AU640112B2 - Estrogen and progestogen containing oral dosage forms - Google Patents

Description

-1I- 640 112

AUSTRALIA

PATENTS ACT 1990 QCOM PLERTER S PE R F Q I C AT T Q N FOR A STANDARD PATENT

ORIGINAL

Name of Applicant: Actual Inventor: /Address for Service: Inenio Tile WARNER -LAMBERT COMPANY ROGER BOI SSONNEAUtLT SHELSTON WATERS Clarence Street SYDNEY NSW 2000 "ESTROGEN AND PROGESTOGEN CONTAINING OPAL DOSAGE FORMS"

Q

**The following statement is a full description of this invention, .4*including the best method of performing it known to me/us:- 4- la therapeutic range. As a result, despite cyclic 0 0 The treatment of menopausal symptoms such as flashing, osteoporosis and other symptoms associated with hormone deficiency is old. Typically, the known 15 formulations for such treatment have contained natural estrogen or other estrogenic component(s) as the only hormonal ingredient. Known formulations were designed to treat symptoms rather than to replace the physiologic deficiency that results from dysfunctional ovaries.

Also known formulations were marketed without adequate dose ranging and dosed in a cyclic fa.hion. The administration of eitrogen in a cyclic fashion was an attempt to rest the endometrium from the continuous stimulation of estrogen. This practice is questionable in that the half-life of equine estrogens can be long (lipid soluble) and the patient never falls out of therapeutic range. As a result, despite cyclic administration, the replacement of estrogen with these types of formulations containing estrogen only has led to evidence of hyperstimulation of the endometrium and, in some cases, subsequent adenocarcinoma.

-2- To minimize the potential for hyperstimulation, 5-14 days of progestional therapy has been included on a monthly basis to slough the endometrium. As a result, the patient experiences a monthly withdrawal bleed similar to the premenopausal state. Market research with physicians indicates that the nuisance of this cyclic bleeding is the single most important reason postmenopausal females refuse or discontinue therapy.

Although progestins protect against hyperstimulation, tney have been associated with a negative effect on blood lipids. As opposed to estrogen's positive effect on lipids, increase HDL/lower LDL, progestin's negative effect on lipids may compromise the cardioprotective state of the premenopausal female.

*0 Applicant has discovered that a fixed combination of estrogenic and progestogenic agents gives relief from menopausal symptoms with minimal side effects. In one preferred embodiment, a composition containing a fixed dosage of ethinyl estradiol, 0.001-0.05 mg-- S* .along with a fixed dosage of norethindrone acetate 0.1-1.0 mg-- yields, when administered in a 28-day or, preferably, a continuous sequence, acceptable hormone levels in patients.

Thus, the invention is concerned with compositions and methods in which a formulation containing a fixed estrogen/progestin ratio is administered to female individuals with resultant relief from hot flashes, osteoporosis and other conditions associated with hormone deficiency.

-3- The invention is also concerned with a new process for preparing fixed combinations of norethindrone acetate and ethinyl estradiol, especially useful for low tablet dosage forms where the ratio of norethindrone acetate may be from about 1:100 to about 1:1000 and ethinyl estradiol from about 1:2000 to about 1:100,000, the final tablet weight. The process employs a two-component drug dilution introduced onto tableting excipients.

s*o. The compositions and processes of the invention have several advantages over those already known in the art. Principal among their advantages are: 1. The compositions contain fixed, constant 15 or unitary, quantities of both the estrogenic and progestogenic agents. This simplifies manufacturing, storage, and packaging.

2. The use of a continuously dosed product minimizes patient compliance problems associated with an 20 alternating sequence of dual therapies.

3. The administration of a single combination product containing fixed quantities of hormonal agents is psychologically beneficial. Also it has been demonstrated that low doses of this combination of hormones results in an atrophic state that obviates the troublesome side effect of monthly withdrawal bleeding.

4. Through the use of dose ranging the invention is designed to replace that which is physiologically lost rather than treat symptoms with supraphysiologic doses of estrogen and progestin. The result is a therapy that is associated with u relatively low incidence of side effects.

The invention has demonstrated efficacy similar to existing therapy (20 mcg, ethinyl estradiol), however, at one-fourth the total dose of estrogen. As a -4result the margin of safety (thromboembolism) has been expanded as measured by effects on clotting factors and angiotensin levels.

6. Ultra low doses of estrogen/progestin dosed in a schedule consistent with the postmenopausal state of endogenous hormone production offers protection against hot flashes, osteoporosis, endometrial hyperplasia, cyclic bleeding, and potentially replicates the cardioprotective state of the premenopausal female.

7. The use of the new and improved process for 1 preparing low tablet dosage forms involving the combination of two drugs in one solution eliminates any error that may occur with distribution of one drug more than the other.

8. The new process also provides for processing to be carried out in one piece of equipment, a P-K solids processor, from ble:nding to addition of lubricant thereby eliminating t,.e need for transfer and drying.

20 9. Other aspects and advantages of the invention will be made apparent by the following description and claims.

The compositions and methods of the invention are based upon the use of a novel combination of synthetic estrogenic and progestogenic ingredients.

The compositions generally contain about 0.001 to 0.05 parts by weight, preferably about 0.001 to about 0.02 parts, or more preferably about 0.001 to 0.01 parts of the estrogenic ingredient and about 0.1 to about parts by weight of the progestogenic ingredient.

Generally, che ratios by weight of progestogenic to estrogenic components in the inventive compositions will be from about 20:1 to about 200:1, preferably about 50:1 to about 200:1, and more preferably about 100:1 to about 200:1.

While milligrams are the preferred units of measurement, any scale can be used so long as the ratio of the active hormonal ingredients remains fixed and is appropriate to the weight ratios set out above. For example, in especially low tablet dosage forms, micrograms are often used as the units of measurement.

The estrogenic ingredient of the inventive 10 compositions can be any suitable synthetic estrogen or functional equivalent thereof. While ethinyl estradiol is the preferred estrogenic substance, other useful substances include conjugated estrogens, estrone sulfate, beta estradiol, quinestrol, and the like.

Mixtures are operable.

The progestogenic ingredient is generally a synthetic progestogen; however, natural progestins may be used. Useful progestogenic substances include medroxyprogesterone acetate and the like. Norethindrone acetate is preferred. Mixtures are operable.

While it is preferred that the synthetic estrogen and progestin be the only pharmaceutically active ingredients in the compositions, the use of other drugs and/or otherwise beneficial substances in the instant compositions is contemplated.

The use of conventional pharmaceutical carriers is contemplated. Other excipients such as perfumes, colorants, stabilizers, fillers, and the like can be used as well.

The compositions of the invention can be administrated via a variety of routes. Any method or combination of method by which a continuous dosage form can be administered is operable. Oral dosage forms are preferred.

When oral dosage forms are employed, it is generally preferred that they be solid or semisolid.

However, liquid compositions are contemplated.

One aspect of the invention involves the packaging of the compositions of the invention, in a solid dosage form, in a pill case or compact for sequential administration. Thus, a package similar to that sometimes used for dispensing contraceptive pills, tablets, and the like can be employed. Thus, the individual who is to ingest the subject composition merely takes the pills, tablets, and/or capsule in a daily regimen in the sequence in which they are 10 presented in the package.

In general, any dosage form and packaging concept can be used in combination so long as the composition is fo.. administered at least once daily for a period of about 20 to about 30 days, preferably about 28 days, during a total cycle of about 30 to about 35 days. One highly preferred regimen calls for continuous administration of the composition.

More preferred dosage forms for the above regimen are those compositions containing a fixed dosage of ethinyl estradiol, 1-20 micrograms (mcg), with a fixed "dosage of norethindrone acetate, 0.1-1.0 milligrams 0:966 wherein the ratio of norethindrone acetate to ethinyl estradiol is from about 50:1 to about 200:1.

Most preferred contain a fixed dosage of 1-10 mcg ethinyl estradiol and 0.1-1.0 mg norethindrone acetate, wherein the ratio of norethindrone acetate to ethinyl estradicl is from about 100:1 to about 200:1.

Particularly valuable compositions contain as active ingredients: 1 mcg ethinyl estradiol and 0.2 mg norethindrone acetate; mcg ethinyl estradiol and 0.5 mg norethindrone acetate; mcg ethinyl estradiol and 1 mg norethindrone acetate, and mcg ethinyl estradiol and 1 mg norethindrone acetate.

-7- The compositions of the invention are useful for treating osteoporosis, hot flashes, withdrawal bleeding, and other disorders and symptoms generally associated with hormone deficiency, many of which are experienced during menopause.

The fixed compositions of the present invention can be prepared by an improved process adaptable as well for ultra low dose formulations which comprise dissolving together in one vessel both the estrogenic and 10 progestogenic ingredients, norethindrone acetate and ethinyl estradiol in alcohol; plating the solution of ingredients onto a mixture of lactose and excipients, removing the alcohol by drying, adding incrementally other excipients, and blending in a lubricant, e.g., calcium stearate, and compressing the resulting mixture into tablets.

The process may be illustrated by the following scheme: sees*: -8- BLENDING SCHEME FOR TWO COMPONENT DRUG DILUTION USED IN NORETHINDRONE ACETATE/ETHINYL ESTRADIOL TABLET GRANULATION BLENDED IN P-K LIQUID/SOLIDS BLENDER WITH INTENSIFIER BAR

A.

ETHINYL ESTRADIOL NORETHINDRONE ACETATE ALCOHOL SD 3A* 10 DISSOLVE ETHINYL ESTRADIOL AND NORETHINDRONE ACETATE IN SD 3A ALCOHOL WITH GENTLE STIRRING.

B.

Sa. LACTOSE FAST FLO TWO COMPONENT DRUG SOLUTION ADD TO IN P-K BLENDER WITH INTENSIFIER BAR AND BLENDER ON. RINSE WITH ADDITIONAL ALCOHOL ml/1 BLEND WITH INTENSIFIER BAR FOR 5 MINUTES.

REMOVE AND DRYt UNTIL ALL ALCOHOL IS EVAPORATED. SCREEN THROUGH A #30 SCREEN 20 C.

DRUG GRANULATION MICROCRYSTALLINE CELLULOSE STARCH CORN NF ADD MICROCRYSTALLINE CELLULOSE WITH STARCH AND BLEND FOR 25 5 MINUTES WITH INTENSIFIER BAR.

D.

DRUG GRANULATION MICROCRYSTALLINE CELLULOSE STARCH CORN NF CALCIUM STEARATE ADD CALCIUM STEARATE AND BLEND FOR 1 MINUTE WITH INTENSIFIER BAR AND 1 MINUTE WITHOUT INTENSIFIER BAR.

Alcohol SD 3A Denatured anhydrous ethanol 100 parts with 5 parts methanol.

t Drying may also be carried out under vacuum in this equipment.

The invention is illustrated by the following example.

Example Each Tablet Ingredients 1.0 mcg 5 100.0 mcg se* :0 0 15 o 1. Ethinyl Estradiol U.S.P.

2. Norethindrone Acetate

U.S.P,

3. Alcohol SD 3A Anhydrous q.s.

4. Lactose USP Hydrous (Fast Flo) q.s.

Starch Corn NF q.s.

6. Cellulose Microcrystalline NF Granular (PH-102) q.s.

7. F.D. C. Blue #1 Lake HT 31% q.s.

8. Calcium Stearate NF q.s.

Per 1000 Tablets 0.001 g 0.100 g 10.000 ml 68.833 g 10.000 g 20.000 g 0.066 g 1.000 g 100.000 g 100.000 mg To make Component 7 was added to components 4 and 5 and blended in a suitable size P-K liquid/solids blender with intensifier bar for five minutes. Component 6 was then added and blended with intensifier bar for another five minutes.

In a separate container, components 1 and 2, the active ingredients, were dissolved in alcohol, component 3, and then added to the blender at a sufficient rate through intensifier bar with bar and blender on. The blender was rinsed with additional alcohol, 3, (20 ml/1 kg) through intensifier bar with blender and bar on. The entire mixture was blended an additional five minutes.

The damp granulated material was removed from the blender and air dried until all the alcohol evaporated, or preferably vacuum dried. The material was then reblended with intensifier bar for five minutes.

10 Component 8 was added and blended with intensifier bar for one minlute and without for one minute.

0 ease The final mixture was compressed 100 mg on 0.208" x 0.250 Oval punches at 6-9 kg units hardness and about 0.130" thickness. One thousand tablets were produced from the composition.

0*0:00 06 0 s* *sees: 0 0

Claims (8)

1. A method for treating menopausal symptoms associated with hormone deficiency in a postmenopausal female host comprising orally administering to said host over a 28-day or continuous sequence a fixed combination of: about 0.001 to about 0.05 parts by weight of at least one synthetic estrogenic ingredient and about 0.10 to about 1.0 parts by weight of at least one synthetic progestogenic ingredient, in a 10 pharmaceutically acceptable dosage form, wherein the ratio of progestogenic to estrogenic ingredient is from about 20:1 to about 200:1.

2. The method of Claim 1 wherein ingredient is echinyl estradiol and ingredient is norethindrone acetate.

3. A method for treating menopausal symptoms associated with hormone deficiency in a postmenopausal female host comprising orally •administering to said host over a 28-day or 5 continuous sequence a fixed combination in the form a pharmaceutical composition for oral administration comprising: about 1-20 mcg ethinyl estradiol, and about 0.1-1.0 mg norethindrone acetate, wherein the ratio of norethindrone acetate to ethinyl estradiol in about 50:1 to about 200:1.

4. The method of Claim 3, wherein the composition comprises: 1-10 mcg ethinyl estradiol, and 0.1-1 mg noreChindrone acetate, wherein the ratio of norethindrone acetate to ethinyl estradiol is about 100:1 to about 200:1. -12- The method of Claim 4, wherein the composition comprises 1 mcg ethinyl estradiol and 0.2 mg norethindrone acetate.

6. The method of Claim 4, wherein the composition comprises 2.5 mcg ethinyl estradiol and 0.5 mg norethindrone acetate.

7. The method of Claim 4, wherein the composition comprises 5 mcg ethinyl estradiol and mg norethindrone acetate.

8. The method of Claim 4, wherein the composition comprises 10 mcg ethinyl estradiol and 1 mg norethindrone acetate.

9. A process for the manufacture of a pharmaceutical composition containing a fixed combination of norethindrone acetate and ethinyl estrldiol where the ratio of norethindrone acetate is from about 1:100 to 1:1000 and ethinyl estradiol from about 1:2000 to 1:100,000 the final tablet weight, which comprises dissolving in one vessel norethindrone acetate and ethinyl estradiol in alcohol; adding the solution onto a mixture of lactose and excipients in a blender; removing the alcohol by drying; adding incrementally other excipients; blending in a lubricant, and compressing the resulting mixture into tablets. A process for the manufacture of a pharmaceutical composition containing a fixed combination of norethindrone acetate and ethinyl estradiol -13- substantially as herein described with reference to the Example. DATED this 3rd Day of Novernber,1989 WIARNER-LAMBERT COMPANY Attorney: IAN ERNST Fellow Institute of Patent Attorneys of Austrr,* of SHE-LSTON WATERS CS CC e3 C 5