US 3792157 A
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United States Patent Office 3,792,157 Patented Feb. 12, 1974 3,792,157 STABLE TABLETS CONTAINING BENZODI- AZEPINE AND AMITRIPTYLINE Prabhakar Ranchhordas Sheth, Nanuet, N.Y., and John James Vance, Montvale, N.J., assignors to Hoifmann- La Roche Inc., Nutley, NJ. No Drawing. Filed Jan. 10, 1972, Ser. No. 216,780 Int. Cl. B44d 11/08; A61k 9/00 US. Cl. 424-35 8 Claims ABSTRACT OF THE DISCLOSURE Stable, film-coated tablets containing a benzodiazepine, such as chlordiazepoxide, and amitriptyline are described. Also described is a method for producing such tablets by utilizing a heating step.
BACKGROUND OF THE INVENTION The 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.
It has been found that a lactam-forming reaction takes place between amitriptyline and members of the benzodiazepine group when they are combined in a single tablet. This reaction has been found to take place in the presence of trace amounts of moisture and also in the presence of trace amounts of organic solvents which are commonly utilized in conventional tablet film-coating procedures, e.g., pan coating and the like.
DETAILED DESCRIPTION OF THE INVENTION 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.
'More particularly, 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.
In accordance with the method of the present invention, 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:
wherein 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. Most preferred among the 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.
The term 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. In the term 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. Thus, 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. Examples of 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.
The amounts of the active ingredients contained in the tablets treated in accordance with the invention is not critical. The method of the invention is applicable to tablets containing amitriptyline and a benzodiazepine which is reactive therewith in any proportions as the reaction of these active ingredients is not dependent on a specific amount of either being present. Generally, however, 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. Preferably, such tablets contain from about'2.5 to about 75 mg. of amitriptyline or an equivalent amount of a pharmaceutically acceptable salt thereof and the usual therapeutic dosage of the benzodiazepine compound which is recognized in the medical art. For example, 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.
As utilized in the practice of this invention, pharmaceutically acceptable acid addition salts of the benzodiazepine compounds and amitriptyline include those conventional inorganic and organic salts recognized in the art. For example, one can use salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or 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.
4 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.
An amount of tablet mass equivalent to 60 mg. of amitriptyline free base was measured and triturated with 25 ml. 0.1 N HCl. The resulting mixture was shaken for 30 minutes with an additional 150 ml. of 0.1 N HCl, diluted to 250 ml. and filtered. Three ml. of the resulting solution was thoroughly mixed with 5 ml. of a pH 5.3 phosphate buffer and 5 ml. 0.1% from Cresol green. The mixture was extracted 5 times with 15 ml. aliquots of chloroform and diluted to ml. with chloroform. The solution was centrifuged and read colorimetrically against a reagent blank at 415 nm. By comparison against a standard amitriptyline solution treated in the same manner, the amount of amitriptyline in the sample was obtained and the amount of lactam calculated.
An amount of tablet mass equivalent to 15 mg. chlordiazepoxide free base was weighed and shaken well with 100 ml. methanol. The solution was filtered and 10 ml. of
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.
Both the chlordiazepoxide and 'amitriptyline assays were verified by thin layer chromatography.
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
(b) a compound selected from those represented by the formulae and Ill] N-A C-B1 R t= Rs wherein R is halogen or nitro; R is lower alkyl, dilower alkyl-amino-lower alkyl, cycloalkyl-lower alkyl or halo-lower alkyl; R is hydrogen or hydroxy; R is phenyl, halophenyl or pyridyl; and
against loss of therapeutic activity as a result of the lactam forming interreaction of said components (a) and (b) in the presence of residual trace amounts of moisture and organic coating solvents resulting in unstable tablets even with minimized contact between said components (a) and (b) and said solvents which comprises treating said tablets which have previously been compressed from a homogeneous mixture resulting from the blending of separate granulations of said components (a) and (h), each such granulation having been dried at about C., for from about 16 to about 20 hours to a final moisture content of under 2% by weight after said film-coating has been completed by a final heating step by heating said coated tablets to a temperature of from about 60 C. to about C. for a period of from about 16 to about 20 hours.
2. A process in accordance with claim 1 wherein said component (b) is chlordiazepoxide.
3. A process in accordance with claim 1 wherein said component (b) is diazepam.
4. A process in accordance with claim 1 wherein said component (b) is medazepam.
5. A process in accordance with claim 1 wherein said component (b) is oxazepam.
6. The stable tablet produced in accordance with the process of claim 1.
7. The stable tablet produced in accordance with the process of claim 2.
8. The stable tablet produced in accordance with the process of claim 6.
References Cited Little et al., Tablet Making, 2nd ed., pp. 57-60 (Drying), pp. 99-106 (Pancoating) (1965).
Derwent Basic 27, 122, South Africa, 66, 70, 42, Holiman La Roche, Mar. 17, 1967.
SI-IEP K. ROSE, Primary Examiner US. Cl. X.R.