CA1058076A - Organic nitrate sublingual tablets - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to a novel organic nitrate tablet com-position, comprising polyvinylpyrrolidone and an organic nitrate thera-peutic agent, and to compressed tablets thereof, and more particularly to a new and improved form of compressed tablet for sublingual administration to the prophylaxis and treatment of acute coronary attacks, which is capable of rapid disintegration when administered thereby allowing rapid buccal ab-sorption of the therapeutic agent contained in said tablet. The present invention also relates to a method of producing sublingual tablets, contain-ing polyvinylpyrrolidone and an organic nitrate therapeutic agent, with an improved formulation which gives an extended shelf life and stabilized potency to the tablets.

Description

i8~ 76 . Organic nitrates, of which pentaerythrityl tetranitrate (PETN) and ., . glyceryl trinitrate (nitroglycerin) are exemplary, have been widely used in : the prevention or reduction in the number of attacks of chest pain in angina pectoris. Although organic nitrates bring about the dilatation of coronary blood vessels, the relief from anginal pain is not believed to be related to `,- coronary vasodilatation but to the effectiveness of nitrates in reducing car-diac workload. The nitrates reduce systemic and pulmonary arterial pressure , and decrease cardiac output. Mycardial oxygen consumption is not changed.
Pharmaceutical preparations containing such organic nitrates are presently available in the form of compressed tablets formed in the conven-tiQ~al manner by compressing a granulation of the organic nitrate in combina-tion with certain inert pharmaceutical ingredients. See for ~xample United ., States Patent No. 3,028,307. These pharmaceutical ingredients may include any of the wellknown gums as well as the conventional tablet-forming lubri-cants such as talc, stearic acid and magnesium stearate. In addition, con-ventional inert diluents such as starch, lactose, calcium sulfate dihydrate, sucrose, dextrose, sorbitol, and the like are conventionally included to pre-vent explosions and provide a tablet of convenient size since only a relative-:
^~ ly small amount of the organic nitrate is present in each tablet.

Tablets formed in this manner are suitable for oral administration ~; where the disintegration of the tablet in the stomach or intestines releases . . ~
the therapeutic agent for absorption into the blood stream, where it is carried through the system. When an acute coronary attack occurs, however, .... .
~ it is absolutely necessary that the complete therapeutic dose of the active ;.
' ingredient, that is the organic nitrate, be absorbed into the blood stream as rapidly as possible in order to have an immediate effact. Sublingual ,, .` administration is a desirable means of administering a preparation where rapid : .
' absorption is desired, since the buccal absorption which follows the sublingual '.:' i i :

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disintegration places the therapeutic ingredient into the blood stream im-mediately.
: Even with absorption of the active ingredients into the blood stream within two or three minutes after sublingual disintegration, the adequacy of the dose is left to speculation. The organic nitrates, for example, nitro-~ ' .
~ glycerin, are volatilized from commercially available tablets upon contact .~: .
with air or are easily adsorbed to container packing materials, and plastic medicine vials. As a resultJ tablets which are stored for even a short period ~ i ~
after manufacture have significantly less potency than when they were manu-factured to a specific controlled potency. This supposition of decreasing potency due to volatilization is accepted universally and reported in "The :. .
Pharmacological Basis of Therapeutics", Second Edition, p. 729, ~1958).
It has now been discovered that formulation of organic nitrate sublingual tablets with specific pharmaceutically acceptable substances will produce a rapidly disintegrating tablet, but yet one which "binds" the active nitrate to the tablet to effect an increased shelf-life and a stabilized ` potency. Furthermore, these specific substances are equally as functional .. . .
when added to the conventional formulations which contain the conventional binders, diluents, tablet~ing aids, etc.
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Heretofore, when rapid release of the therapeutic agent following sublingual administration was desired, it had been conventional to prepare the tablet by a wet molding technique, well known in the art. Such a technique ; . . .:
is, however, disadvantageous to the manufacturer since it is time consuming ~; and in addition the finished tablets are relatively soft, are subject to ., ,, ,~
crumbling on handling and their size, weight, and shape are difficult to con-` trol.
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j~ It is the object of this invention to disclose a novel organic .'- nitrate tablet composition which shows a stability of the nitrate concentra-.. : :
'~ tion upon exposure to air.

~` 30 It is a further object of this invention to disclose a novel :,.,,; :
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It is a further object of this invention to disclose a method of forming a compressed organic nitrate tablet for use in acute coronary attacks which has the desired characteristics of a tablet prepared by the wet molding techniques well known in the art.
` Other objects and advantages of this invention will become apparent to those skilled in the art from the following detailed description.
The present invention provides a rapidly disintegrating tablet for sublingual administration comprising a pharmaceutically active organic nitrate, a tabletting lubricant, a pharmaceutical diluent, a disintegrant, and poly-vinylpyrrolidone, said tablet having a ratio of organic nitrate to polyvinyl-pyrrolidone of from about 1 : 2 to about 1 : 4 by weight, and said polyvinyl-pyrrolidone having a molecular weight of from 10,000 to about 700,000.
In one preferred embodiment, the invention provides a rapidly dis-integrating tablet for sublingual administration comprising nitroglycerin, calcium stearate, lactose, starch, microcrystalline cellulose and polyvinyl `` pyrrolidone, said tablet having a ratio of organic nitrate to polyvinylpyr-:.
`~ 20 rolidone of from about 1 : 2 to about 1: 4 by weight, and said polyvinylpyr-:;.-rolidone having a molecular weight of from about 10,000 to about 700,000.

The invention also provides a process for the preparation of a ~- rapidly disintegrating tablet for sublingual administration, said process comprising the admixing of a pharmaceutically active organic nitrate, a tab-~:
; letting lubricant, a pharmaceutical diluent, a disinfectant and polyvinyl-.~ pyrrolidone, the ratio of organic nitrate to polyvinylpyrrolidine being from ,;,, :
i; about 1 : 2 to 1 : 4 by weight, said polyvinylpyrrolidone having a molecular ; weight of from about 10,000 to about 700,000.

In another preferred embodiment, the invention provides a process . ~
~- 30 for the preparation of a rapidly disintegrating tablet for sublingual adminis-~; tration, said process comprising the admixing of nitroglycerin, calcium stear-, .:
ate, lactose, starch, microcrystalline cellulose ~nd polyvinylpyrrolidone, ' ~ - 3 -~s"
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- ~herein the said nitroglycerin and polyvinylpyrrolidone are in a ratio from about 1 : 2 to about 1 : 4 by weight, and said polyvinylpyrrolidone has a molecular weight of from about 10,000 to about 700,000.
In the accompanying drawings, Figure 1 shows the thermograms ob-- 5 tained by subjecting tablets according to the invention as well as samples of `
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commercial tablets to thermogravimetric analysis (TGA). Figures 2 and 3 : show plots of the nitroglycerin remaining in such tablets after exposure to . TGA at 80C for 4 hours.
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Method of Preparation Blend the microcrystalline cellulose, starch and lactose together.
Pass the mixture through a No. 60 wire cloth. Dissolve polyvinylpyrrolidone in glyceryl trinitrate spirit mixed with about 50% of alcoholJ and slowly add to the blend with continuous mixing to insure uniformity. Rinse the con-tainer with the remainder of alcohol and add to the blend. Mix until uniform.
Place the mass on stainless steel trays and dry at about 35 in a drying oven with very little air flow. Screen the dried mass through a No. 60 wire cloth.
Mix a portion with calcium stearate powder. Pass through a No. 60 wire cloth.
Blend with the remainder of the granulation. Compress using 5/32 inch flat f~ced punches to a hardness of about 1.5 - 2.0 Kg. ~Heberlein apparatus) and to a thickness of 0.087 - 0.093 inch to make tablets containing 0.6 mg. nitro-glycerin. Standard concave punches of the same diameter may be used giving tablets of about the same hardness but having a breakness of about 0.108 -O~ 110 inch.

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This formulation yields a nitroglycerin and polyvinylpyrrolidone ratio of 1 : 2.

This method of preparation is also followed for Examples 2, 3 and 4.
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Example 1 is similar to Example 4; the formula of Example 1 yields a nitroglycerin/polyvinylpyrrolidone ratio of l : 2J whereas the ratio of ~-Example 4 is 1 : 4.
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The microcrystalline cellulose used in the above formulations is a purified partially depolymerized cellulose prepared by treating ~-cellulose - with mineral acids. One such microcrystalline cellulose is supplied by .. i .
American Viscose Company under their trademark, AVICEL PH-102, and is supplied as fine white odorless free-flowing nonfibrous granular, particles insoluble . . . . . . .
ln water and dilute acid and sllghtly soluble ln sodlum hydroxlde solutlon, : i.e. 1 in 20.
The polyvinylpyrrolidone (PVP) used in the above formulations is poly[l-~2-oxo-1-pyrrolidinyl)ethylene]. This is a synthetic polymer consist-s 10 ing essentially of linear 1-vinyl-2-pyrrolidone groups. It is produced commercially as a series of products having mean molecular weights ranging from about 10,000 to about 700,000. One such polyvinylpyrrolidone is supplied i; by GAF Corporation under their trademark, PLASDONE K-30, and is a white to creamy white, odorless, free-flowing hygroscopic powder soluble in water, alcohol and chloroform, but insoluble in ether. It has a relative viscosity .; ~
of about 1.229 to about 1.27~ which corresponds to a K-value of 29 to 32;
other polyvinylpyrrolidones encompassed within this invention, i.e. those ~ "
~ having molecular weights of between about 10,000 to about 700,000, would ,. .: , naturally differ in their viscosities and K-values.
To show the improved characteristic of the above formulations with formulations commercially available, a comparison of nitroglycerin stability in various tablet formulations was done in which the formulations of the pre-:~ sent invention were compared to two commercial products identified as A and j B.
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. Table 1 shows the initial assay results of several nitroglycerin ` tablet formulations. As can be seen, the relative standard deviation of the~ .: .. .
-~ formulations according to the present invention is lower than that for the two commercial products, t'A'1 and "B". Thus, the amount of nitroglycerin with--~ in the tablet of the present invention varies much less from the desired con-tent than those presently available.

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Tables 2 and 3 show the comparison of nitroglycerin stability .~, in various tablet formulations after 1 and 4 weeks of storage in open dishes , at four different temperatures.
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The results clearly show the superiority of Examples 1 and 4 over ~ the commercial products. After one-week's storage at room temperature, for ; example, the commercial formulations contained less than 86 percent of the initial dosage, while the formulations containing microcrystalline cellulose -- PVP still had up to 96.5 per cent of the initial nitroglycerin content. After ` four weeks of storage, the results are even more startlingin that the micro-i, , .
crystalline cellulose - PVP formulations contained more than 70 percent of the initial nitroglycerin content while the commercially available product ` contained a maximum of 41.8 percent of the initial nitroglycerin content.
Dissolution of nitroglycerin tablets, Example 1, was determined and compared with commercial product "A".
Experiments were conducted by placing 15 tablets in 600 ml of distilled water maintained at 37 with agitation, filtered samples were taken at selected intervals, diluted and subjected to a colorimetric assay [Bell, F.K., J. Pharm. Sci., 53:752 ~1964)] for nitroglycerin content. The results ~, . .
~` summarized in Table IV show that the microcrystalline cellulose - PVP formula-tions provide a fas~.er dissolution rate than the commercial product "A".
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Experiments were designed to compare the stability of the Example 1 formulation with commercially available formulations A and B by thermo-gravimetric analysis ~TGA). In an attempt to determine the rates of nitro-glycerin volatilization from the samples, the weight of a single tablet was ` monitored as a function of ~ime using the DuPont Model 950 Thermogravimetric Analyzer in conjunction with the Model 900 Console. The tests were conducted at a constant temperature of 80 for 90 minutes and in an atmosphere of nitro-gen gas at a constant flow rate of 20 cc./min. over the sample. Figure 1 is a summary of the thermograms obtained.
As is apparent from Figure 1, the total weight loss from all ~ablets, except "B", exceeds the amount of nitroglycerin originally present ~ .
~0.6 mg.). It can also be seen that the thermograms obtained with Example 1 ; are characterized with a sharp decline in tablet weight in the initial 20 minutes. This considerable weight loss is due to the water present in two tablet ingredients, starch and microcrystalline cellulose, as evidenced from the shape of ~he curve representing the placebo formulation. -. .~ , . .Consequently; it was found necessary to analytically determine ~` the nitroglycerin contents of the tablets after 90 minutes at 80C in the TGA
p in order to ascertain the volatility of nitroglycerin from the samples under :.::i -: ,, ` 20 study. The colorimetric method of Bell was employed as the assay procedure. ~ -:.
~x Two tablets representing each formulation were assayed in duplicate. The nitroglycerin content remaining in the tablets was calculated and the results ; are listed in Table V.
It is seen that the loss of nitroglycerin potency is most pro-nounced with "B" tablets followed by "A".
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In order to elucidate further the role played by PVP in the stability of nitroglycerin tablets, and in order to examine whether the pre-Sence of microcrystalline cellulose has any appreciable effect toward promoting nitroglycerin stability, a series of tablet formulations shown in Table VI
were prepared and studied for their stability. This was a full factorial i: experimental design where microcrystalline cellulose was included at three levels 0, 25 and 50%, and PVP was included to obtain various ratios of nitro~- -glycerin to PVP; that is, 1:0, 1:1, 1:2 and 1:4. Experimentally, two samples representing each formulation were subjected to TGA at 80 for four hours to permit adequate opportunity for volatilization and subsequently were assayed , for nitroglycerin content.
The average percentages of original nitroglycerin content remain-ing in tablets are presented in Table VII. The percentages are based on the nitroglycerin content present in corresponding tablets not subjected to TGA.
The data pertaining to Table VI are also depicted in Figures 2 and 3 as func-tions of nitroglycerin-PVP ratio and microcrystalline cellulose concentration, ~` respectively.
~t,, The picture which emerges from Figlres 2 and 3 are quite clear.
Both PVP and microcrystalline cellulose are capable of drastically reducing j~; ,.
` 20 the volatility of nitroglycerin in compressed tablets. It is evident that this effect can be best seen in the absence of one of these tablet components.
The preferred nitroglycerin formulation with 50% Avicel and with a nitroglycerin-PVP ratio of 1:2 affords minimal loss of nitroglycerin potency, while retaining the desirable disintegration and dissolution properties of ~ ;
~ the tablets which might be adversely affected at higher nitroglycerin-PVP
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These investigations havc shown that polyvinylpyrrolidone signi-ficantly reduces the volatility of nitroglycerin when used as an additive in nitroglycerin tablets. In an attempt to facilitate explanation of this ob-servation, experiments were designed to evaluate the effect of some other ;~
commonly used tablet binders on the volatility of nitroglycerin in tablets.
Nitroglycerin tablets containing Starch USP, anhydrous lactose USP
; and microcrystalline cellulose were made by granulating the powder mix with nitroglycerin spirit to which the desired amount of binder was previously A added. Ethylcellulose ~Ethocei, 100 cps, Hercules Inc.), PVP, hydroxypropyl methylcellulose (Methocel 60HG, 50 cps, Dow Chemical Co.) and gelatin USP were employed as binders. When necessary, water was used to aid dispersion of the binder in nitroglycerin spirit. The quantity of binder used in each formula-tion was held constant to give a nitroglycerin-binder ratio 1:2. Micro-crystalline cellulose was included at two levels, 0 and 25%. Samples were subjected to thermogravimetric analysis ~TGA) at 80 for 90 minutes and were subsequently analyzed for nitroglycerin content.
The results shown in Table VIII demonstrate that the volatility of nitroglycerin is affected by the type of binder used in the formulation. of the four binders studied, PVP produces the most stable nitroglycerin tablets.
It seems evident that this is a result of an interaction between PVP and nitro-glycerin; however, no plausible explanation can be offered as to its mechanism. -~
A point with regard to the use of binders other than PVP is that they produce slow disintegrating tablets. This undesirable property does not exist in the tablets made with PVP.
Polyvinylpyrrolidone may of course be added to tablets made by com-:. :
pression or wet-mold techniques and which already contain conventional binders.
These tablets will also show the increased binding of nitroglycerin. It becomes apparent, therefore, that the polyvinylpyrrolidone is not merely act-ing as a conventional tabletting binding agent, but when used in the nitro-glycerin formulations disclosed exhibits a new and unexpected binding char- `acter heretofor unknown.

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Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A rapidly disintegrating tablet for sublingual administration com-prising a pharmaceutically active organic nitrate, a tabletting lubricant, a pharmaceutical diluent, a disintegrant, and polyvinylpyrrolidone, said tab-let having a ratio of organic nitrate to polyvinylpyrrolidone of from about 1 : 2 to about 1 : 4 by weight, and said polyvinylpyrrolidone having a mole-cular weight of from about 10,000 to about 700,000.

2. The tablet of claim 1 wherein the organic nitrate is nitroglycerin.

3. The tablet of claim 1 or 2 which further comprises microcrystalline cellulose.

4. The tablet of claim 1 or 2 which further comprises microcrystalline cellulose in an amount of about 50 percent of the tablet weight.

5. A rapidly disintegrating tablet for sublingual administration com-prising nitroglycerin, calcium stearate, lactose, starch, microcrystalline cel-lulose and polyvinylpyrrolidone, said tablet having a ratio of organic nitrate to polyvinylpyrrolidone of from about 1 : 2 to about 1 : 4 by weight, and said polyvinylpyrrolidone having a molecular weight of from about 10,000 to about 70,000.

6. A process for the preparation of a rapidly disintegrating tablet for sublingual administration, said process comprising the admixing of a pharma-ceutically active organic nitrate, a tabletting lubricant, a pharmaceutical diluent, a disinfectant and polyvinylpyrrolidone, the ratio of organic nitrate to polyvinylpyrrolidone being from about 1 : 2 to 1 : 4 by weight, said poly-vinylpyrrolidone having a molecular weight of from about 10,000 to about 70,000.

7. The process of claim 6 where the said pharmaceutically active or-ganic nitrate is nitroglycerin.

8. The process of claim 6 or 7 which further includes admixing micro-stalline cellulose.

9. The process of claim 6 or 7 which further includes admixing micro-crystalline cellulose in an amount of about 50 percent of the tablet weight.

10. A process for the preparation of a rapidly disintegrating tablet for sublingual administration, said process comprising the admixing of nitro-glycerin, calcium stearate, lactose, starch, microcrystalline cellulose and polyvinylpyrrolidone, wherein the said nitroglycerin and polyvinylpyrrolidone are in a ratio from about 1 : 2 to about 1 : 4 by weight and said polyvinyl-pyrrolidone has a molecular weight of from about 10,000 to about 700,000.