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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients

Definitions

• a sustained release pharmaceutical tablet characterized by a substantially constant rate of drug release comprising: (a) a medicament; (b) a hydrophobic dissolution retardant; (c) an acid-insoluble release agent; and (b) a water-soluble or dispersible binder.
• This invention relates to novel orally administrable dosage forms.
• it relates to the preparation of sustained release tablets capable of disintegrating at a constant and uniform rate.
• dosage forms enable the physician to more carefully regulate the level of drug administration to the patient.
• a further advantage of sustained release dosage forms to the patient is the fact that a lesser number of them need be taken during the course of treatment.
• one means for obtaining the above objective is to employ capsules or tablets which release the drug at a uniform rate during the capsules passage through the gastro-intestinal tract.
• this object has been achieved by admixing one or more inert ingredients with the drug in such a manner that these inactive materials interfere with the disintegration of the tablet or the dissolution of the drug.
• An obvious form of such a tablet is one wherein a core containing the active ingredient is surrounded by a layer of inert materials.
• the tablet may be coated with an enteric substance, in which case the tablet passes unchanged through the stomach and disintegrates in the intestinal tract.
• tablets can be composed of several alternate layers of medicament and inert material. In this manner, as each alternate protective layer disintegrates the patient receives a further dose of medicament.
• tablets of this type suffer from the disadvantage of not providing a uniform and constant drug release. Furthermore, such tablets are difficult to prepare with precision so that in many instances the desired dosage level cannot be assured.
• the present invention describes sustained release dosage forms which will provide a uniform and constant liberation of medicament
• This invention comprises a sustained release pharmaceutical tablet comprising: (a) a medicament; (b) a hydrophobic dissolution retardant; (c) an acid insoluble release agent; and (d) a water soluble or dispersible binder.
• the product of this invention is characterized by having a substantially constant erosion rate in gastro-in- 3,577,514 Patented May 4, 1971 testinal fluid wherein the medicament is released at a constant and uniform rate.
• This invention further comprises a sustained release pharmaceutical tablet containing up to 70% by weight of a medicament, 15-50% by Weight of a hydrophobic dissolution retardant, 0.l5.0% by weight of an acid-insoluble release agent and 5-15 by weight of a water soluble or dispersible binder.
• the formulation comprises an intimate uniform blend of a water soluble or insoluble medicament, a hydrophobic dissolution retardant, an acid-insoluble release agent, and a water soluble or dispersible binder.
• Other customary tablet ingredients such as fillers, colorants, lubricants, stabilizers and excipients can also be included in the formulation as required. Tabletting of this blend provides a pharmaceutical tablet wherein the aforesaid constituents are uniformly dispersed throughout the tablet matrix.
• the blend can be formulated into a capsular form as well.
• the range of the basic ingredients can be varied over a considerable latitude and yet will provide an orally administrable dosage form having a constant and uniform rate of disintegration, Thus, the following ranges have been found to be effective (the percentages are by weight): up to 70% of medicament; 15-50% of hydrophobic dissolution retardant; 0.l5% of acid insoluble release agent; and 5-15 of a water soluble binder.
• a preferred formulation would comprise about 5-25% of medicament; 2030% of hydrophobic dissolution retardant; 05-10% of acid-insoluble release agent; and -11% of water-soluble binder.
• An outstanding advantage of the present invention is the fact that a mixture of Water soluble and insoluble medicaments can be incorporated into the blend and after tableting each individual medicament will he released from the tablet at a uniform and constant rate.
• a sustained release dosage form containing theophylline, ephedrine sulfate and hydroxyzine hydrochloride, wherein each pharmaceutical has been found to be released in simulated intestinal fluid at a reasonably constant and uniform rate.
• medicaments can be used in the instant invention, such as antihistamines, hypoglycemics, antidepressants, coronary vasodilators, bronchodilators, sedatives, decongestants, antispasmodics, vitamins, and the antibiotics.
• hydrophobic dissolution retardants by virtue of their water insolubility, function by retarding the dissolution and diffusion of the drug from the tablet or granulates into the gastro-intestinal fluid
• hydrophobic dissolution retardants that we have found effective are the natural and synthetic waxes, resins and plastics. Of these we prefer carnauba wax, beeswax, spermaceti, and the commercial product Sterotex K-lOO, which is a hydrogenated cottonseed oil available from Capital City Products, Columbus, Ohio.
• Enteric substances insoluble in the acidic stomach juices, are the preferred acid-insoluble release agents.
• cellulose acetate phthalate and the other acetate phthalates are preferable.
• the esters of the carbohydrate polymers are preferable.
• the phthalic acid derivatives of polyacrylic acid are preferable.
• the effect of the water-soluble or dispersible binder is to insure a uniform release of the drug.
• the binders of choice are the polyvinyl pyrrolidones, acacia and other water-soluble or dispersible binders well known to those skilled in the art, may be used.
• antioxidants e.g., ascorbic acid, sodium metabisulfite
• lubricants e.g., talc, magnesium stearate and sodium lauryl sulfate
• fillers e.g., calcium diphosphate
• colorants are generally added to further improve the product.
• the tablets can be prepared from the blended ingredients in the usual manner, e.g., dry blending followed by compression into tablets, or dry slugging and granulating the blended ingredients prior to compressing them into tablets, etc.
• the tablets may also be prepared by first wet granulating the blend with a suitable solvent or binder solution or dispersion, such as alcohol or polyvinyl pyrrolidone colloidal solution.
• the tablet erosion studies are conducted with the tablet distintegration apparatus described in U.S.P. XVII. Simulated gastro-intestina] fluids, the preparation of which are described in U.S.P. XVII, are used in the test.
• the tablets are placed in the apparatus and initially contacted with simulated gastric juices for one hour. The weight loss of the tablets is then determined. The gastric juice is then removed, simulated intestinal fluid is added to the apparatus, and the course of the disintegration of the tablets is followed over the course of the next few hours by periodically determining the weight loss of the tablets.
• the drug dissolution rate is also determined in this test by periodically assaying the amount of drug that dissolves in these fluids over the course of several hours. The drug dissolution rate ran also be determined by the in vitro test for timed-release capsules and tablets outlined in the second supplement of N. F. XII.
• EXAMPLE I The ingredients listed below are dry blended and directly compressed into tablets on a rotary or single punch tableting machine:
• Time/hours percent percent I First hour in gastric juice; thereafter in intestinal fluid.
• the particles are passed through a 40 mesh screen using a Fitzmill, hammers leading at medium speed.
• the mixture is reblended for 30 minutes and moistened with 50 g. of methanol in a Hobart blender.
• the moist mixture is passed through a 40 mesh screen (Fitzmill, hammers leading at medium speed).
• the final mixture is air dried without heat for 3045 minutes.
• the magnesium stearate is then added and the mixture is blended for 5 to 10 minutes.
• the tablets are prepared by compressing on a rotary tablet press using in. standard round concave punches and dies, to a thickness of 014110.005 in. thick and a hardness of 7 kg. (Pfizer tester).
• the rate of drug dissolution is determined in the same manner as detailed above.
• EXAMPLE III With the exception of magnesium stearate, the ingredients listed below are dry-blended for 15 minutes and passed through a 40 mesh screen:
• the ingredients are reblended for 30 minutes and moistened with 75 g. of 2B ethanol.
• the mixture is stirred in a Hobart mixer until nearly dry and passed through a 40 mesh screen and reblended.
• the mixture is then air dried until the odor of the solvent is no longer detectable, and the lubricant is added.
• the mixture is briefly blended and compressed into tablets under the following conditions: the dry powder granulates are placed in the hopper without further processing and compacted into tablets using in. standard round concave punches and dies on a rotary tablet press to a hardness of 7 kg. (Pfizer tester).
• EXAMPLE V With the exception of magnesium stearate, the ingredients listed below are blended together for 30 minutes in a suitable blender, after passage through a 40 mesh screen 5 on a Fitzmill comminator. A portion of the magnesium th The "E qif g fi lgdetmumd ldenucany to stearate (1.5%) is added, and the mixture is briefly blende Prevlous Y 6 met 0 ed and slugged with /2 in. standard round flat punches D RUG DISSOLUTION RATES and dies to a hardness of 8 kg. and 400 mg. weight.
• the Amount slugs are granulated through an 18 mesh screen on an Cumulattive Amr mnt oi (lumulat ive g1 bma 10 oscillating granulator.
• the remainder of the magnesium 3,1 3,233.3 i fig gggg g fg g, stearate is blended into the resultant granulation.
• the Ti r a d. h u r e blend is compressed on a suitable tablet press, to a weight perm percent pmen perm of 512.5 mg. for a hardness of 10 kg. (Pfizer tester).
• Theophylline 400 200 (39 J 5 5 4 m Ephedrine sulfate 100 50 9. @9 3 I First hour in gastric juice; thereafter in intestinal fluid. giggg y g gi ggggggg fi f ffi g 87%) Oab'O-SiI III 10 5 EXAMPLE IV Sterotex K-IOO 260 130 (25.
• Fines 60 mesh are separated and 0 53: Pfiggent thoroughly blended with the metamlne. This mixture con- 3 Time/hours 1035 g; taining the active drug is blended with the remainder, the 229 22 9 dry granulation. The remaining half of magnesium stearate is added to the total blend of granules, followed by 1 15.8 13.1 brief reblending. Tablets are prepared by compressing on 15:9 arrgcsgrgzblet press in accordance with previously defined mm hour in gastric juice; thereafter In intestinal fluid.
• EXAMPLE VI I First hour in gastric juice; thereafter in intestinal fiuid. The rate of drug dissolution is as follows:
• the rate of disintegration and rate of drug dissolution of these tablets are found to be constant and uniform when determined according to the tests described in the preceding examples.
• the rate of disintegration and rate of drug dissolution of these tablets are found to be constant and uniform when determined according to the tests described in the preceding examples.
• Tests A, B, and C below are conducted with the disintegration apparatus described in USP XVII.
• Tests A and B the tablets are contacted with gastric juice to 1 hour and then with intestinal fluid to 4 hours. At the end of the 4 hour period the tablets are contacted with fresh intestinal fluid to 7 hours.
• Test C the tablets are contacted with gastric juice for the first hour and thereafter 'with intestinal fluid, with hourly change to fresh fluid.
• Test C.l44 tablets Amount of metamine Time/hours: released/ time interval 1 30.4
• Test D This test is conducted according to the procedure in N.F. XII, using 12 tablets per screw cap bottle.
• Metamine dissolution rate Metamlne dissolution rate l A sustained released pharmaceutical tablet essentially containing, uniformly dispersed throughout the tablet matrix, about 5 up to 70% by weight of a medicament, 550% by weight of a hydrophobic dissolution retardant selected from the group consisting of hydrogenated cottonseed oil, hydrogenated castor oil, carnauba wax, beeswax, spermaceti, and shellac, ill-5.0% by Weight of an enteric acid-insoluble release agent selected from the group consisting of cellulose acetate phthalate, starch acetate phthalate and a phthalic acid derivative of polyacrylic acid, and 5-15% by weight of a water-soluble or dispersible binder, eifective to insure a uniform release of the medicament, selected from the group consisting of polyvinyl pyrrolidone and acacia.
• a hydrophobic dissolution retardant selected from the group consisting of hydrogenated cottonseed oil, hydrogenated castor oil, carnauba
• a sustained release pharmaceutical tablet according to claim 1 comprising: (a) 56% by weight of triethanolamine trinitrate biphosphate; (b) 22-25% by weight of carnauba wax; (c) 0.80-1.20% by weight of cellulose acetate phthalate; and (d) 812% by weight of polyvinyl pyrrolidone.
• a sustained release pharmaceutical tablet according to claim 1 comprising: (a) 57% by weight of triethan0l amine trinitrate biphosphate; (b) 2225% by weight of butabarbital; (c) 13-17% by weight of hydrogenated cottonseed oil; (cl) 24% by weight of cellulose acetate phthalate; and (e) 13-18% by weight of polyvinylpyrrolidone.
• a sustained release pharmaceutical tablet comprising: (a) 37-41% by weight of theophylline; (b) 8-1l% by weight of ephedrine sulfate; (c) 4-6% by weight of hydroxyzine dihydrochloride; (d) 23- 10 26% by weight of cottonseed oil; (e) (LS-1.2% by weight of cellulose acetate phthalate; and (f) 812% by weight of polyvinylpyrrolidone.

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Cited By (27)

Families Citing this family (3)

• 1968
  • 1968-06-10 US US735571A patent/US3577514A/en not_active Expired - Lifetime
• 1969
  • 1969-05-16 GB GB25235/69A patent/GB1235787A/en not_active Expired
  • 1969-05-28 DE DE19691927130 patent/DE1927130A1/de active Pending
  • 1969-05-30 FR FR6917833A patent/FR2010541A1/fr not_active Withdrawn

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