CA1288349C - Analgesic tablet of aspirin, acetaminophen and caffeine containinglow-substituted hydroxypropyl cellulose - Google Patents

Abstract

Abstract of Disclosure An analgesic. tablet containing Aspirin,TM
acetaminophen and caffeine of improved dissolution rate containing low-substituted hydroxypropylcellulose.

Description

~.c98~3A~
ANALGESIC TABL~T OF ASPIRIN, ACETAMINOPHE~ AND CAFFEINE CONTAINING
LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE

This invention relates to t~blets contsining, in combination, ~spirin, acetaminophen and caffeine. More particularly it concerns tablets of this charscter having improved di6solution rates.

The combin~tion of a6pirin, acetaminophen and caffeine i6 popular in analgesic preparations nnd finds widespread use, particularly in over-the-counter (O.T.C) products. Moreover, a ~idely used dosage form for delivering this combination drug i6 still the tablet. Since these products are also likely to be subjected to elevated temperatures while in storage in warehouses and in homes, it has become customary in course of manufacturing such tablets to store them ut elevated temperatures for extended periods of time to test their, stability and the in-vitro availability of the active ingredients; i.e., aspirin, acetaminophen and caffeine for pharmaceutical action. One method for measuring the latter has been to measure the dissolution rates of the tablets. If the tablets meet a certain standard for dissolution rate, the active ingredients should be available for absorption into the blood stream within an acceptable period of time after ingestion.
TM
Aspir~n, acetaminophen, or caffeine when used separately in tablets or the combination of aspirin and acetaminophen in tablets have not presented any partic~lar problem with respect to the acceptability of their dissolution rates. However, when all three are combined in a tablet, serious problems do arise. Such tablets have proven to have dissolution rates which do not meet the standards set. The reason for this is not clearly understood. Nevertheless, it is known that the three ingredients react physically to form a eutectic mixture. This is manifested by a slowdown in the dissolution rate of aspirin accompanied by a high free salycilic acid (FSA) level resulting from the hydrolysis of the aspirin.

It has now been found, quite unexpectedly, that the dissolution rates of tablets conlaining aspirin, acetaminophen and caffeine that have been stability tested under various conditions can be dramatically improved by incorporating in said tablet a low-substituted hydroxypropylcellulose ~hereinafter referred to as L-HPC) in sufficient amount to serve as a secondary disintegrant.
.~, ,~;, ~.~.28~34g C. Car~nell~, ~t al, in their Articlo, "~he Role of Swelling ln the Disintegr~tion Proce66", Int. J. Phs~n. ~ech. 6 Prod. Mfr. 5~2) l-S, 1984, studied the di~integrating proces6 of certain ~pecific t~blet~ and the rel~tionship of the character of certain disintegrant~ to the di~integration proces~. The tsblets employed in these studies were a series of t~blets containing 500 mg of ~spirin, 2% talc and 4~ di~integrant. Among the several disin~egrant6 tested, the author~ mention L-HPC and Polyplasdone XL. The authors conclude that di~integration efficiency is related to what is referred to ~s the swelling force and particularly the "disintegrating force development rate". In T~ble 3 of this article at the top of page 4 the authors summarize certain of their results. Thus they note that the disintegrating force developed in the tablet containing Polyplasdone XL is 4.3 + .1 in both isotonic saline and O.lN HCl, but for L-HPC the values were 2.2 + .1 and 2.0 + .2. Similarly, for the disintegration time in the tablet containing Polyplasdone XL, the value was 10 ~ .2 and 9 + .2 sec.; whereas, for the aspirin tablet containing L-HPC, the values were 18 ~ 3 and 19 4 3 sec. On the basis of this study, one skilled in the art might expect that if L-HPC were incorporated in a tablet containing aspirin, acetaminophen and caffeine that the dissolution rate would be lower than that obtained with the use of Polyplasdone XL. As wili be shown in more detail below, unexpectedly, the reverse has been found to be the case and the dissolution rates were higher with the use of L-HPC
than with the Polyplasdone XL. This dissolution rate was measured as tne time in minutes that it takes to dissolve 75% of the active ingredients in the tablet. Accordingly, the lower the value, the greater the dissolution rate.
-In their search for a suitable disintegrant that would give thedesired results, applicants have tested a number of ~aterials all of which proved to bq~e1unsatisfactory. Thus, other cellulose material such as Ac-Di-Sol (internally cross-linked form of sodium carboxymethylcellulose) was tried without succass. It produced only a marginal benefit in dissolution rate while affecting the stability of the aspirin negatively generating high values of FSA. Similarl~
such commercially available disintegrants as Explotab and Primogel were tried and also found unacceptable.

8~334!~

The L HPC's that are useful for the practice o~ the present are available in a variety of grades that are classified on the basis of their ~ hydroxypropyl content. These extend over the range of from ~bout 10~ to about 16~ hydroxypropyl. Of special utility in the present inventi~n are the L-HPC's that contain a hydroxypropyl content of from about 10~ to about 13~. Such products are cold on the market by the Shin-Etsu Chemical Company under the tr~de designation low-substituted hydroxypropylcellulose Grade LH-21 or LH-ll. These differ from each other in particle size.
.
These materi~ls conform to the general formula, ' -- ~- OH CH2c)c~acH~oH)cH3 1 _ ~ H ~ O

H ~ ~ ~ ~ H J
CHlOH H OH ~
wherein n is the degree of polymerization. They are non-ionic type cellulose ethers with a neutral p~ range (5.0 - 7.5) that do not react with amines or other ionic ingredients. The particle size of these materials may vary somewhat. However, in the preferred grade (LH-21) the particle 6izes are as follow:
74 um pass: not less than 90 105 um on: less than 1%
The quantity of L-HPC that will be contained in the tablets of the present invention may vary somewhat. However, again qui~e unexpectedly, it has been found as little as 1~ or less of the L-HPC, based on the total weight of the tablets, have given excellent results. This is to be contrasted with the concentrations of from 3%
- 15% which have been recommended for these materials when used as a binder/disintegrant for tablets. Generally, in accordance with this invention, the L-HPC will constitute from about 0.5~ to about 5% by weight based on the total weight of the tablet. However, the preferred range for the L-HPC is from about 0.8~ to about 2.0% on the same weight basis.

The aspirin, acetaminophen and caffeine will be contained in the present tablets at concentrations at which these ingredients are generally employed in analgesic tablets. That is to say that they ~l2~3~334~

will be contained in analgesic quantities. However, th~ general ranges and the preferred ranges for these ingredient6 are those that are given in the tabl~ below expres6ed in terms of percent by weight based on the total weight of the tablet.

Table I
~ W/W of Tablet In~redient General Ranqe Preferred Range Aspirln from about 22% to from about 30 % to about 75% about 45 ~
Acetaminophen from about 22% to from about 30% to ,~bout 75% about 45%
Caffeine from about 4~ to from about 9~ to abou~ 19% about 11~

The products of the present invention will be made up into tablets that may be taken comfortably by oral administration. Again, the quantity of ingredients that will be contained in each tablet may vary over a range. Table II below gives the general and preferred quantity range of the ingredients contained in each tablet expressed in terms of mg/tablet.

~able II
mq/Tablet Ingredient General Ranqe Preferred Ranqe L-HPC about 5 mg to about 5 mg to about 35 mg about 10 mg Aspirin about 150 mg to about 200 mg to about 500 mg about 300 mg Acetaminophen about 150 mg to about 200 mg to about 500 mg about 300 mg Caffeine about 30 mg to about 60 mg to about 130 mg about 70 mg In addition to the L-HPC, aspirin, acetaminophen and caffeine, the tablets of the present invention may also contain other tablet adjuvants that are well known to those skilled in this art. These 1.2~383~9 are added for a number of purpo6e6, .9. ~cilltate tabl~ting, improve the orgAnol~ptics of th~ tabl~t, improve ~tability of the tablet, improve the e~se of administration of thQ tablot6, otc. By way of example, tablet adjuvants that may b~ incorporated in the present tablet include lubricants (e.g. ctearic acid, zinc ctear~te), flow agents (e.g. fumed silica, precipitated silica), and wetting agents (Tween 80, sodium lauryl sulfat2).

No special technique i5 required to prepare the tablets of this invention. Generally, the ingredients will be dry blended (e.g. Twin Shell Blender) and the ~ixture i8 then filled into a tablet press and then compressed into a tablet. Alternatively, the L-HPC can be incorporated into wet granulations of the other ingredients and the mixture then compressed into tablets.

The regimen for administering the tablets of this invention may vary somewhat depending on the size of the tablet~, the racommended daily dose for the ingredient, and the condition being treated with these tablets. Generally, this will amount to about 1 to 2 tablets with each dose about 4 times a day and preferably 1 to 2 tablets 3 or 4 times a day.

The following e~amples are given to further illustrate the present invention. It i5 to be understood, however, that the invention is not limited thereto.

Exam~le 1 Formula CW 3446-58 3Osage Unit Amt Item mqlTablet _ No. Inqredients ~ WLW
75.00 1 Aspirin 40 mesh 11.12760 175.00 2 Aspirin 80 mesh 25.96439 250.00 3 Acetaminophen Granular37.09199 65 00 4 Caffeine, Anhydrous Powder 9.64392 100 00 5 Cellulose, Microcrystalline 14.83679 5.00 6 Low-substituted Hydroxypropyl Cellulose Grade LH-21 (Shin-Etsu Chemical Co.) 0.74184 4.00 7 Stearic Acid, Powdered C.59347 674.00 100.00000 ~ X~83~9 Procedure:
A. Screen caffeine through n ~20 mesh 6creen.
B. Screen ~tearic acid through a ~50 mesh 6creen.
C. Mix all ingredients except stearic acid for 15 minutes in a Twin Shell Blender.
D. Add stearic scid to (C) and mix for five minutes.
E. Compress to specifications shown below.

Appearance: White Tablets Punch: 7/16"
Tablet Weight: 674.0 mg.
Thickness: 0.245" + 0.005"
Hardness: 15-20 SCU (Heberlein) Disintegration: water, 37C/l min.
USP basket apparatus ~ - `~
~1 28~3349 Example_2 Formula CW 3446-38 Dosage Unit Amt Item mgLTablet _ Ingredient6 75.00 1 Aspirin 40 me~h 175.00 2 Aspirin 80 mesh 250.00 3 Acetaminophen Granular U.S.P.
Mallinckrodt, Grade 0057 65.00 4 Caffeine, Anhydrous Powder 100.00 5 Cellulose, Microcrystalline 2.50 6 Stearic Acid 5.00 7 L-HPC LH-21 -672.50 ExamPle 3 Formula CW 3589-9 (8 mq L-HPC Formula?
Dosage Unit Amt Item mqlTable~ No. In~redients 75.00 1 Aspirin 40 mesh 175.00 2 Aspirin 80 mesh 250.00 3 Acetaminophen Granular U.S.P.
65.00 4 Caffeine, Anhydrous Powder 100.00 5 Cellulose, Microcrystalline 2.50 6 Stearic Acid 8.00 7 L-HPC LH-21 67 5 ~ 50 F.xamPle 4 Formula CW 3446-94 (10 mq L-HPC Formula~
Dosage Unit Amt Item mq/Tablet No. Inqredients ~
75.00 l Aspirin 40 mesh `
175.00 2 Aspirin 80 mesh 250.00 3 Acetaminophen Granular ~.S.P.
65.00 4 Caffeine, Anhydrous Powder 100.00 5 Cellulose, Microcrystalline 2.S0 6 Stearic Acid 10.00 7 L-HPC LH-21 67i . SO
The procedure for Examples 2, 3 and 4 are similar to that `~
de!scribed in Example 1.
Two criteria are important in determining the acceptability of tablets containing aspirin, acetaminophen and caffeine. One is the ~2~l83~9 di6solutioo rAte of the t~blet after storage for a period of time ~nd the second is the ~SA (free salicylic acid) analysis. The first is important in that it is an in-vitro indication of the avail~bility of the active ingredients for absorption into the blood etream. The second is important since it is a measure of the ~tability of the tablet. High FSA values indicate that significant aspirin hydrolysis has taken place with the release of free salicylic acid.
.
Tests were carried out comparing the dissolution rates and/or the FSA values of tablets of the present invention with essentially two different types of tablets. The first category of tablets are essentially the sarne as those of the present invention excepting that they do not contain the L-HPC. The second category of tablet are those in which a different disintegrating agen~ is employed.

The tablets of this invention were tested after storage at various coDditions of time and temperature and in various types of containers and found to give acceptable dissolution rates and FSA
values. Tb insure that the tablets would perform acceptably under all the reasonably anticipated field conditions' in their tests applicants also stored the tablets under stressed conditions and measured their performance after such treatment. These stress conditions are described in more detail below. For purposes of comparison other tablets were also subjecled to these stress conditions and their dissolution rate and FSA values were determined.

Test Procedure A. Stress Testinq:
Test Tablets stored at room temperature in glass bottles; this was the u~stressed storage condition. Other samples of the same tablet were stored at 60C and 60~ relative humidity in an opan petri dish for 6 days. The latter are considered stress conditions.
FSA values were determined on test tablets that were stress tested;
i.e., stored at 60C and 60% relative humidity in an open petri dish for 6 days.

B. Dissolution Rate Test:

The dissolution method used to evaluate these tablets employs the dissolution test described in the USPXXI p. 14. The dissolution ~l28~

test c~lls for the use o ~00 ml. water maintnined at 37~ and the USP paddle, known as Apparatus 2, rotated at 50 rpm.

The tablet is placed in the beaker of water nnd after 45 minutes of paddle rotation at 50 rpm, ~n eliquot of solution is analyzed for aspirin, acetaminophen an~ caffeine content.

The analysis can be done via high pressure chromatography or via spectrophometric analy6is using a multi-component analysic on HP8450 or HP8451 ~pectrophotometer.

As a criteria for acceptability, applicants have adapted a dissolution rate such that at least 75~ of the tablet dissolves in under 45 minutes.

Table III below gives the formulas for each of the tablets which were tested. The quantities of the various ingredients are given in terms of mg/tablet.

Table III
*CW-3446-*CW~3446- *CW-3446- ~CW-3446- CY3513-Ingredient 38B 38A 54B 58 Aspirin, 40 mesh 75 75 75 75 __ Aspirin, 80 mesh 175 175 175 175 --Acetaminophen 250 250 250 250 --Caffeine, Anhy.
Powder 65 65 65 65 --Microcrystalline Cellulose 100 100 100 100 --Stearic Acid2.5 2.5 2.5 4 3 L-HPC ~LH21 5 -- -- 5 --Crospovidone XL-10 (Polyplasdone XL-10) -- -- 5 -- --Caffeine Starch Granulation (Eq. to 65 mg.
Caffeine) -- -- -- -- 100 _ g _ ~1 28~3349 ' Aspirin 12/50 Granul~tlon (Eq. to 250 mg. I
Asplrin) ~ -- -- 277.8 APAP 10~ Starch 145 (Eq. to 250 mg APAP) -- -- -- -- 277.8 TOTAL 672.5 667.50672.5 674.0 658.6 Subjected to stxess test.

The results of these tests are summarized in Table IV below. It will be noted that the tablets CW 3446-38A do not meet the criteria of a dissolution of 75~ of the tablet in under 45 minutes, whereas, tablets CW 3446-38B do so readily. As is clear from Table III,tablets CW-3446-38A differ from CW-3446-38B in that the latter also contain 5mg of L-HPC #LH21. Similarly it is to be noted that tablets CW 3446-54B also do not meet the criteria of a dissolution of 75~ of the tablet in under 45 minutes. Tablets CW 3446-54B, as Table III shows, contain 5mg of Polyplasdone XL-10 as a disintegrant, whereas, tablets CW 3446-38B of this invention contain 5mg of L-HPC
~lH21 as the disintegrant. In addition, the product containing the Polyplasdone XL-10 (CW 3446-54B) is less stable after stress testing than the product of this invention (CW 3446-38B?. The amount of salicylic acid produced by degeneration of aspirin .in the former is 2.2 mg/tab, whereas, in the latter it is 0.57mg/tab. This is about 4 times as much.

- ln -2~38349 T~ble IV
~issOlution R~tes 1/900 ml H20/37/P~ddlo 50 rpm T _e ~minutesL

T~blet T25 _ ~AP CAr~ ASA APAP CAFF ASA APAP CAFF

60C~60% ~H
6 days 20 15 945 29 18 45 45 31 4545 36 60C/60% RH8 4 39 7 8 16 11 11 1813 12 6 days C~-3446-548 60C/60% RH27 11 845 27 16 45 45 27 4545 30 6 days (2 tab) (2 tab)(2 tab) Stability: 60Ct60~ R.H. in open petri dish 6 days.

Salicylic Acid mq/tab Cw 3446-38A 0.46 CW 3446-38B 0.57 CW 3446-54B 2.2 .
~ .

.' ' `' ' , ~1 2~8349 .
T~blets CW 3446-56 involved in this invention were also compared to ~ comparable product that doe~ not contain the L-HPC LH21 disintegrant; i.e., tablets CY 3513-1 (see Table III), as to their dissolution rate at various conditions of storage and in different types of containers. In addition, they were al60 compared AS to their st~bility as measured by the FSA values. These measurement6 were made after 2 months storage. The results of these studies are summarized in Table Y below.

~2~1~3349 ~ T~ble V
! Dissolution Rates 1/900 ~l H20/37C/Paddle 50 rpm -- - .

T25 T50 _ ~75 TabletASA APAP CAFF ASA APAP CAFF ASA APAP CAFF

Initial 2 2 1 4 3 2 7 5 4 Two Months Poly~tyrene/
Safety Ca~e_ H/H 12 8 7 20 15 lZ 32 24 20 Polyethylene/ :~
Safetv Cap `

Slide Box `

Initial 3 2 2 6 4 3 14 6 6 Two Months Polystyrene/
Safety CaP
RT 3 3 3 7 5 5 14 lO 9 H/H 19 6 8 36 15 17 45 (3) 30 31 Polyethylene/
Safety Cap 125/F 23 7 10 41 17 24 45 (4) 36 45 (1) Slide Box H/H 7 3 4 13 6 7 25 lO ll Stability:

~l288349 Salicyllc Acidl _g¦Tab., 1 Month __ _~04F!7 5% RH
125/~ _ P/S S. Ca~ HD/PE S. Cax PIS Slide Box HD/PE S. Ca~
CW 34~6-56 1.7 0.7 2.2 3.0 CY 3513-1 0.6 0.5 1.1 3.4 As i~ clear from Table V, tablets CY 3513-1 are acceptable only when packaged in a 61ide box. Tablets CW 3446-58, however, were acceptable under all the storage conditions; that is to say, they had an acceptable dissolution rate. As to st~bility, these respective products are quite comparable.

Claims (9)

1. A tablet containing in combination aspirin, acetaminophen and caffeine in analgesic effective quantities; said tablet also having incorporated therein a sufficient quantity of low-substituted hydroxypropylcellulose to serve as a disintegrant for said tablet.

2. A tablet according to Claim 2 where the said low-substituted hydroxypropylcellulose has a hydroxypropyl degree of substitution in the range of from about 10% to about 16%.

3. A tablet according to Claim 2 wherein the hydroxypropyl degree of substitution is in the range of from about 10% to about 13%.

4. A tablet according to Claim 1 containing the ingredients within the following ranges expressed as a percent by weight based on the total weight of the tablet:

(a) Aspirin: from about 22% to about 75%;
(b) Acetaminophen: from about 22% to about 75%:
(c) Caffeine: from about 4% to about 19%;

5. A tablet according to Claim 1 containing the ingredients within the following ranges expressed as a percent by weight based on the total weight of the tablet:

(a) Aspirin: from about 30% to about 45%;
(b) Acetaminophen: from about 30% to about 45%;
(c) Caffeine: from about 9% to about 11%;

6. A tablet according to Claims 1, 2, 3, 4 or 5 wherein the low-substituted hydroxypropylcellulose is present in the range of from about 0.5% to about 5% by weight based on the total weight of the tablet.

7. A tablet according to Claims 1, 2, 3, 4 or 5 wherein the low-substituted hydroxypropylcellulose is present in the range of from about 0.8% to about 2.0% by weight based on the total weight of the tablet.

8. A tablet according to Claims 1, 2 or 3 containing the ingredients in the following amounts; said amounts being expressed as the number of milligrams of the ingredient per tablet:

(a) Aspirin: from about 150mg to about 500mg;
(b) Acetaminophen: from about 150mg to about 500mg;
(c) Caffeine: from about 30mg to about 130mg;
(d) Low-substituted hydroxypropylcellulose: from about 5mg to about 35mg;

9. A tablet according to Claims 1, 2 or 3 containing the ingredients in the following amounts; said amounts being expressed as the number of milligrams of ingredient per tablet:
(a) Aspirin: from about 200mg to about 300mg:
(b) Acetaminophen: from about 200mq to about 300mg;
(c) Caffeine: from about 60mg to about 70mg;
(d) Low-substituted hydroxypropylcellulose: from about 5mg to about 10mg.