross-linked amylose are not resistant to amylase attack and accelerated dose release can occur in vivo or in the presence of enzymes instead of controlled release.
Another feature of cross-linked amylose is its ability to release drugs at a constant rate, following zero-order kinetics, such as described in S.T.P. Pharma 1986, 2, 38-46 (Peppas et al.). The approach called ‘swelling-controlled’ systems consists of glassy polymers into which a water front penetrates at a constant rate. Behind this front, the polymer is in a rubbery state. Provided the drug diffusion coefficient in the rubbery polymer is much higher than in the glassy polymer, a zero order release can be achieved to a certain degree. However, the delivery rate is constant only for a limited fraction of the release, usually around 60% of the total amount of contained drug, and requires a low initial drug concentration.
X-ray diffraction studies show different morphologic forms for amylose in correlation with its origin, preparation mode or hydration state (French D. 25—“Organization of starch granules”—in Starch: Chemistry and Technology [Whistler R., L., BeMiller J., N. and Paschall E. F., Eds.], Acad. Press, 1984). The structures of A and B-type amylose are based on double helices parallel stranded and antiparallel packed, the individual strands being in a right-handed sixfold helical conformation (Wu H. C. and Sarko A., Carbohydr. Res., 61, 7-25, 1978). Amylose A contains 8 molecules of H2O and Amylose B (hydrated) contains 36 molecules of H2O per elementary cell unit. V-Amylose is made from single helix chains and exists as complexes with small organic molecules, water or iodine. Even though the inside of the helix channel of V-Amyloses is primarily hydrophobic, intrahelical water has been found in anhydrous (Va), as well as in the hydrated (Vh) forms. Some intermolecular hydrogen bonds are formed through interstitial water molecules. It has been suggested that the presence of a substantial amount of complexing agent (e.g., ethanol) can mainly stabilize single helices of amylose, whereas a predominance of water can induce conformational changes leading to the formation of double helices (Buleon A., Duprat F., Booy F. P. and Chanzy H., Carbohydr. Polymer, 4 161-173, 1984). All forms of amylose become B-type in gel phase (Wu H. C. and Sarko A., Carbohydr. Res., 61, 27-40, 1978); the interchange of morphological structures tends to reach the more stable double helix form with the corresponding molecules of water.
Accordingly, it would be desirable to provide a slow release system following a zero-order kinetics, and allowing a controlled release of a drug at a constant rate until all the drug is released, whatever the concentration of the drug in the system.
Suitable covalent cross-linking agents are 2,3-dibromopropanol, epichlorohydrin, sodium trimetaphosphate, linear mixed anhydrides of acetic and di- or tribasic carboxylic acids, vinyl sulfone, diepoxides, cyanuric chloride, hexahydro-1,3,5-trisacryloyl-s-triazine, hexamethylene diisocyanate, toluene 2,4-diisocyanate, N,N-methylenebisacrylamide, N,N′-bis(hydroxymethyl)ethyleneurea, phosgene, tripolyphosphate, mixed carbonic-carboxylic acid anhydrides, imidazolides of carbonic and polybasic carboxylic acids, imidazolium salts of polybasic carboxylic acids, guanidine derivatives of polycarboxylic acids, and esters of propanoic acid.
Suitable agents that could be used as additives to high amylose starch for controlled release prior to cross-linking of the high amylose starch include, but are not limited to, polyvinyl alcohol, β-(1-3) xylan, xanthan gum, locust bean gum and guar gum.
In accordance with the present invention there is now provided a solid slow release oral pharmaceutical dosage unit which comprises a solid dosage unit made up of an admixture of a therapeutic dosage of an orally effective pharmaceutical product and covalent cross-linked polymer of high amylose starch made by reacting high amylose starch with a suitable cross-linking agent, wherein the covalent cross-linking of the polymer has been carried out with from about 0.1 to about 30 g of cross-linking agent per 100 g of amylose.
In a further aspect of the invention, there is provided a solid slow release oral pharmaceutical dosage unit made up of an admixture of a therapeutic dosage of an orally effective pharmaceutical product, an optional polysaccharide or polyol and a cross-linked polymer of high amylose starch made by reacting high amylose starch with a suitable cross-linking agent.
In another aspect of the invention, the pharmaceutical product is present in the tablet in an amount of from 0.01 to 80% w/w.
In a further aspect of the invention, a method is described to obtain a matrix resistant to all types of amylase, obviating the concern over premature degradation of the tablet and accelerated release of the orally effective pharmaceutical product.
The cross-linking of amylose is well known in the literature. For example, the desired cross-linking can be carried out in the manner described in BIOCHMIE 1978, 60, 535-537 (Mateescu) by reacting amylose with epichlorohydrin in an alkaline medium. In the same manner, amylose can also be cross-linked with 2,3-dibromopropanol, sodium trimetaphosphate and other suitable cross-linking agents described herein.
Essentially, the high amylose starch is swollen in water by generally known gelatinization techniques such as alkaline or heat treatment and after homogenization, an appropriate amount of cross-linking agent is added. After substantial homogenization, the reaction medium is transferred onto a water bath and heated for one hour at a temperature of from 40° to 45° C. and the temperature is then raised from 60° to 75° C. for a further period of from 1 to 2 hours after which time the reaction is complete. The duration of heating can be varied as well as the amount of cross-linking agent used in the reaction.
The resulting cross-linked material is then sieved in wet form and the granules ranging from about 25 to about 700 um are collected for the preparation of the slow-release tablet of the present invention. The granules of 25 to about 300 um representing at least 50% of the granules are selected for use in accordance with the presented invention.
The preferred cross-linked polymers of high amylose starch with covalent cross-linking agents suitable for the purposes of the present invention are those where from about 0.1 to about 30 g of covalent cross-linking agent have been used to cross-link 100 g of high amylose starch. More preferred cross-linked polymers were obtained when from about 0.5 g to about 6.0 g of covalent cross-linking agents over 100 g of high amylose starch were used.
It has been surprisingly found that when a mixture of amylose and amylopectin between about 10-60% amylopectin by weight is cross-linked by a covalent cross-linking agent comprising sodium trimetaphosphate, 2,3-dibromopropanol, epichlorohydrin, and epibromohydrin or mixed with a suitable polysaccharide or polyol are compressed into tablets, those tablets are resistant to amylase degradation provided that the lubricant used for tableting is not magnesium stearate. These tablets can then be used for the controlled release of oral pharmaceutical products. Conversely, when the objects of the invention are dispersed as a powder in an amylase medium, they are readily degraded. Therefore, when placed in a tablet, it was entirely unexpected that the objects of the invention were stable to amylase.
It has also been surprisingly found that when covalently cross-linked high amylose starch of the invention is exposed to water, it predominantly forms a double helix similar to the B-form of amylose. Upon placement of a high amylose cross-linked starch tablet in water, a gel is formed very quickly at the polymer surface. As the progression of the gel front toward the center of the tablet ceases rapidly, water diffuses into the polymer and reaches the center in about 30 min. As water continues to penetrate, the water gradient in the core progressively diminishes and the core expands, mainly radially. This process goes on for several hours, until the core turns into a gel and equilibrium swelling is reached. In the gel state, the cross-linked high amylose starch, which was initially arranged mainly in the amorphous state and in V type single helices, progressively adopts the B-type double helices conformation, forming a three-dimensional physical network over a long distance. Both amylose and PVA can adopt helical confirmations. PVA is an interesting polymer with alternating hydrophilic (CHOH) and hydrophobic (CH2) groups, and consequently, undergoes lower swelling in water than amylose.
α-amylase (EC 3.2.1.1) from Bacillus species from Sigma Chemical Co.,
acetic acid glacial, monobasic and dibasic sodium phosphate (from Anachemia);
NaOH and acetone (ACS quality);
A. Synthesis of Cross-Linked Polymers-Cross-Linked High Amylose Starch (CLA), and Co-Cross-Linked High Amylose Starch-PVA
A.1. Synthesis of Cross-linked High Amylose Starch (CLA-0, CLA-3, CLA-6, CLA-8 and CLA-14)
For each synthesis, a quantity of 300 g of high amylose starch powder and a volume of 1.75 L of 0.85 N sodium hydroxide (55° C.) were mixed in a Hobart® planetary mixer tank N-50, maintaining the temperature at 50° C. for gelatinization. After 20 minutes of homogenization, a volume of 0 mL, 7.60 mL, 15.24 mL, 20.30 mL or 38.10 mL of epichlorohydrin (corresponding to the required cross-linking degree) was respectively added in each synthesis batch. For instance, for CLA-6 a volume of 15.24 mL of epichlorohydrin corresponding to 18 g (d=1.19 g/mL) was added. Each reaction mixture was again homogenized for 20 minutes. The reaction was continued for a period up to 1 h, under moderate heating (40-70° C.). The mixture was neutralized with acetic acid, and then thoroughly washed on a Buchner funnel with a solution of water/acetone (15:85 v/v) in a first step and then with water/acetone (60:40). The CLA was finally dried with acetone and then exposed to the air during 24 hours. Other drying procedures (spray-drying, lyophilization) can also be used. The dry polymer was sieved (mesh openings of 75-300 um) and stored at room temperature.
Other CLA polymers with different cross-linking degrees (x) can be obtained in similar conditions, with the mention that the added quantities should be of “x” g epichlorohydrin/100 g of amylose.
A.2. Synthesis of Co-Cross-Linked CL(A-PVA) Polymer Co-Cross-Linked CL(A-PVA)-6 Polymer Synthesis, With Different Ratios A/PVA (3/1; 1/1; 1/3)
The cross-linking degree was maintained constant (clx=6) and different amylose/PVA initial polymer ratios were prepared: A/PVA—(3/1) corresponding to 225 g A/75 g PVA; A/PVA=(1/1) corresponding to 150 g A/150 g PVA; A/PVA—(1/3) corresponding to 75 g A/225 g PVA.
For each synthesis, the required amount of PVA powder (MW 9,000-146,000, 87-89% hydrolysis degree) was suspended in 1 L of 1.5 N sodium hydroxide and heated at 95° C. with strong stirring. After the system became macroscopically homogeneous, the temperature was decreased at 50° C. Separately, for each synthesis, the corresponding amount of high amylose starch (Hylon VII) was suspended in 750 mL cold distilled water in the Hobart® mixer and heated, under stirring, at 50° C. Subsequently, the PVA/NaOH solution was slowly added to the corresponding high amylose starch suspension, under continuous stirring and the system kept for 20 min at controlled temperature (50-55° C.) for high amylose starch gelatinization.
a) Synthesis of CL(A-PVA)-6 With Epichlorohydrin As Cross-Linking Agent
For each gelatinized batch (at 40-60° C.), an amount of 18 g epichlorohydrin (clx=6) was added. After 1 hour at 50° C., the mixture was neutralized with 0.75 M acetic acid solution, and then washed and dried with acetone. Other drying procedures (spray-drying, lyophilization) can also be used. The powders were sieved and kept in dark bottles at room temperature.
b) Synthesis of CL(A-PVA)-6 With Sodium-Trimetaphosphate (STMP) as Cross-Linking Agent
The gelatinized batch, was treated with an amount of 18 g STMP. After 1 h at 50° C., the mixture was neutralized with 0.75 M acetic acid solution, and then washed and dried with acetone. Other drying procedures (spray-drying, lyophilization) can also be used. The powders were sieved and kept in dark bottles at room temperature.
10% pseudoephedrine tablets
Pseudoephedrine HCl 10%
The CLA used in this example was cross-linked with sodium trimetaphosphate. The drug was mixed with CLA in a bag for 2-3 minutes and the blend was compressed using a tablet press with round {fraction (15/32)} inch toolings. The weight of the tablets was 500 mg.
The dissolution release profile of the tablets was determined using a USP type III dissolution apparatus. The dissolution system was set up with different dissolution fluids that mimic the GI tract environment with or without enzyme (4500 I.U./L). One international unit (I.U.) will liberate 1 mg of maltose from starch in three minutes at pH 6.9 at 20° C. The drug release was recorded spectrophotometrically with an automated sampling system.
1. A solid controlled release oral pharmaceutical dosage unit in the form of a tablet comprising a blend of 0.01-80% by weight of the tablet of a dry powder of a pharmaceutical product, and 20-99.99% by weight of the tablet of a dry powder of high amylose starch, wherein said high amylose starch comprises a mixture of from about 10-60% by weight of amylopectin and from about 40-90% amylose, wherein said high amylose starch has been covalently cross-linked with a covalent cross-linking agent wherein the cross-linking has been carried out with from about 0.1 g to about 30 grams of cross-linking agent per 100 g of said high amylose starch, wherein said dosage unit is resistant to degradation by amylase.
2. A solid controlled release pharmaceutical dosage unit according to claim 1, wherein said covalent cross-linking agent is 2,3-dibromopropanol, epichlorohydrin, sodium trimetaphosphate, linear mixed anhydrides of acetic and di- or tribasic carboxylic acids, vinyl sulfone, diepoxides, cyanuric chloride, hexahydro-1,3,5-trisacryloyl-s-triazine, hexamethylene diisocyanate, toluene 2,4-diisocyanate, N,N-methylenebisacrylamide, N,N′-bis(hydroxymethyl)ethyleneurea, phosgene, tripolyphosphate, mixed carbonic-carboxylic acid anhydrides, imidazolides of carbonic and polybasic carboxylic acids, imidazolium salts of polybasic carboxylic acids, guanidine derivatives of polycarboxylic acids, or esters of propynoic acid.
3. A solid controlled release pharmaceutical dosage unit according to claim 1, wherein said pharmaceutical product is pseudoephedrine hydrochloride.
4. A solid controlled release pharmaceutical dosage unit according to claim 1, wherein said pharmaceutical product is acetaminophen.
5. A solid controlled release pharmaceutical dosage unit according to claim 1, wherein said covalent cross-linking agent is epichlorohydrin.
6. A solid controlled release pharmaceutical dosage unit according to claim 1, wherein said covalent cross-linking agent is sodium trimetaphosphate.
7. The solid controlled release pharmaceutical dosage unit of claim 1 further comprising a polysaccharide or a polyol.
8. The solid controlled release pharmaceutical dosage unit according to claim 7, wherein said polysaccharide is a β-(1-3)glycan, xanthan gum, locust bean gum or guar gum.
9. The solid controlled release pharmaceutical dosage unit according to claim 7, wherein said polyol is polyvinylalcohol.
10. A method for imparting sustained release to a pharmaceutical product, comprising the steps of:
(a) providing the pharmaceutical product in dry powder form; and
(b) blending the pharmaceutical product with a powder comprising a high amylose starch, wherein said high amylose starch comprises a mixture of from about 10-60% amylopectin and 40-90% amylose, wherein said high amylose starch has been covalently cross-linked with a cross-linking agent wherein the cross-linking has been carried out with from about 0.1 g to about 30 g of cross-linking agent per 100 g of said high amylose starch; and
(c) compressing the blend to form a tablet.
11. A method according to claim 10, wherein step (b) comprises mixing the pharmaceutical product in an amount of from 0.01 to 80% by weight of the tablet with a powder comprising cross-linked high amylose starch in an amount of from 20-99.99% by weight of the tablet.
12. A method according to claim 10, wherein the cross-linking agent is sodium trimetaphosphate.
13. A method according to claim 10, where step (b) is carried out with from about 0.1 g to about 30.0 g of sodium trimetaphosphate per 100 g of high amylose starch.
14. A solid controlled release pharmaceutical dosage unit in the form of a tablet comprising:
(a) a pharmaceutical product;
(b) high amylose starch, wherein said high amylose starch comprises 10-60% by weight amylopectin and 40-90% by weight amylose; and
(c) a polysaccharide or a polyol;
wherein said high amylose starch and said polysaccharide or said polyol have been covalently co-cross-linked with a covalent cross-linking agent wherein the cross-linking has been carried out with from about 0.1 g to about 30 g of cross-linking agent per 100 g of high amylose starch.
15. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said polysaccharide is a β-(1-3)glycan, xanthan gum, locust bean gum or guar gum.
16. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said polyol is polyvinylalcohol.
17. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said covalent cross-linking agent is 2,3-dibromopropanol, epichlorohydrin, sodium trimetaphosphate, linear mixed anhydrides of acetic and di- or tribasic carboxylic acids, vinyl sulfone, diepoxides, cyanuric chloride, hexahydro-1,3,5-trisacryloyl-s-triazine, hexamethylene diisocyanate, toluene 2,4-diisocyanate, N,N-methylenebisacrylamide, N,N′-bis(hydroxymethyl)ethyleneurea, phosgene, tripolyphosphate, mixed carbonic-carboxylic acid anhydrides, imidazolides of carbonic and polybasic carboxylic acids, imidazolium salts of polybasic carboxylic acids, guanidine derivatives of polycarboxylic acids, or esters of propynoic acid.
18. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said pharmaceutical product is pseudoephedrine hydrochloride.
19. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said pharmaceutical product is acetaminophen.
20. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said covalent cross-linking agent is epichlorohydrin.
21. A solid controlled release pharmaceutical dosage unit according to claim 14, wherein said covalent cross-linking agent is sodium trimetaphosphate.
(a) providing the pharmaceutical product in dry powder form;
(b) blending the pharmaceutical product with a powder comprising a high amylose starch, wherein said high amylose starch comprises 10-60% by weight amylopectin and 40-90% by weight amylose, wherein said high amylose starch has been covalently co-cross-linked with a polysaccharide or polyol and a cross-linking agent wherein the cross-linking has been carried out with from about 0.1 g to about 30 g of cross-linking agent per 100 g of said high amylose starch; and
23. A method according to claim 22, wherein step (b) comprises blending said polysaccharide or polyol with high amylose starch prior to cross-linking the high amylose starch.
24. A method according to claim 22, wherein said polyol is polyvinylalcohol.
25. A method according to claim 22, wherein said polysaccharide is a β-(1-3)glycan, xanthan gum, locust bean gum or guar gum.
(b) blending the pharmaceutical product with a powder comprising a high amylose starch, wherein said high amylose starch comprises 10-60% by weight amylopectin and 40-90% by weight amylose, wherein said high amylose starch has been covalently cross-linked using a covalent cross-linking agent wherein the cross-linking has been carried out with from about 0.1 g to about 30 g of cross-linking agent per 100 g of said high amylose starch;
(c) blending the powder of step (b) with a polysaccharide or polyol; and
(d) compressing the blend to form a tablet.
30. The method according to claim 29, wherein said polyol is polyvinylalcohol.
31. The method according to claim 29, wherein said polysaccharide is a β-(1-3)glycan, xanthan gum, locust bean gum or guar gum.
32. The method according to claim 29, wherein the cross-linking agent is sodium trimetaphosphate.
33. The method according to claim 29, where step (b) is carried out with from about 0.1 g to about 30.0 g of sodium trimetaphosphate per 100 g of high amylose starch.
34. The method according to claim 33, wherein step (b) comprises mixing the pharmaceutical product in an amount of from 0.01 to 80% by weight of the tablet with a powder comprising cross-linked high amylose starch in an amount of from 20-99.99% by weight of the tablet.
WO2012116434A1 (en) * 2011-03-01 2012-09-07 4413261 Canada Inc. (Spencer Canada) Two speed monolithic system for controlled release of drugs
US20170072069A1 (en) * 2014-02-27 2017-03-16 B-Organic Films Corp. Bioactive agents under water dispersible solid forms for food, nutraceutical, agricultural and pharmaceutical applications
CN107106725A (en) 2014-12-19 2017-08-29 巴克斯特国际公司 Flowable hemostatic composition
CN104784738B (en) * 2015-04-03 2016-12-07 四川大学 A natural release medical sponge pleiotropic
CN106279453A (en) * 2015-05-28 2017-01-04 易媛 Crosslinked high molecular compound, preparation method thereof, hydrogel, water-base fracturing fluid, and applications of crosslinked high molecular compound
CN105536058A (en) * 2016-01-22 2016-05-04 青岛中腾生物技术有限公司 Medical starch sponge and preparation method and application thereof
US5830884A (en) * 1995-01-18 1998-11-03 National Starch And Chemical Investment Holding Corporation Pharmaceutical products containing thermally-inhibited starches
US4072535A (en) * 1970-12-28 1978-02-07 A. E. Staley Manufacturing Company Precompacted-starch binder-disintegrant-filler material for direct compression tablets and dry dosage capsules
US4369308A (en) * 1981-07-24 1983-01-18 National Starch And Chemical Corporation Low swelling starches as tablet disintegrants
CA2041774C (en) * 1990-11-27 1994-04-19 Mircea A. Mateescu Use of cross-linked amylose as a matrix for the slow release of biologically active compounds
US5616343A (en) * 1993-03-25 1997-04-01 Labopharm, Inc. Cross-linked amylose as a binder/disintegrant in tablets
CA2173818A1 (en) * 1996-04-10 1997-10-11 Francois Chouinard Time-released pharmaceutical compound containing a cured amylose-based support and hydroxypropylmethylcellulose
US5879707A (en) * 1996-10-30 1999-03-09 Universite De Montreal Substituted amylose as a matrix for sustained drug release
US5807575A (en) * 1997-02-14 1998-09-15 Rougier Inc. Manufacture of cross-linked amylose useful as a excipient for control release of active compounds
US7705135B2 (en) 1998-05-13 2010-04-27 Nanotherapeutics, Inc. Pharmaceutical compositions comprising aloe pectins, and methods for their production and use
US8487002B2 (en) 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
US7988998B2 (en) 2002-10-25 2011-08-02 Labopharm Inc. Sustained-release tramadol formulations with 24-hour efficacy
US20090011014A1 (en) * 2004-12-24 2009-01-08 Universite De Montreal Tablet Formulation for Sustained Drug-Release
US9439866B2 (en) 2005-09-09 2016-09-13 Angelini Pharma, Inc. Trazodone composition for once a day administration
US8414919B2 (en) 2005-09-09 2013-04-09 Angelini Labopharm, Llc Sustained drug release composition
US8962019B2 (en) 2005-09-09 2015-02-24 Angelini Pharma, Inc. Sustained drug release composition
US8795723B2 (en) 2005-09-09 2014-08-05 Angelini Pharma Inc. Sustained drug release compositions
US8895066B2 (en) 2007-10-16 2014-11-25 Paladin Labs Inc. Bilayer composition for the sustained release of acetaminophen and tramadol
US3431338A (en) 1969-03-04 Coated dosage form adapted to oral emetine or dehydroemetine therapy
Krishnaiah et al. 2002 In vitro drug release studies on guar gum-based colon targeted oral drug delivery systems of 5-fluorouracil
Kinget et al. 1998 Colonic drug targeting
Draget et al. 1997 Alginate based new materials
Ashford et al. 1994 Studies on pectin formulations for colonic drug delivery
Prasad et al. 1998 In vitro evaluation of guar gum as a carrier for colon-specific drug delivery
Krishnaiah et al. 1998 Evaluation of guar gum as a compression coat for drug targeting to colon
Berger et al. 2004 Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications
Kast et al. 2002 Design and in vitro evaluation of a novel bioadhesive vaginal drug delivery system for clotrimazole
Philip et al. 2010 Colon targeted drug delivery systems: a review on primary and novel approaches
Bajpai et al. 2004 Investigation of swelling/degradation behaviour of alginate beads crosslinked with Ca2+ and Ba2+ ions
Turkoglu et al. 2002 In vitro evaluation of pectin–HPMC compression coated 5-aminosalicylic acid tablets for colonic delivery
Jain et al. 2007 Perspectives of biodegradable natural polysaccharides for site-specific drug delivery to the colon
US5399362A (en) 1995-03-21 Once-a-day metoprolol oral dosage form
US5445826A (en) 1995-08-29 Delivery system containing a gel-forming dietary fiber and a drug
Friend 2005 New oral delivery systems for treatment of inflammatory bowel disease
Sriamornsak 2003 Chemistry of pectin and its pharmaceutical uses: A review
Sriamornsak 1998 Investigation of pectin as a carrier for oral delivery of proteins using calcium pectinate gel beads
Rubinstein et al. 1993 In vitro evaluation of calcium pectinate: a potential colon-specific drug delivery carrier
Yang et al. 2002 Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation
US20070077305A1 (en) 2007-04-05 Biocompatible polymeric matrix and preparation thereof
US6642363B1 (en) 2003-11-04 Polymers containing polysaccharides such as alginates or modified alginates
Coviello et al. 2007 Polysaccharide hydrogels for modified release formulations
US20050249716A1 (en) 2005-11-10 Galenic formulation for colon targeted delivery of active principles
Lin et al. 2005 pH-sensitive polyelectrolyte complex gel microspheres composed of chitosan/sodium tripolyphosphate/dextran sulfate: swelling kinetics and drug delivery properties