CA2014659C - Pharmaceutical compositions for relief of dysmenorrhea and/or premenstrual syndrome and process - Google Patents

Abstract

A pharmaceutical composition for the relief of dysmenorrhea and/or premenstrual syndrome in humans contains in unit dose form essentially as the only pharmacologically active ingredients about 50 to about 800 mg ibuprofen and about 1 to about 50 mg of hydrochlorothiazide. The pharmaceutically active ingredients are present in the composition in amounts sufficient to afford relief from the symptoms of dysmenorrhea and/or premenstrual syndrome with the ibuprofen/hydrochlorothiazide ratio being from about 16:1 to about 64:1.

Description

20146~9 Field of Inventlon This invention relates to pharamaceutical compositions useful in the treatment of dysmenorrhea and/or premenstrual syndrome.

Background of Invention Dysmenorrhea is a term used to describe painful menstrua-tion. The pain may range from minor cramping to intense pain accompanied by diarrhea, nausea and vomiting, with sensations of pelvic heaviness and breast fullnes5. Premenstrual syndrome refers to the tension accruing prior to the onset of menstruation, and is characterized by headache5, nervousness and edema. Once menstruation has begun, there is noticeable polyuria and rapid disappearance of the edema.

PharmaceutiCal products for the treat~ent of dysmenorrhea and/or premenstrual syndrome are known in the prior art and have been marketed commercially. Thus, for example, a number of commercially available products contain a combination of acetaminophen and pamabrom or a combination of acetaminophen, pamabrom and pyrilamine maleate. Products of this character do not contaln a non-steroidal anti-inflammatory agent, such as ibuprofen or aspirin, which are highly important but not optimal in relieving the symptoms of dysmenorrhea and/or premenstrual syndrome. The acetaminophen used in such products is known to be an effective analgesic but is not generally recognized as exhibiting significant anti-inflammatory properties.

- 1 - ~

There ig at least one commercial product containing a non-steroidal anti-inflammatory such a8 aspirln that i9 mar~eted for use in treating dysmenorrhea and/or premenstrual syndrome Disadvantageously, this product doeg not contain a reliably effective diuretic which, when combined with an effective NSAID, provides relief of the array of symptoms of dysmenorrhea and/or premenstrual ~yndrome. Thu~, this product contains a mixture of aspirin, cinnamedrine and caffeine. Cinnamedrine is conventionally recognized as an antispasmodic. Caffeine, although it is recognized as a diuretic, is not a highly potent diuretic. Moreover, the latter has the disadvantage of inducing sleeplessness in the sub~ects to whom it is administered, an important consideration for evening utility.

Compositions for use in the treatment of dysmenorrhea, which are disclosed in European Patent Application 0 081 823, are "combinations of analgesics (including prostaglandin synthetase inhibitors such aspirin, indomethacin and ibuprofen), diure~ics, antihistamines and antispasmadics." The invention of this European Patent Application i~ said to reside in also incorporating 5-500 mg dextromethorphan hydrochloride with one or more of: a conventional diuretic such as ammonium chloride, pamabrom and hydrochlorothiazide; a conventional antihistaminic such as pyrilamine maleate; a conventional antispasmodic, for example, cinnamedrine, or a conventional analgesic such as, for example, aspirin, acetamlnophen, indomethacin, ibuprofen or naproxen.

G. F. Shah et al, Effect of Nonsteroidal Antlinflammatory Drugs (NSAIDS~ on Diuretic ProPerty of HYdrochlorothiazide, Indian J. Pharm., 17:224-8 (1985), studied the effects of several NSAIDs including ibuprofen on hydrochlorothiazide (HCTZ) induced changes in urinary volume, sodium, potassium and creatinine * Trade mark excretion, in conscious rats. Shah et al concluded that the diuretic effect as well as the increased urinary sodium and potassium excretion elicited by HCTZ at 2.5 and 5 mg/kg were inhibited after oral administration of NSAIDs such as indomethacin, oxyphenbutazone, ibuprofen and naproxen, in doses which inhibited the rat carrageenin induced hind paw oedema.

Shah et al reports that of the NSAIDs tested, ibuprofen was found to be the most potent in antagonizing diuretic and natriuretic activity. Thus, a dose of 12.5 mg/kg ibuprofen inhibited the diuretic activity of 5 mg/kg HCTZ, while 25 mg/kg ibuprofen significantly antagonized the diuretic activity of 10 mg/kg HCTZ. It is further seen from Table 4 of Shah et al that as the ratio of ibuprofen to HCTZ increased at a constant dose of HCTZ, there was a concomitant reduction in the diuretic activity.
For example, at 10 mg/kg HCTZ, the reported diuretic activity is 2.2++0.16, while at 10 mg/kg HCTZ and 25 mg/kg ibuprofen, the diuretic activity was 1.6+0.07, a reduction of about 28%.
Similarly, Shah et al observed like reductions in natriuretic activity.

It is noteworthy that Shah et al administered each of the ibuprofen and the HCTZ in a gum arabic suspension. As pointed out in Bowman & Rand, Textbook of Pharmacology~ p. 40.10 (2nd Edition 1980), the activity of HCTZ is preparation-dependent.
Accordingly, Shah et al's observations are not predictive of the performance of a tablet comprising ibuprofen and HCTZ.
Summary of the Invention According to an aspect of the invention, a pharmaceutical composition for the relief of dysmenorrhea and/or premenstrual syndrome in humans contains in unit dose form essentially as the only pharmacologically active ingredients about 50 to about 800 mg ibuprofen and about 1 to about 50 mg of hydrochlorothiazide.
The pharmaceutically active ingredients are present in the composition in amounts sufficient to afford relief from the symptoms of dysmenorrhea and/or premenstrual syndrome with the ibuprofen/hydrochlorothiazide ratio being from about 16:1 to about 64:1.

According to a preferred aspect of the invention, the composition may optionally include an antihistamine, such as pyrilamine which has been shown to be a safe and effective calmative which relieves the tension of dysmenorrhea and/or premenstrual syndrome.

According to another aspect of the invention, namely the use of the composition of the invention in the relief from the symptoms of dysmenorrhea and/or premenstrual syndrome.
Detailed Description of the Invention The non-steroidal anti-inflammatory agents useful in the compositions herein disclosed are ibuprofen or aspirin.
Combinations of these drugs may also be employed but ordinarily either one or the other will be utilized. The quantity of said anti-inflammatory agent contained in the present composition may be expressed in the form of the daily average dose for this agent, which will vary with anti-inflammatory drug selected.
Generally for ibuprofen this will be about 100 to about 2000 mg/day with the preferred range being about 200 to about 1200 mg/day. In the case of aspirin the general average daily dose will be about 200 mg/day to about 5 gm/day, the preferred range being about S00 to about 2000 mg/day.

In similar fashion, the quantity of the particular diuretics of use in the present invention and contained in the present products may also be expressed on the basis of the daily average dose for the diuretics (i.e. pamabrom, hydrochlorothiazide or combinatlon thereof), which also will vary with the partlcular diuretic selected. When the diuretic i8 hydrochlorothiazide the general average daily dose for this drug provided by the product will be from about 5 to about 250 mg/day and in the case of pamabrom from about 5 to about 500 mg/day. In both cases the preferred range i5 about 25 to about 200 mg/day.

When the antihi6tamine (i.e. pyrilamine or itB pharmaceu-tically acceptable salts) ls employed in the practlce of this invention its level of use is also expressible on the basis of its daily average dose. In this case, the daily average dose will be from about lS mg to about 400 mg. However, the preferred daily average dose for the antihistamine will fall in the range of from about 30 mg to about 200 mg.

Any of the pharmaceutically acceptable salts of pyrilamine may be utilized in carrying forward the purpoee of this invention. By way of example mention may be made of pyrilamine maleate citrate, hydrochloride or sulfate.

The products of this invention will generally be administered in a convenient unit dosage form, preferably in solid dose form such as a tablet, powder, capsule, and the like.
The quantity of the respective ingredients that may be contained in this unit dosage form is given in the table below:

201~6~!~

Unlt Dosage Form General Range in mg Preferred Range in mg Ibuprofen 50 mg to 800 mg 100 mg to 400 mg Aspirin 50 mg to 975 mg 150 mg to 650 mg Pamabrom 1 mg to 100 mg 5 mg to 50 mg Hydrochlorothiazide1 mg to S0 mg 5 mg to 2S mg Pyrilamine Salt0 mg to 100 mg lS mg to 50 mg Optimàlly each unit dosage form will contain from about 200 mg to about 400 mg of ibuprofen or from about 325 to 500 mg of aspirin.

The prior art Shah et al article demonstrate~ significantly antagonized diuretic activity of HCTZ when administered in the presence of ibuprofen at ibuprofen/HCTZ ratios of 0.625:1 to 10:1. Surprisingly and unexpectedly, it has been found by Applicants that the diuretic activity antagonism did not worsen as anticipated at higher ratios of ibuprofen to HCTZ, as demonstrated hereinafter with regard to Examples 8 and 9. In the compositions of the present invention, the ratio of ibuprofen to HCTZ is above about 16:1, preferably from about 16:1 to 64:1, most preferably from about 24:1 to 48:1.

In addition to the pharmacologically active ingredients mentioned above, the products of thi~ inYention may also contain other excipients. These to a large extent will depend on the nature of the unit dosage form selected for dispensing the present composition.

The present products may be made into capsules, tablets, - 20 1 46~9 powders, caplets and may be fllm coated, enteric coated or formulated into sustained release dosage for~s or liquid dosage compositions. When formed lnto tablets or caplets they may contain ad~uvants that facilitate the tableting of the product or enhance its elegance or dissolution rates. Generally illustrative of the ad~uvants that may be contained in the various dosage forms encompassed in the present invention are:
disintegrating agents, binders, lubricants, fillers, glidents, surfactants, flavoring agentg, sweeteners, solvents, liquid carriers, suspending agents, preservatives, etc. More particularly the adjuvants that may be contained in the various dosage forms over and above the activ2 ingred~ents are as follows:

Caplet and Tablet: Cellulose, lactose, corn starch, stearic acid, water, gelatin, talc, Sterotex, magnesium stearate, terra alba, sucrose, Cab-O-Sil, acacia, etc.

Capsule: spray dried lactose, dimethylsiloxane, corn starch, magnesium stearate, sucrose, Cab-o-Sil, etc.

Liquid Dosage Forms: polyethylene glycol, sucrose, Povidone, sodium citrate, citric acid, flavor, color, quinine, water, etc.

Sustained release compositions may contain such things as glyceryl monostearate, glyceryl distearate, cellulose ethers such as hydroxypropyl methylcellulose and hydroxy propylcellulose, stearic acid, etc.

In general, the products of the present invention may be prepared using the standard technique well known to those skilled in this art, e.g., standard tableting or capsule preparing procedures. However, when pamabrom is utilized as the diuretic and ibuprofen as the non-steroidal anti-inflammatory it has been * Trade mark found advantageous to granulate the pamabrom before mixing it with the ibuprofen. These ingredientg, when mixed together in standard procedureg, tend to form eutectic mixtures with the result that tablets containing such a mixture become soft upon exposure to stress testing conditions and capsules turned pasty.
In addition both of these dosage forms also changed color from white to yellow or orange when prepared using the standard procedures.

When an antihistamine, e-g-, pyrilamine maleate, is used in conjunction with the pamabrom and ibuprofen, it is often advantageoUS to granulate th~ combination of pamabrom and antihistamine before mixing this combination with the ibuprofen.
This mixture, with or without other ad~uvants may then be used to prepare the dosage forms, e.g., capsule, tablets.

The products of this invention may be administered using a variety of regimens. Ordinarily the acceptable daily dose will be provided by taking the product twice, three times or four times a day.

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

The following are the chemical definitions of the materials used in the Examples and identified therein by their trade designations:

Avicel PH 101 and 102: Microcrystalline Cellulose, FMC Inc.

Starch 1500: Pregelatinized starch, Colorcon Inc., West Point, Pa.

Trade mark ~ ` -- r -sllicone Oil: Dimethicone (U.S.P.), Dimethylpolysiloxane 350 CS, Dow Corning Twee~ 80: Polysorbate 80 (CTFA-Cosmetic Ingredient Dictionary, Third Edition, p. 247) Cab-O-Sil: Fumed Silica, Cabot, Inc.

Povidone: Polyvinyl pyrrolidone, GAF Corp.

Crospovidone X~10: Cros~ linked Polyvinylpyrrolidone, AF
Corp.

The "Ibuprofen Granulation" used in Examples 5 and 6 below is prepared by first mixing ibuprofen (200 mg) and corn starch (50 mg). An aqueous granulating solution, prepared containing Povidone X29-32 (6 mg), Avicel PH 101 (41.5 mg) and Crospovidone XL-10 (1.5 mg), wa8 used to granulate the ibuprofen/starch mixture.

Ibuprofen/Pamabrom/Pyrilamine Maleate: Capsules Formula CE 3375-70 Ingredients Amount Per Dose a. Ibuprofen 150.00 mg b. Pamabrom 25.00 "
c. Pyrilamine Maleate 15.Q0 "
d. Avicel pH 101 50.00 n e. Starch 1500 117.50 "
f. Silicon Oil 2.00 "
g. Tween 80 0.50 -h. Cab-O-Sil 0.25 "
360.25 mg * Trade mark ~. ~ 201~659 Method A. 81end b, d and 30 mg e B. Dlssolve c in water and use to granulate A, then dry C. Blend 87.5 mg e, f and g D. Blend B, C, a and h. Fill lnto slze ~ 1 capsules Ibuprofen/Pamabrom: Capsules Formula CS 3570-05 Ingredients Amount Per Dose a. Ibuprofen 150.00 mg b. Pamabrom 25.00 ~
c. Avlcel pH 10182.50 n d. Starch 150090.00 n e. Sillcon Oll2.00 n f. Tween 80 0.50 n 350.00 mg Method:
A. Mlx b, 50 mg d and 42.5 mg c, granulate with water and dry B. Mix 40 mg d, e and f C. Mix A, B, a and 40 mg c D. Flll C into size # 1 capsules EXAMPLES 3 and 4 Ibuprofen/Hydrochlorothiazide HCl: Capsule Example 3 Example 4 Formula CS 3570-14 Fornula CS 3570-31 Ingredlents Amount Per Dose Amount Per ~ose a. Ibuprofen 200.00 mg 300.00 mg b. Hydrochlorothiazide HCl 12.50 ~ 12.50 "
c. Starch lS00 134.50 " 183.50 "
d. Silicon Oil 2.00 n 2.80 "
e. ~ween 80 0.50 ~ 0.70 "
f. Cab-O-Sil o.50 ~ 0.50 -350.00 mg 500.00 mg Method:
A. Blend all ingredlents B. Fill blend~ for CS3570-14 into size ~ 1 capsules and for CS3570-31 lnto size # O capsules.

Ibu~rofen/Pamabrom/Pyrilamine Maleate Tablets Formula CS 3570-34 Ingredients Amount Per Dose a. Pamabrom 25.00 mg b. Pyrilamlne Maleate 15.00 H
c. Starch 1500 75.00 n d. Povidone, USP (K29-32) 0.75 N
e. Hydroxypropyl methycellulose4.11 "
E5-Premium f. Propylene Glycol o,go -g. Ibuprofen Granulation 224.24 "
(Equivalent to 150 mg Ibuprofen) h. Silicon Oil 2.00 "
i. Tween 80 0,50 n . Starch 1500 35.00 n 382.50 mg Method:
A. Blend a, b and c, granulate with water and dry B. Dissolve d, e and f ln water and use to spray coat A
C. Blend h, i and ~
D. Blend B, C and g and compress into tablet Ibuprofen/Pamabrom/Pyrilamine Maleate Tablets Formula CS 3570-32 In~redients Amount Per Dose a. Pamabrom 25.00 mg b. Pyrllamine Maleate 15.00 n c. Avic~l P~ 101 50.00 n d. Po~idone, USP (K29-32) 6.74 n e. Hydroxypropyl methylcellulose6.63 n E5-Premlum f. Propylene Glycol 1.24 "
g. Ibupro~en Granulation 224.24 "
(Equivalent to 150 mg Ibuprofen) h. Starch 1500 35,00 n 1. Silicone oll 2.00 n . Tween 80 0,50 n 366.3S mg C`` ~ 20146~9 ~ethod A. Blend a, b and c B. Di5solve 5.6 mg d in water and use to granulate A, then dry C. Dis601ve 1.14 mg d, e and f in water and use to spray coat B
D. Blend h, i and ~
E. Blend C, D and g and compress into tablet Ibuprofen/Hydrochlorothiazide HCl Tablets Formula CS 3570-15 Inqredients Amount Per Dose a. Ibuprofen 200.00 mg b. Corn Starch NF 50.00 ~
c. Povidone, X29-32 6.00 n d. Avicel PH 101 41. 50 n e. Avicel PH 102 136. 50 "
f. HydrochlorothiaZide HCl, USP 12.50 n g. crospovidone X~10 2 . 50 n h. Cab-0-Sil 0. 50 n i. Magnesium Stearate 0. 50 n 450.00 mg Method:
A. Blend all ingredients geometrically B. Compress into tablet~

A preclinical diuretic efficacy study was conducted in two stages (Experiments A and ~), the experiments being run fifteen days apart and each experiment lasting two days.

In Experiment A, five doses of hydrochlorothiazide (HCTZ) ranging from 0.25 to 4 mg/kg were tested, while in Experiment B, four doses of HCTZ ranging from 1.5 to 12 mg/kg were used and coadministered with a constant dose of 96 mg/kg ibuprofen.

!i~ ~ 2014659 Also tested in Experiment A was a control containing no actives (vehicle only), and also tested in Experiment B was a first control containing no actives and a second control containing 96 mg/kg ibuprofen.

Ten male Wistar rats were used per dose in each experiment.
The rats were fasted overnight prior to testing and during testing. After the study dose (or vehicle) was administered, each animal was given a hydrating dose of normal saline (30 ml/kg). Each rat was placed in an individual cage and urine collected for five hours. Total urinary volume, total urinary sodium and potassium excretion, and urinary pH were determined, which parameters were analyzed as ml/kg body weight, mEq/kg body weight, and pH, respectively.

The results of the tests are provided below.

~0 1 4659 Experiment A

HCTZ Volume Na K
~mq/kq) (ml/k~) (mEq/kg~ (mEa/k~ E~
-o- 18.69 2.53 0.73 5.72 0.25 23.17 3.47 0.80 5.78 0.50 22.01 3.33 0.95 5.76 1.0 28.61 4.09 o.g7 5.61 2.0 32.91 5.20 1.16 5.26 4.0 37.04 5.29 1.58 5.64 Experiment B

HCTZ (mg/kg) Volume Na K
w/96 mq/k~ Ibuprofen(ml/Xg) ~mEq/k~)(mEa/kg) ~a -o- w/o Ibuprofen 20.24 2.93 0.80 6.11 -0- w/Ibuprofen 12.61 1.49 0.55 6.22 1.5 22.98 3.57 1.19 6.06 3.0 17.08 2.92 0.99 5.98 6.0 22.97 3.66 1.08 5.75 12.0 26.37 4.42 1.22 6.05 The urinary excretion data from Experiment A demonstrate a clear-cut dose response for HCTZ. The data collected for the two controls (-O- mg HCTZ w/o ibuprofen and -0- mg HCTZ w/lbuprofen) in Experiment B illustrate the extent to which ibuprofen itself causes urinary concentration. The data reflect urinary excretion of sodium and potassium, and reduced volume. Unexpectedly, when combined with ibuprofen, the diuretic efficacy of HCTZ i5 exhibited as increased urinary volume, as well as the content of sodium and potassiu~. In Shah et al, a significant inhibition of diuresis was observed at the 5:1 ibuprofen/HCT2 ratio. To the contrary, in these studies above the antidiuretic efficacy of ibuprofen was significantly offset at ratios of ibuprofen to HCTZ of 16:1 to 64:1.

2nl~6~s Example 9 A single blind, randomized, four-treatment, four-period crossover study of ibupro~en and hydrochlorothiazide (HCTZ) interaction was conducted with 16 female human adults. The study medications were: (a) a placebo, (b) 12.5 mg HCTZ, (c) 400 mg ibuprofen, and (d) in combination, 400 mg ibuprofen and 12.5 mg HCTZ (32:1 ibupro~en/HCTZ ratio).

Alcohol consumption was not permitted for 48 hours before dosing; caffeine was restricted for 24 hours before dosing. The test subjects were held to a controlled diet with fluid intake, sodium and potassium restricted.

Urine was collected and pooled for 24 hours prior to each drug, and was collected voluntarily from the te9t sub~ects at 1, 2, 3, 4, 5, 6, 9, 12, 15 and 24 hours post treatment.

The 6- and 24-hour urinary excretion data is reported below.
Cumulative 6-Hour Urinary Excretion Urine Na K
Volume Excretion Excretion Medication ~ml~ (mEa) ~mEq~
(a) Placebo gjs 44 14.2 (b) 12.5 mg HCTZ 1405 98 19.3 (c) 400 ~g Ibupro~en 799 29 11.9 (d) 400 ~g Ibupro~en 1165 76 17.7 12.S ~g HCTZ

~014~9 Cumulative 24-Hour Urlnary Excretion Urine Na X
Volume Excretion Excretlon Medlcation (ml~ (mEq) (m Eq) (a) Placebo 2172 157 45.0 (b) 12.5 mg HCTZ 2681 193 45.5 (c) 400 mg Ibuprofen 2078 138 39-5 (d) 400 mg Ibuprofen 2641 190 43.5 12.5 mg HCTZ

Shah et al observed approximately a 25% decrease in diuretic activity at ibuprofen/HCTZ ratios of 5:1 and 10:1.
Given a typical dose response, one of ordinary qkill in the art would anticipate logically that inhibition of urinary activity would be greater as the ibuprofen/HCTZ ratio increased.
Unexpectedly, the data above demon8trate that the anticipated dose response doeg not occur. Thu8, at the end of the 6-hour period, the suppresgion in urine volume wag only 17%. After 24 hours the urine output of those te8t gub~ects taking the ibuprofen/HCTZ medication wa5 e8sentially no different from those taking HCTZ only -- up about 23% compared to placebo. Those test sub~ects tAk~n~ ibuprofen alone had a guppression in urine output of 12% as compared to placebo over the 24-hour period.
Similarly, after 24 hourg the godium excretion level for the ibuprofen/HCTZ do~ing is about the same as for HCTZ alone, while ibuprofen alone had a 34% decrease, all as compared to the placebo.

Extrapolation of the data in Shah et al would suggest total inhibition of HCTZ-induced natriuresis at the 32:1 ibuprofen/HCTZ
ratio. Unexpectedly, this was clearly not the case in the clinical studies reported on above. Moreover, the excretion of Na+ without concomitant equivalent 1088 of X+ as observed herein provides a safety advantage for the ibuprofen/HCTZ
combination reported on above.

Claims (11)

1. A pharmaceutical composition for the relief of dysmenorrhea and/or premenstrual syndrome in humans containing in unit dose form essentially as the only pharmacologically active ingredients about 50 to about 800 mg ibuprofen and about 1 to about 50 mg of hydrochlorothiazide, said pharmaceutically active ingredients being present in said composition in amounts sufficient to afford relief from the symptoms of dysmenorrhea and/or premenstrual syndrome with the ibuprofen/hydro-chlorothiazide ratio being from about 16:1 to about 64:1.

2. The composition of Claim 1 wherein the unit dosage form contains from about 100 to about 400 mg ibuprofen and from about 5 to about 25 mg hydrochlorothiazide.

3. The composition of Claim 1 or 2 wherein the ibuprofen/hydrochlorothiazide ratio is from about 24:1 to about 48:1.

4. The composition of Claim 1 or 2 also containing an anti-histamine at an antihistaminicly calmative effective level.

5. The composition of Claim 4 wherein the unit dosage form contains from about 15 to about 50 mg antihistamine.

6. The composition of Claim 5 wherein the ibuprofen/hydro-chlorothiazide ratio is from about 24:1 to about 48:1.

7. The composition of Claim 6 wherein said antihistamine is pyrilamine maleate.

8. The composition of Claim 5 wherein said antihistamine is pyrilamine maleate.

9. The composition of Claim 1 or 2 wherein the ibupro-fen/hydrochlorothiazide ratio is about 32 :1.

10. The composition of Claim 8 wherein the ibuprofen/hydro-chlorothiazide ratio is 32 :1.

11. The composition of Claim 1 or 2, including a pharmaceutical carrier.