GB1567727A - Constant rate release tablets - Google Patents

Constant rate release tablets Download PDF

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Publication number
GB1567727A
GB1567727A GB638378A GB638378A GB1567727A GB 1567727 A GB1567727 A GB 1567727A GB 638378 A GB638378 A GB 638378A GB 638378 A GB638378 A GB 638378A GB 1567727 A GB1567727 A GB 1567727A
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Prior art keywords
tablet
water
min
mm
soluble
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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
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GB638378A
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Nippon Kayaku Co Ltd
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Nippon Kayaku Co Ltd
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Priority to JP2321377A priority Critical patent/JPS603286B2/ja
Application filed by Nippon Kayaku Co Ltd filed Critical Nippon Kayaku Co Ltd
Publication of GB1567727A publication Critical patent/GB1567727A/en
Application status is Expired legal-status Critical

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms

Description

(54) IMPROVEMENTS IN AND RELATING TO CONSTANT RATE RELEASE TABLETS (71) We, NIPPON KAYAKU Co., LTD., a Japanese Company of New Kaijo Bldg., 2-1, I-Chome Marunouchi Chiyoda-Ku, Tokyo, Japan; do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to a constant-rate duting medicinal tablet and a method of producing such tablets.

Gradually eluting type tablets have many advantages in practical use; such as reduced frequency of medicinal administration, re duced side-effects and prolonged retention of effective concentration of a medicine in the blood.

Several types of gradually eluting medi cinal tablets are known such as; those hav ing a coating film which is permeable to the medicine; those dissolved and eluted by the action of a digestive enzyme; those gradu ally eluted as the tablet absorbs water and are thereby swollen in the alimentary canal; and those eluted under the influence of pH in the digestive canal. However, the first said gradually eluting tablet has the dis advantages that the elution of the medicine commences only slowly, that the elution is not at constant rate but sinusoidal and that it is unsuited to medicines which are spar ingly soluble in water. Other gradually elut ing tablets have a serious disadvantage in that their gradual elution properties are greatly affected by the circumstances in the alimentary canal. For these reasons, it has been difficult when using these known types of gradually eluting tablets to maintain the effective concentration of the medicine in the blood at a constant level.

In an attempt to overcome such difficul ties there was developed a constant-rate eluting device having a fine passage (U.S.

Patent 3,845,770). But this device is rather impractical because it requires much time and labour as well as skill for its production; for instance, it is required to drill or punch the fine passage or to embed a fine tube in the device.

According to the present invention there is provided a constant-rate eluting tablet which elutes an active principle at constant rate comprising a core including the active principle and having a hollow or hollows in its surface and containing a water-soluble component coated with an agent soluble in or ganic solvents or hydrous organic solvents and insoluble in water but having water permeability, said hollows measuring 0.1 to to 1.0 mm in width, 0.1 to 0.4 mm in depth and greater than 0.1 mm in length, and an area of less than 1/6 of the overall surface area of the tablet.

According to a further aspect of the invention there is provided a method of producing a constant-rate eluting tablet comprising the steps of braying and moulding a composition containing a water soluble component andl or an active ingredient with a punch having a convexity of convexities to form a tablet having a concavity or concavities, said concavity measuring 0.1 to 1.0 mm in width, 0.1 to 0.4 mm in depth and greater than 0.1 mm in length, and an area of less than 1/6- of the overall surface area of the tablet, and then coating the tablet with a coating agent which is soluble in organic solvents or hydrous organic solvents and insoluble in water but has water permeability.

It is to be noted that if the width, depth and length are all less than 0.1 mm, the surface hollow portion is perfectly covered with the coating film so that the active ingredient won't be eluted out from the hollow portion and instead the so-called first order elution takes place. On the other hand, if the recession width is greater than 1.0 mm and the depth is greater than 0.4 mm.

the recessed portion is also perfectly covered with the coating film just like the tablet having no recession, and hence, in this case, too, the elution effected is of the first order mode and no constant-rate elution takes place.

The surface recession or hollow may be of any suitable configuration provided that the abovesaid requirements are met. The size and number of the hollow(s) may be correctly determined by taking into account the size of the tablet, the desired rate of elution of the active principle, and other factors.

The coating agent used for the tablet of this invention is of the type which is not only insoluble in water and water-permeable but is also soluble in the organic solvents or hydrous organic solvents. Preferred examples of such coating agents include:-- methacrylic acid-methacrylic acid ester copolymers such as Eudragit retard S Eudragit retard L and Eudragit L-S (all trade names of Rohm and Hass), methyl acrylate-methacrylic acid methyl methacrylate copolymers such as MPM-06 (Tanabe Pharmaceutical Co. Ltd.), ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose acetate phthalate and hydroxypropyl cellulose phthalate. As for the water soluble component, no specific water-soluble excipient is needed if the active principle of the tablet is easily soluble in water thus said water soluble component may be the active principle per se. However the use, in such circumstances, of an excipient easily soluble in water is recommended. For example such excipients may be selected from a saccharoid such as lactose, mannitol, sorbitol, pulverized sucrose, maltose, or glucose where the active principle is difficulty soluble in water. The difficulty water-soluble or water-insoluble excipients usable in this invention may also include, for example, calcium citrate, calcium phosphate, calcium monohydrogenphosphate, synthetic aluminum silicate and pulverized methacrylic acid-methacrylic acid ester coplymers.

The active principle of the tablet may be either of the water-soluble, difficultly watersoluble, or water-insoluble type; the latter if said principle a medicament which is desired to stay in the stomach and intestinal canal for a long time. The following are examples of active principles for use in the tablet of this invention: antibiotics such as penicillin, cephalosporin system antibiotics, erythromycins, tetracyclines and macrolide antibiotics; antifebriles or anodynes such as asprin, - sulpyrine, peraaminoacetophenol or sodium diclophenac, antihistamines such as d-chlorophenylamine maliate, diphenylpyraraine or diphenyldramine, psychotropic drugs such as diazepam, chloropromazine or lithium carbonate; vitamins; antidiabetic medicines such as tolubutamide; cardiacs such as prehnylamine lactate or -digitoxin; narcotics such as a barbituric acid system; diusetics such as sodium salicylate or theobromine; and anti-malignant tumor agents such as 5-FU. The medicaments usable in this invention are not limited to those cited above.

These substances may be used in any suitable combination in any desired physical form, i.e. powdered and/or further regulated to a desired grain size according to the purpose of use. Said substances are then brayed and moulded by a pestle having a convexity according to a normal method to form the tablets with a concave recession or hollow in the surface.

The tablet coating method and other preparation techniques should be suitably selected according to the purpose of use. The solvent for the coating base, is preferably an alcohol such as methanol, ethanol or isopropyl alcohol; a hydrocarbon chloride such as methylene chloride, methylchloroform or chloroform, or a mixture thereof, or a mixture thereof with water. Such a solvent preferably has a boiling point of less than 100"C. The coating thickness may also be suitably determined depending on the purpose of use, but usually a thickness within the range of 30 to 150 y is suggested to take into account the possibility of handling damage.

If desired, the constant-rate eluting tablet of this invention may be formed into an inner core compressed tablet (generally called inner core tablet) using the tablet of this invention as a nucleus and subsequently coated to form water-soluble film coated tablets or sugar-coated tablets. In this case, by applying an active principle in the crust constituent, it is possible to provide a "booster dose" for said gradually eluting tablets.

The following is a description by way of example only of methods of carrying the invention into effect. Parts are by weight unless otherwise stated.

EXAMPLE 1 6 gm of maleic d-chlorophenylamine maleate, 100 gm of lactose, 11 gm of corn starch and 2 gm of polyvinyl pyrrolidone are mixed together, and 22 ml of ethanol is added thereto, the resultant mixture is kneaded, granulated and dried to obtain granules.

To the so-obtained granules 1.2 gm of magnesium stearate is added. These granules are then subjected to moulding by using a single punch with diameter of 7 mm and curvature of 11 mm and having a convexity measuring 0.5 mm in width, 0.2 mm in depth and 3 mm in length and another single punch with the same dimensions but without said convexity, under the moulding pressure of 1,500-50 Kg/cm2 to form the tablets weighing 120 mg per tablet.

The thus formed products are put into a test film coating pan and coated with a coating solution comprising 5 parts of ethyl cellulose having viscosity of 10 cps, 0.5 parts of stearic acid, 1 part of triacetin, 40 parts of isopropyl alcohol and 43.5 parts of chloroform and the coating being completed at the point where the weight of one tablet has become 126 mg on the average.

When the thus prepared tablets were subjected to a disintegration test with a disintegration tester of the Japanese Pharmacopeia by using the first solution (pH 1.2) according to tbe enteric tablet test specs -fications of the Japanese Pharmacopoeial, maleic acid d-chlorophenylamine was observed eluting out gradually at a constant rate (1.003%/min.).

When the same test was conducted on the control tablets with no coating (control sample 1) and those with no concavity (control sample 2), the former completed elution in approximately 3 minutes while the latter showed obvious delay in start of elution and, more typically, the elution was of the primary pattern and also imperfect.

The relation between elution time and elution rate is shown below.

Products of this Control Control Time invention sample 1 sample 2 2 min. 2% 95% 0% 5 min. 4% 100% 1% 10 min. 9% 2% 30 min. 31% 4% 60 min. 62% 12% 90 min. 95% 20% 120 min. 100% -- 37% I80 min. -- -- 78 This relationship is shown in the graph of Figure 1. As is apparent from the graph, the medicine elutes out at a constant rate from the products of this invention, whereas the elution completes quickly in control sample 1 and the elution pattern is of a first order and is imperfect in control sample 2.

EXAMPLE 2 Granules were formed from a mixture of 50 gm of triperizone hydrochloride, 45 gm of lactose, 12 gm of corn starch and 2 gm of polyvinyl pyrrolidone in the same way as Example l, and to these granules 1.1 gm of magnesium stearate was added. The resultant product was -then moulded into tablets with an average weight of 120 mg per tablet by using a single punch with diameter of 7 mm, curvature of 11 mm and having an inverted V-shaped (acute angle: 60 ) convexity with width of 0.2 mm, depth of 0.2 mm and length of 3.5 mm and a similar punch with no convexity; under a moulding pressure of 1,350+50 Kg/cm2.

The thus-formed tablets were then put into a test film coating pan and coated with a coating solution comprising 5 parts of Eudragit retard S, 1 part of myvacet, 74 parts of isopropyl alcohol and 24 parts of acetone, with the coating being completed at the point when each tablet weighed 128 mg on average.

The thus obtained tablets were subjected to the same test as conducted in Example 1 (by using one tablet for each test).

In the products of this invention the medicine eluted out only gradually and at a constant rate, whereas in the uncovered tablets (control sample 1), the medicine was dissolved very quickly while in the tablets with no concavity (control sample 2) the elution was imperfect, not constant and also slow to start. The results are tabulated below, Products of this Control Control Time invention sample 1 sample 2 2 min. 1% 79% 0% 5 min. 3% 100% 0% 10 min. 7% I% 1% 30 min. 19% 2% 60 min. 41% 8% 90 min. 63% 16% 120 min. 81% -- 27% 150 min. 97% -- 39% 180 min. 100% -- 58% The above-shown relation between elution time and elution rate is shown in Figure 2.

EXAMPLE 3 A mixture consisting of 125 gm of finely powdered grislo-fulvin (specific surface area: 1.52 m2/g; average surface area of body (diameter); approximately 2.7), 40 gm of lactose, 7 gm of corn starch and 2 gm of polyvinyl pyrrolidone was granulated using distilled water, It was then dried, regulated in grain size, and 1.7 gm of magnesium stearate was then added.

Then the thus obtained granules were moulded into tablets weighing average 175 mg per tablet by using a single punch with diameter of 8 mm and curvature of 12 mm and having a cruciform convexity measuring 0.4 mm in width, 0.25 mm in depth and 4 mm in length, and another similar punch having no such convexity, under the moulding pressure of 1,100+50 Kg/cmS.

These tablets were then coated with the coating solution as used in Example 2 until each tablet weighed 183 mg on average.

When the thus prepared tablets were tested after the manner of Example 1, the products of this invention were gradually swollen by permeation of water and the medicinal substance was seen effusing out gradually from the hollow portion. Also, measurement of the elution rate showed that although the elution starts somewhat later than the tablets of Examples 1 and 2, such elution proceeds at a constant rate (0.533to/ min.).

Elution occurred relatively early in the uncovered tablets (control sample 1) while, in the case of the tablets with no concavity (control sample 2), substantially no elution took place, even 300 minutes after start of the test.

The relation between elution time and elution rate in the products of this invention as well as control samples 1 and 2 are shown below.

Products of this Control Control Time invention sample 1 sample 2 10 min. 1% 5% 0% 20 min. 6% 9% 0% 30 min. 11% 15% 0% 60 min. 26% 39% 1% 120 min. 60% 82% 1% 180 min. 92% 100% 2% 240 min. 100% 2% 300 min. - - 4% EXAMPLE 4 Granules were prepared from a mixture of 25 gm of sodium diclophenac, 80 gm of mannitol, 17 gm of corn starch and 2 gm of hydroxypropyl cellulose by using distilled water, and the formed granules were dried and the grain size thereof adjusted; followed by addition of 1 gm of magnesium stearate.

The thus obtained granules were then moulded into tablets weighing 125 mg per tablet by using a single punch with diameter of 8 mm and curvature of 12 mm and having a circular convexity 0.3 mm in diameter and 0.3 mm in depth and another single punch with no such convexity under the moulding pressure of 1,300+50 Kg/cni.

The formed tablets were coated with a coating solution same as used in Example 1 un til the average weight of each tablet reached 133 mg. When the thus prepared tablets were subjected to the same tests as in Example 1, the content of medicinal substance was seen effusing out at a constant rate (1.467%1 min.) from the hollow portion of each tab let of this invention tested.

The uncovered tablet (control sample 1) was very quick to elute while the tablet with no hollows (control sample 2) gave only 20% elution even 240 minutes after start of the test.

The results are tabulated below.

Products of this Control Control Time invention sample 1 sample 2 10 min. 13% 32% 20 min. 29% 88% 30 min. 45% 100% 40 sun. 58% 50 min. 74% 60 min. 88% 4% 90 min. 100% 5% 120 min. -- -- 8% 180 min. -- -- 14% 240 min. 20% EXAMPLE 5 30 mg (14.5 mg in weight) of bleomycin hydrochloride, 140 mg of calcium citrate and 0.5 mg of magnesium stearate were admixed and this mixture was moulded into tablets weighing 155 mg per tablet by using a 10x4 mm rectangular pestle having an inverted V-shaped convexity with acute angle of 600, a width of 0.2 mm, a depth of 0.2 mm and straight line portion length of 2 mm under a moulding pressure of 980+50 Kg/cm'.

Then the thus formed tablets were coated with the coating solution as used in Example 3 until each table weighed 183 mg.

When the test of Example 1 was conducted on the prepared tablets by using a phosphate buffer with pH 6.8 as eluent, the tablets of this invention induced elution of the medicine at a constant rate (8.5%/hr.) from the hollow portion of the tablet.

Whereas in the uncovered tablet (control sample), the elution occurred very quickly and was completed in 30 minutes. The results are tabulated below.

Products of this Control Time invention sample 30 min. 6% 100% 1 her. 10% 2 hr. 18% 4 hr. 36% 6 hr. 49% 8 hr. 67% 10 hr. 83% WHAT WE CLAIM IS:- 1. A constant-rate eluting tablet which elutes an active principle at constant rate comprising a core including the active principle and having a hollow or hollows in its surface and containing a water-soluble component coated with an agent soluble in organic solvents or hydrous organic solvents and insoluble in water but having water permeability, said hollows measuring 0.1 to to 1.0 mm in width, 0.1 to 0.4 mm in depth and greater than 0.1 mm in length, and an area of less than 1/6 of the overall surface area of the tablet.

2. A tablet as claimed in claim 1 wherein the water-soluble component is also the active principle.

3. A tablet as claimed in either preceding claim including a water-soluble excipient.

4. A tablet as claimed in any preceding claim, wherein the "water-soluble" component consists of a water-soluble active principle and a difficultly water-soluble or "water-insoluble" excipient.

5. A tablet as claimed in any one of claims 1 to 3 wherein the "water-soluble" component consists of a difficulty watersoluble or "water-insoluble" active principle and a "water-soluble" excipient.

6. A tablet as claimed in any preceding claim wherein the coating agent insoluble in water but having water permeability is selected from a methacrylic acid-methacrylic acid ester copolymer, ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose acetate phthalate or hydroxypropyl cellulose phthalate.

7. A tablet as claimed in any preceding

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (1)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    The formed tablets were coated with a coating solution same as used in Example 1 un til the average weight of each tablet reached 133 mg. When the thus prepared tablets were subjected to the same tests as in Example 1, the content of medicinal substance was seen effusing out at a constant rate (1.467%1 min.) from the hollow portion of each tab let of this invention tested.
    The uncovered tablet (control sample 1) was very quick to elute while the tablet with no hollows (control sample 2) gave only 20% elution even 240 minutes after start of the test.
    The results are tabulated below.
    Products of this Control Control Time invention sample 1 sample 2
    10 min. 13% 32%
    20 min. 29% 88%
    30 min. 45% 100%
    40 sun. 58%
    50 min. 74%
    60 min. 88% 4%
    90 min. 100% 5% 120 min. -- -- 8% 180 min. -- -- 14% 240 min. 20% EXAMPLE 5
    30 mg (14.5 mg in weight) of bleomycin hydrochloride, 140 mg of calcium citrate and 0.5 mg of magnesium stearate were admixed and this mixture was moulded into tablets weighing 155 mg per tablet by using a 10x4 mm rectangular pestle having an inverted V-shaped convexity with acute angle of 600, a width of 0.2 mm, a depth of 0.2 mm and straight line portion length of 2 mm under a moulding pressure of 980+50 Kg/cm'.
    Then the thus formed tablets were coated with the coating solution as used in Example 3 until each table weighed 183 mg.
    When the test of Example 1 was conducted on the prepared tablets by using a phosphate buffer with pH 6.8 as eluent, the tablets of this invention induced elution of the medicine at a constant rate (8.5%/hr.) from the hollow portion of the tablet.
    Whereas in the uncovered tablet (control sample), the elution occurred very quickly and was completed in 30 minutes. The results are tabulated below.
    Products of this Control Time invention sample
    30 min. 6% 100% 1 her. 10%
    2 hr. 18%
    4 hr. 36%
    6 hr. 49%
    8 hr. 67%
    10 hr. 83% WHAT WE CLAIM IS:- 1. A constant-rate eluting tablet which elutes an active principle at constant rate comprising a core including the active principle and having a hollow or hollows in its surface and containing a water-soluble component coated with an agent soluble in organic solvents or hydrous organic solvents and insoluble in water but having water permeability, said hollows measuring 0.1 to to 1.0 mm in width, 0.1 to 0.4 mm in depth and greater than 0.1 mm in length, and an area of less than 1/6 of the overall surface area of the tablet.
    2. A tablet as claimed in claim 1 wherein the water-soluble component is also the active principle.
    3. A tablet as claimed in either preceding claim including a water-soluble excipient.
    4. A tablet as claimed in any preceding claim, wherein the "water-soluble" component consists of a water-soluble active principle and a difficultly water-soluble or "water-insoluble" excipient.
    5. A tablet as claimed in any one of claims 1 to 3 wherein the "water-soluble" component consists of a difficulty watersoluble or "water-insoluble" active principle and a "water-soluble" excipient.
    6. A tablet as claimed in any preceding claim wherein the coating agent insoluble in water but having water permeability is selected from a methacrylic acid-methacrylic acid ester copolymer, ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose acetate phthalate or hydroxypropyl cellulose phthalate.
    7. A tablet as claimed in any preceding
    claim wherein the coating thickness is within the range of 30 to 150 j.
    8. A tablet as claimed in claim 1 and substantially as described in any one of the specific examples hereinbefore set forth.
    9. A method of producing a constant rate eluting tablet as claimed in any one preceding claiim comprising the steps of braying and moulding a composition containing a water soluble component and/or an active ingredient with a punch having a a convexity of convexities to form a tablet having a concavity or concavities, said concavity measuring 0.1 to 1.0 mm in width, 0.1 to 0.4 mm in depth and greater than 0.1 mm in length, and an area of less than 1/6 of the overall surface area of the tablet, and then coating the tablet with a coating agent which is soluble in organic solvents or hydrous organic solvents and insoluble in water but has water permeability.
    10. A method as claimed in claim 9 and substantially as described in any one of the specific examples hereinbefore set forth.
GB638378A 1977-03-03 1978-02-17 Constant rate release tablets Expired GB1567727A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2321377A JPS603286B2 (en) 1977-03-03 1977-03-03

Publications (1)

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GB1567727A true GB1567727A (en) 1980-05-21

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Application Number Title Priority Date Filing Date
GB638378A Expired GB1567727A (en) 1977-03-03 1978-02-17 Constant rate release tablets

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JP (1) JPS603286B2 (en)
DE (1) DE2808505C2 (en)
FR (1) FR2382234B1 (en)
GB (1) GB1567727A (en)

Cited By (22)

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WO1984002843A1 (en) * 1983-01-26 1984-08-02 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
US8309060B2 (en) 2003-08-06 2012-11-13 Grunenthal Gmbh Abuse-proofed dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US8420056B2 (en) 2003-08-06 2013-04-16 Grunenthal Gmbh Abuse-proofed dosage form
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt

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US3851648A (en) * 1973-10-11 1974-12-03 Mead Johnson & Co Zero-order release device

Cited By (25)

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GB2143734A (en) * 1983-01-26 1985-02-20 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
WO1984002843A1 (en) * 1983-01-26 1984-08-02 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8309060B2 (en) 2003-08-06 2012-11-13 Grunenthal Gmbh Abuse-proofed dosage form
US8420056B2 (en) 2003-08-06 2013-04-16 Grunenthal Gmbh Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
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Also Published As

Publication number Publication date
DE2808505A1 (en) 1978-09-07
DE2808505C2 (en) 1987-02-26
JPS53113008A (en) 1978-10-03
FR2382234A1 (en) 1978-09-29
FR2382234B1 (en) 1982-05-07
JPS603286B2 (en) 1985-01-26

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