US3792157A - Stable tablets containing benzodiazepine and amitriptyline - Google Patents

Stable tablets containing benzodiazepine and amitriptyline Download PDF

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Publication number
US3792157A
US3792157A US00216780A US3792157DA US3792157A US 3792157 A US3792157 A US 3792157A US 00216780 A US00216780 A US 00216780A US 3792157D A US3792157D A US 3792157DA US 3792157 A US3792157 A US 3792157A
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US
United States
Prior art keywords
amitriptyline
tablets
benzodiazepine
accordance
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00216780A
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English (en)
Inventor
P Sheth
J Vance
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Roche Products Inc
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Application granted granted Critical
Publication of US3792157A publication Critical patent/US3792157A/en
Assigned to ROCHE PRODUCTS INC., A PANAMA CORP. reassignment ROCHE PRODUCTS INC., A PANAMA CORP. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ROCHE PRODUCTS INC.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991—Coated

Definitions

  • benzodiazepines are an art-recognized group of chemically similar therapeutic agents possessing valuable pharmacologic activity as tranquilizers, skeletal muscle relaxants, and the like.
  • 5-(3-dimethylaminopropylidene) dibenzo[a,d] [l,4]cycloheptadiene, hereinafter amitriptyline, and its pharmaceutically acceptable acid addition salts are likewise known compounds possessing antidepressant activity.
  • the present invention is concerned with stable tablets therapeutically useful particularly in the treatment of patients exhibiting symptoms of severe, nonpsychotic depression with varying degrees of anxiety. More particularly, the invention is concerned with such tablets containing conventional pharmaceutically adjuvants and excipients and as the active ingredient, a combination of a benzodiazepine compound and amitriptyline.
  • the present invention is based on the discovery that heating finished, film-coated tablets containing a benzodiazepine and amitriptyline to high temperatures for extended periods of time does not degrade such tablets as would be expected but instead stabilizes them.
  • film-coated tablets containing a benzodiazepine compound and amitriptyline are subjected to a heating step within a reasonable time after the completion of the final film-coating operation, preferably not more than 72 hours thereafter. While the tablets can be heated to a rather wide range of temperatures, the upper limit cannot be so high that decomposition of the ingredients takes place. It has therefore been found that heating such coated tablets to temperatures of from about 50 C. to about 85 C., preferably from about 60 C. to about 75 C. for from about 6 to about 24 hours, preferably from about 16 to about 20 hours, is satisfactory.
  • This unusually high temperature heat treatment removes traces of moisture within the tablet as well as small amounts of solvents present in the coating composition in one economical operation thus rendering the tablets stable without loss of therapeutic activity.
  • the apparatus by which this heating operation is carried out is in no way critical to the invention. Conventional drying ovens or any comparable equipment recognized in the art may conveniently be utilized.
  • the process of the invention is applicable to tablets containing amitriptyline and members of the art-recognized group of pharmaceutically active benzodiazepines.
  • Suitable benzodiazepines useful in the tablets containing amitriptyline are selected from those represented by the formulae:
  • R is halogen or nitro;
  • R is lower alkyl, di-lower alkylamino-lower alkyl, cycloalkyl-lower alkyl or halolower alkyl;
  • R is hydrogenor hydroxy;
  • R is phenyl, halophenyl or pyridyl; and
  • A is and pharmaceutically acceptable salts thereof.
  • benzodiazepines for use in accordance with the present invention are: 7-chloro-2-methylamino-5- phenyl 3H 1,4 benzodiazepine 4 oxide, hereinafter chloridazepoxide; 7 chloro-1,3-dihydro-l-methyl-S-phenyl-2H-1,4-benzodiazepine-2-one, hereinafter diazepam; 7- chloro-2,3-dihydro-l-methyl-5-phenyl 1H 1,4-benzodiazepine, hereinafter medazepam; and 7-ch1oro-1,3-dihydro-3-hydroxy-5-phenyl 2H 1,4 benzodiazepin-Z-one, hereinafter oxazepam.
  • halogen as utilized herein includes all halogens With chlorine being preferred.
  • the preferred halophenyl group is para-chlorophenyl
  • the term lower alkyl includes both straight and branched chain alkyl groups having from 1 to 7 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl and the like.
  • cycloalkyl-lower alkyl it is contemplated that the cycloalkyl portion shall contain from 3 to 5 carbons, i.e., cyclopropyl to cyclopentyl.
  • a particular advantage of the method of the present invention is that it is not restricted to tablets prepared with a specific group of suitable pharmaceutically accept able adjuvants, binders, excipients or solvents.
  • suitable pharmaceutically accept able adjuvants binders, excipients or solvents.
  • the choice of these materials may reasonably remain within the purview of a person skilled in the art. The only requirements for such materials are that they must be compatible With the active ingredients and stable at the temperatures contemplated herein.
  • Such materials include fillers such as, for example, calcium carbonate, anhydrous dicalcium phosphate, lactose, microcrystalline cellulose and the like; disintegrating agents such as, for example, corn starch, potato starch, alginic acid and the like; lubricating agents such as, for example, stearic acid, calcium stearate, talc and the like.
  • the tablets treated in accordance with the invention are film-coated utilizing compositions and methods common to the art.
  • Suitable materials include alcohol-soluble film-forming agents such as, for example, cellulose ethers such as ethyl cellulose and hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, shellac and the like; surfactants such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and the like; plasticizers such as triacetin and volatile solvents such as ethanol, isopropanol, methylene chloride and the like.
  • the method of applying the coating and the specific apparatus utilized are not of critical importance to the invention and are considered to be within the purview of a person skilled in the art. Thus, conventional coating methods such as, for example, pan coating, can be used.
  • the method of forming the tablets to be treated in accordance with the invention is likewise not particularly critical to the essence of the invention.
  • Common methods of tablet formation such as, for example, wet granulation, dry granulation (slugging) or direct compression may be utilized. It is important, however, to keep contact between the active ingredients and solvents as minimal as possible during tablet production by the use of techniques such as, for example, separately granulating each active ingredient. It should be pointed out that, even if any of the above methods of preparation are effected with the greatest possible care in minimizing contact between the active ingredients and solvents, stable tablets would not result unless said tablets are treated in accordance with the present invention.
  • tablets treated in accordance with the invention contain from about 0.25 to about 5.0 parts by weight of amitriptyline or an equivalent amount of a pharmaceutically acceptable acid addition salt thereof for each part by Weight of the benzodiazepine or an equivalent amount of pharmaceutically acceptable acid addition salt thereof.
  • such tablets contain from about'2.5 to about 75 mg.
  • chloridazepoxide would be present in each tablet in from about 2.5 to about 30 mg
  • diazepam would be present in from about 1.0 mg. to about 15.0 mg.
  • medazepan would be present in from about 5.0 mg. to about 50.0 mg. and the like. It is also within the purview of the present invention to utilize equivalent amounts of pharmaceutically acceptable acid addition salts of the benzodiazepines described above.
  • pharmaceutically acceptable acid addition salts of the benzodiazepine compounds and amitriptyline include those conventional inorganic and organic salts recognized in the art.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • salts with an organic acid such as acetic acid, benzoic acid, lactic acid, malic acid, maleic acid, salicylic acid and the like. It should be understood that the invention is operable when the active ingredients of the tablets are used as the free base or the acid addition salt.
  • Example 1 5.2 grams of chloriazepoxide base, 15.0 g. of corn starch and 97.8 g. of lactose were blended in a suitable mixer and passed through a Fitzpatrick mill using a No. 2 screen, knives forward, at medium speed. 12.0 grams of polyvinyl pyrrolidone were then added as a 40% weight to volume aqueous solution with thorough mixing and the resulting Wet granulation was milled using a No. 5 screen, knives forward, at medium speed. The granulation was then dried on trays in an oven at 60 C. for from 16 to 20 hours to a final moisture content of under 2%. The dried granulation was then remilled using a No. 2 screen, knives forward, at medium speed.
  • a granulation of 14.1 mg. amitriptyline hydrochloride was prepared in an identical manner with the single exception being that the polyvinyl pyrrolidine was added as a 40% weight to volume solution in anhydrous isopropyl alcohol.
  • the chlordiazepoxide granulation and the amitriptyline hydrochloride granulation were then blended in a suitable mixer for approximately 15 minutes. 1.5 grams of magnesium stearate were added and the whole blended for 2 minutes. The resulting homogeneous mixture was then compressed on a suitable conventional tablet press to form tablets weighing approximately 280 mg. and containing 5 mg. chlordiazepoxide plus 4% manufacturing excess and 14.1 mg. amitriptyline hydrochloride equivalent to 12.5 mg. free base, plus a 3% manufacturing excess.
  • the resulting tablets were coated by the conventional process of building up coats by alternatively spraying them with a color-containing, film-forming solution and drying the coating using conventional equipment suitable for such operations.
  • the formulation utilized in coating the tablets comprised, in addition to a suitable certified coloring agent, 1.22 parts hydroxypropyl methylcellulose 60 Hg, 15 cps, 0.35 part ethylcellulose l0 cps. and 0.53 part triacetin in a solvent mixture consisting of 16.45 parts methylene chloride and 16.45 parts anhydrous alcohol.
  • Example 2 Tablets were prepared in the same manner as Example 1 utilizing per tablet 10.4 mg. of medazepam free base plus 4.0% manufacturing excess and 29.14 mg. amitriptyline hydrochloride equivalent to 25.0 mg. free base plus 3.0% manufacturing excess.
  • Example 3 Film-coated tablets prepared in accordance with Examples 1 and 2 were trayed and dried in an oven at 70 C. for 18 hours. The tablets were then placed under an accelerated storage test for 3 days at 70 C. in closed containers. A similar batch of coated tablets not treated by a final heating step was placed under similar accelerated storage conditions. Stability of each group of tablets was determined by the percentage of lactam present in accordance with the following method illustrating the tablets of Example 1.
  • the filtrate was diluted to 100 ml. with acidified alcohol.
  • the resulting solution was measured colorimetrically against a standard at 311 nm. and the amount of clordiazeperoxide present was obtained and the amount of lactam calculated.
  • Example 3 The following table summarizes the stability of representative samples of coated tablets both treated with a final heating step as in Example 3 and untreated. Stability is represented as a percentage of lactam present.
  • TABLE Percent lactam 1 A process of stabilizing a pharmaceutical tablet film coated with a mixture of hydroxypropyl methyl cellulose and ethyl cellulose containing as an active ingredient a combination of (a) amitriptyline or a pharmaceutically acceptable acid addition salt thereof; and
  • SI-IEP K. ROSE Primary Examiner US. Cl. X.R.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00216780A 1972-01-10 1972-01-10 Stable tablets containing benzodiazepine and amitriptyline Expired - Lifetime US3792157A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US21678072A 1972-01-10 1972-01-10

Publications (1)

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US3792157A true US3792157A (en) 1974-02-12

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US00216780A Expired - Lifetime US3792157A (en) 1972-01-10 1972-01-10 Stable tablets containing benzodiazepine and amitriptyline

Country Status (7)

Country Link
US (1) US3792157A (ja)
AU (1) AU4986472A (ja)
BE (1) BE793775A (ja)
DE (1) DE2300888A1 (ja)
FR (1) FR2181660A1 (ja)
NL (1) NL7300356A (ja)
ZA (1) ZA728553B (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571395A (en) * 1980-01-21 1986-02-18 Burroughs Wellcome Co. Lorazepam and bupropion, compositions and methods
US5407686A (en) * 1991-11-27 1995-04-18 Sidmak Laboratories, Inc. Sustained release composition for oral administration of active ingredient

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034035A (en) * 1975-07-14 1977-07-05 Merck & Co., Inc. Method of preparing multi-toned tablets

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571395A (en) * 1980-01-21 1986-02-18 Burroughs Wellcome Co. Lorazepam and bupropion, compositions and methods
US5407686A (en) * 1991-11-27 1995-04-18 Sidmak Laboratories, Inc. Sustained release composition for oral administration of active ingredient

Also Published As

Publication number Publication date
DE2300888A1 (de) 1973-07-19
FR2181660A1 (ja) 1973-12-07
ZA728553B (en) 1973-08-29
NL7300356A (ja) 1973-07-12
BE793775A (fr) 1973-07-09
AU4986472A (en) 1974-06-13

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Owner name: ROCHE PRODUCTS INC., MANATI, PUERTO RICO A PANAMA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ROCHE PRODUCTS INC.;REEL/FRAME:004082/0177

Effective date: 19821221