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Publication numberUS3409721 A
Publication typeGrant
Publication dateNov 5, 1968
Filing dateSep 15, 1967
Priority dateSep 15, 1967
Publication numberUS 3409721 A, US 3409721A, US-A-3409721, US3409721 A, US3409721A
InventorsApplezweig Norman
Original AssigneeNeomed Lab Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Oral dosage system effective to control the reproduction cycle
US 3409721 A
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Description  (OCR text may contain errors)

Nov. 5, 1968 N. APPLEZWEIG ORAL DOSAGE SYSTEM EFFECTIVE TO CONTROL THE REPRODUCTION CYCLE Filed Sept. 1.5, 1967 Noam/m H o/enwmj BY L n/M7 M/w United States Patent 3,409,721 ORAL DOSAGE SYSTEM EFFECTIVE TO CONTROL THE REPRODUCTION CYCLE Norman Applezweig, New York, N.Y., assignor to Neomed Laboratories, Inc., New York, N.Y., a corporation of New York Continuation-in part of application Ser. No. 296,838, July 18, 1963, which is a continuation-impart of application Ser. No. 110,927, May 18, 1961. This application Sept; 15, 1967, Ser. No. 671,917

9 Claims. (Cl. 424-239) ABSTRACT OF THE DISCLOSURE A method of administering drugs related to the menstrual cycle of a woman and a System for unalterably achieving a prescribed regimen related to the ovarian or menstrual cycle comprises a package containing successively available unit doses, doses 1 to 4 being placebos, doses 5 to 19 containing an estrogen and doses 20 to 24 containing an estrogen and/or a progestogen. Other unit dose combinations of estrogen and progestogens as well as systems with increased numbers of unit doses are provided.

The present application is a continuation-in-part of applicants co-pending application, Serial No. 296,888, filed July 18, 1963 now abandoned, which in turn was a continuation-in-part of applicants then co-pending application, Serial No. 110,927, filed May 18, 1961, now abandoned.

The present invention relates generally to medication dispensing systems and is particularly concerned with cyclic therapy sequential dosage regimens of drugs administered during and for their effects upon the ovarian or menstrual cycle and a simplified accurate device for unalterably dispensing medication to patients on sequential days on which each of the doses of the medication is to be taken in accordance with prescribed regimens and dosage schedules.

The inter-relationship of the gonadal steroids and the pituitary gonadotropins in the physiologic control of ovulation has long been recognized. However, the full eX- planation of the hypothalamic-pituitary-ovarian mechanisms involved in this relationship remains the subject of continued research in reproductive physiology. Nevertheless, the successful inhibition of ovulation by orally administered medication is now a generally accepted physiologic fact. The particular and unique character of the type of therapy required for this purpose is based upon the complicated inter-related and sequential nature of the physiologic and biochemical processes of the ovarian or menstrual cycle and the phenomenon of ovulation.

The administration of an estrogen during the first part of each treatment cycle inhibits ovulation through the suppression of pituitary gonadotropins. A progestogen is added to the estrogen during the last 5 days of the treatment cycle to insure more complete maturation and shedding of the endornetrium and to bring about the prompt occurrence of withdrawal bleeding. Unlike the progestogen-estrogen combination, the sequential administration of the hormones does not produce a hostile cervical mucus. However, during the period of estrogen administration the glandular portion of the endometrium is typical of an early-to-intermediate proliferative phase and the strome is moderately edematous. The period of estrogen-progestogen administration is marked by a progressive development of progestational changes characteristic of a secretory'endometrium. The sequential administration of these hormones produce neither the involutional changes leading to an atrophic endornetrium nor to the scanty with- "ice drawal bleeding that is seen in patients taking the progestogen-estrogen combinations. The brief course of progestogen administration during sequential therapy and the consistent pattern of the withdrawal bleeding are said to resemble more closely the events of normal menstrual cycle.

Because of the interdependent and sequential character of the changes observed during the ovarian cycle, it is essential for the attainment of therapeutic objectives, e.g., inhibition of ovulation, correction of menstrual disorders, or the like, that medications which are used for their specific effects upon the organs and processes involved in this cycle to be administered in specific sequence, at specific times and for specific durations which correspond with the particular phases which it is desired to influence or modify without significantly altering the normal periodicity of the normal adult female.

The sequential oral administration of the hormonal estrogen-progestogen hormonal agents is for a period of 20 to 24 days in each treatment cycle. Counting from the first day of withdrawal bleeding, beginning with the 5th day, the estrogenic component is taken in a single daily dose for 15 or 16 days, that is, from the 5th to the 20th or 21st day of the cycle. The mixture of the estrogen and the progestogen is then administered for the next 4 days. Withdrawal bleeding usually begins within 2 to 5 days after completion of the cycle of medication. Adjustment of this regimen may be made according to the individual patient needs.

Although these regimens have been determined by worldwide clinical study to be highly effective, the therapeutic methods employed possess a serious inherent limitation. It has been determined that a strict adherence to the treatment schedule is of critical importance. In virtually all instances of medication failures it has been determined that the failure of the patient to rigidly adhere to the prescribed therapeutic regimen was the determining factor. Thus, Dr. Joseph W. Goldzieher and Dr. Egris Rice- Wray, writing in their book, Oral ContraceptionMechanism and Management (Charles C. Thomas, Chicago, Ill., 1966), state that:

Some investigators, well aware of the diflicnlties of taking medication 20 days per month, month after month without error, and equally well aware of the frailty of human memory, state flatly that they have never seen a medication failure. It is reasonable to assume, however, that no medication is perfect, even when taken exactly as directed, and that sometimes, for some reason, true medication failures will occur. (Page 39.)

for the vast majority of failures with oral contraceptives are obvious improper-use failures (Page 39.)

The price that must be paid for such results is rigid adherence to the schedule of tablet intake. (Page 40.)

The incidence of therapeutic failure associated with the omission of medication is of special interest. A large clinical study reported that rate of therapeutic failure was nearly SO-times higher when 1 to 5 tablet omissions per cycle were recorded than in those instances where no tablet omission was admitted. Even in highly educated patients in advanced cultures the remembering to take the pill each day and the counting of days from the beginning of menstruation and the days following the discontinuance of the pill requires not only the following of a calendar, but also the remembering of the responsibility of each day for 20 days, while disregarding the responsibility for 7 or 8 days. This intermittent procedure is taxing and inherently fraught with failure because of the discontinuity of the regimen.

It is, therefore, a principal object of the present invention to provide by objective means the elimination of this inherent failure of the present therapeutic regimens through an improved medication regimen and dispensing system. Another object of the present invention is to provide an improved system for dispensing prescribed doses of endocrine active and inactive medication in a predetermined unalterable sequence which eliminiates reliance on memory, thereby avoiding the iatrogenic therapeutic failure. Still another object of the present invention is to provide an improved disposable dispensing device of the above nature characterized by its simplicity of accurate use, even by those who are illiterate, and its low cost and convenience. A further object of the present invention is to provide an improved sequential dosage dispensing system which may be put up by conventional automatic packaging equipment.

The above and other objects of the present invention will be apparent from a reading of the following description taken in conjunction with the accompanying drawing wherein:

FIGURE 1 is a top plan fragmentary view of a medication dispensing package in accordance with the present invention, illustrated in an extended position;

FIGURE 2 is a sectional view taken along line 2-2 in FIGURE 1; and

FIGURE 3 is an end view of the partially depleted package in rolled form.

The invention finds its preferred embodiment in a method of transparent strip film or foil packaging in common use for pharmaceutical packaging which provides a separate sealed pocket for each dose unit, e.g., tablets, capsules, suppositories, powders, etc. It is proposed to have a continuous strip of such separate and sealed pockets attached to and contiguous with each other, the line of demarkation between the pockets being a series of perforations which afford a ready means of detaching an individual dose of the medication. It is intended that each such individual dose be taken as the daily dose and that the daily doses be taken as hereinafter indicated.

In view of the accuracy required in the timing and sequence of administration of endocrine active medications in relation to various phases of the ovarian or menstrual cycle, it is of the utmost importance to avoid confusion on the part of the patient in attempting to carry out the physicians instructions. Since the method and device which constitute this invention eliminates the need for reliance on memory or written instructions and obviate the possibility of confusion on the part of the patient, it not only facilitates accurate compliance with the prescribed therapeutic regimen and dosage schedule, but it also helps to insure patient cooperation in maintaining the therapeutic regimen.

Referring now to the drawing which illustrates a preferred embodiment of the present invention, the reference numeral generally designates the improved dispensing system or package which includes a plurality of envelopes 11 connected in end-to-end relation to form an elongated strip. Each of the envelopes is completely sealed along its respective peripheral border 12 and successive envelopes 11 are delineated from each other by intermediate lines of Weakness 13 which may be score lines or lines of perforations and facilitate the detachment of successive envelopes. The envelopes 11 are formed of a transparent frangible material such as cellophane, polyethylene, or the like, and are preferably of a heat-sealable nature.

Disposed in each of the envelopes 11 is a medication dosage 14 which may be in the form of a pill, tablet, capsule, suppository, powder or the like. The formulation of the tablets 14 in the successive envelopes 11 is in accordance with the sequence in which the are to be taken or administered, and the respective tablets are suitably identified by coloring the tablets according to their composition or by providing other easily discernible suitable means of identification in association with the respective tablets as, for example, distinctive shapes. In

its preferred form, the strip 10 contains 24 successive envelopes 11 which may be easily rolled into a compact spiral package 16, as illustrated in FIGURE 3 of the drawing, and the envelopes 11 may be detached in sequence from the outer end of the package 16. v

The strips 10 may be produced by conventional automatic packaging equipment in the known manner by bringing two bands of heat-scalable material into superimposition, sandwiching between them in spaced relationship the tablets 14 in the desired sequence. The bands are heat-sealed to each other along the envelope borders 12 to individually house the tablets 14 and the lines of weakness 13 are impressed between successive envelopes 11.

As a component feature of the present invention, it is proposed that color may be utilized as an indicator of the particular medication to be taken by the patient on specific days. The color may be incorporated in the coating or included as an integral part of the particular dosage form of the drug to be administered, e.g., tablets, capsules, powders, etc., the color being visible to the patient through the transparent film comprising the individual pockets above referred to. It is further proposed that varied colors may be used in a sequence to correspond with certain phases of the menstrual or ovarian cycle, i.e., menstruation, proliferative and secretory phases. For example, the first 4 tablets (or another preferred dosage form) to be taken by the patient may be colored red, the next 15 tablets may be white, and the last 5 tablets may be yellow. Such distribution of color is used for illustrative purposes only and is not intended as a limitation of the colors which may be utilized nor on their sequential arrangement, but merely to illustrate the principle involved when using color in this invention. The use of the color coating serves an additional purpose in not only describing the phase of the cycle, but also to disclose the nature of the medication being administered at any given time interval of the cycle. A combination of the color coating and the sequential dosage administering device provides a significant advantage to both the patient and the physician in monitoring the results of therapy. In view of the complex chemical nomenclature and the confusing similarity among the various names adopted for the particular medications, the color coating provides a ready means of communicating to the physician, the exact composition and dosage of the medication taken on a particular day. Through this simplified means of communication between the patient and the physician, a more accurate and sensitive control of therapy results even when large numbers of illiterate population are being treated.

Should it be preferred to introduce still another means of identifying the sequence of medication to be administered to correspond with particular phases of the menstrual or ovarian cycle, then special shapes may be assigned to particular medication to be administered at articular phases of the cycle. The sequential nature of the medication to be administered may thereby be easily maintained and identified. For example, the first 4 tablets may be square-shaped and the next 15 tablets the conventional round shape, whereas the last 5 tablets may be triangularshaped. Similar shaping of a unit dosage form may be accomplished with capsules, utilizing the oval or eggshaped capsule as one identifying characteristic whereas the conventional elongated or tubular capsule serving as an alternate distinguishing shape. Under certain conditions it might be desirable to combine both the color coding and the distinctive shape of the unit dosage form to provide still more discernible means of identification and sequential arrangement of medication.

When it is desired to utilize the medication dispensing system and device of the present invention, then the appropriate tablets or capsules or other unit dosage form containing the particular medication of the prescribed regimen and dosage schedule to be administered in a pre-determined sequential order, are placed in the envelopes or pockets prepared substantially as described above, to provide a therapeutic course for a period of 24 days of the conventional 28 day cycle. The administration of the first tablet is begun on the first day of the menstrual period. The first 4 tablets are intended to correspond with the menstrual phase and for this period the tablets are inactive or placebo dosage forms. Beginning on day 5, that is on the 5th day after the onset of bleeding, irrespective of whether or not the menstrual flow has ceased, the patient takes active medication until day 19. Such active medication to be administered during this period is estrogenic in nature, and the naturally occurring estrogenic hormonal agents or their chemically altered derivatives or the chemically synthetic estrogenic compounds may be used for this purpose.

The most potent secretory hormonal product of the ovary is 17-estradiol. This estrogenic compound is readily oxidized in the body to estrone which, in turn, is hydrated to estriol. These transformations take place mainly in the liver, where there is a free interconversion between estrone and estradiol. In order to make the natural estrogenic compounds effective after oral administration, certain chemical alterations have been accomplished which protect these compounds from inactivation by the liver. Ethinyl estradiol is an example of such chemical alteration of the natural estrogenic compound and is one of the most highly potent estrogens known. Examples of other chemically altered estrogenic compounds are esterdiol benzoate, estradiol cyclopentylpropionate, estradiol dipropionate and piperazine-estrone sulfate.

While the naturally occurring estrogenic compounds and their chemically altered derivatives are steroidal in chemical composition, certain non-steroidal synthetic chemical compounds have been found to possess estrogenic activity. The most potent of this latter group of compounds is diethylstilbestrol. Closely related congeners, including hexestrol, dienesterol, benzesterol, promethesterol dipropionate, methallanstril and chlorotrianisene, as well as certain of their ether and ester derivatives, are also effective therapeutically as active estrogenic compounds. Each of the aforenamed compounds possesses its own particular degree of eflectiveness and has certain advantages over the others so that the particular estrogenic compound to be used in a particular therapeutic regimen will depend upon the specific needs of the patient.

From day 20 to day 24, the medication to be administered is a combination of an estrogen and a progestogen. The hormonal compound, progesterone, is secreted by the ovary mainly from the corpus luteum during the second half of the menstrual cycle. Secretion of the progestogen actually begins from the follicle that is destined to release an ovum just before ovulation. Abrupt termination of the release of progesterone from the corpus luteum, at the end of the cycle is the main determinant of the onset of menstruation. Thus the sequence of medication, that is, the following of the period of estrogen administration with a combination of estrogen and progestogen, is intended to physiologically exhaust the therapeutic cycle and bleeding usually starts within a period of 2 to 5 days after the taking of the last therapeutic dose.

A number of chemically altered synthetic steroidal compounds having progestational activity are now known. Basically these are of two general classes of compounds: (a) those compounds related to 17-alpha-hydroxyprogesterone, and (b) certain derivatives of testosterone. Although progesterone itself is relatively minimally effective when taken orally, the chemically altered derivatives have been shown to be highly active when taken by mouth. Examples of the progesterone derivatives which may be utilized are, medroxyprogesterone acetate and didrogesterone. Examples of the group of testosterone derivatives which have progestational activity are, ethisterone, norethindrone, norethynodrel, ethynodiol diacetate, diamethisterone and chlormadinone acetate.

With the onset of menstruation, a new cycle of therapeutic administration is initiated and the administration of the medicaments in the same sequence as before is repeated. The continued and repetitive administration of the therapeutic agents in the sequence described may be maintained for as long as is desired without detriment to the patient. Since a physiologic state is maintained by the sequential administration of these hormonal agents there is no problem of an adaptation developing nor is there a toxic threat to the patient.

The critical determinate for achieving and maintaining therapeutic success is the rigid adherence to the sequential administration of the hormonal compounds without interruption or dosage lapse. By means of the present invention, this inherent limitation of the older methods is avoided and therapeutic success may be assured. The patient is not challenged to remember the nature and type of medication to be taken on any particular day since the habit pattern of taking one tablet each day becomes re-enforced. The device of the present invention which provides an unalterable sequential administration of proper medication during a 28-day cycle does not depend upon either patient judgment or memory. This is particularly advantageous when therapy is to be continued on an uninterrupted basis for two or more cycles. In this instance, furthermore, a variation may be introduced in the design of the strip containing the medication to be administered during a cycle, as described above, by aflixing two or more strips of medication in a continued series to provide sequential medication for a period of 28 days and for as long a duration as may be desired.

When continuous sequential cyclic therapy is required, the patient proceeds to take the next series of 28 tablets in proper sequence without break or interval by beginning the administration of the placebo medication immediately after the conclusion of the intake of active estrogenprogestogen medication. The placebo tablets consisting of physiologically and therapeutically inert substances provide the continuity during the period of the abrupt sensation of therapy to allow for menstruation. The adminstration of the active compounds is begun once again, as in the previous cycle, on day 5 irrespective of whether menstruation has begun or terminated. The major advantage of this variation resides in the elimination of doubt on the part of the patient as to the correct day for the initiation of the second course of cyclic therapy. If there is uncertainty as to the first day of menstruation or if the menstrual flow is interrupted for one or more days, the scientifically uninformed layman would have difiiculty in making the proper judgment for continued administration of the drug. Since such cyclic therapy is intended for mass population use, where the accessibility to scientific medical advice may not be readily available, patient doubt may lead to therapeutic failure resulting from the omission of medication.

The system for cyclic therapy provided by the present invention permits the obtainment of certain therapeutic objectives without the danger of failure to understand and comply with instructions. This is of the utmost importance since dosage regimens specially designed for use in the prevention and treatment of certain pathologic states may be readily administered to all types of patients at the appropriate and critical times in the ovarian cycle without dependence upon memory or understanding of the therapy involved. If the doses of such medication are not used in their proper sequence, the patient may be unnecessarily exposed to the dangers of the respective conditions since at the same time the patient is abandoning other forms of treatment by relying on the prescribed course of medication. On the other hand, failure to properly use the medication intended for cyclic hormonal therapy may also result in an abnormal menstrual cycle, excessive bleeding and may even interfere with normal physiology of the body.

A further advantage of this invention is that it permits the development of an inexpensive treatment regimen by allowing certain of the ingredients to be withheld until those days when they are absolutely needed to exert their pharmacologic effect in the physiologic cycle. Thus, the patient need not purchase a variety of different medications and to remember to take certain of these medications on special days nor is the patient subjected to the cost of purchasing excess medication beyond that which is required for particular course of therapy prescribed for her.

While a common use of sequential therapy has been for the control of ovulation, there are a number of other pathologic states which is amenable to cyclic hormonal treatment and which requires special sequential therapy. Such conditions are functional uterine bleeding, dysmenorrhea, pre-menstrual tension, endometriosis, threatened and habitual abortion, the evaluation of ovarian function and diagnosis of pregnancy.

Functional uterine bleeding is a common disorder characterized by grossly irregular menstrual cycles with episodes of prolonged and sometime exsanguinating hemorrhage. While this condition may arise at any time during the menstrual life of the patient, it is more frequently observed in young girls before regular ovulatory cycles are established and again with the approach of the menopause when fibroids is the frequent diagnosis. The endocrine basis for functional uterine bleeding is the steady, early cycling action of estrogen uninterrupted by the action of progesterone. The immediate problem in therapy is to stop the bleeding, and the long range aim is to regulate the cycle. Both estrogens and androgens have been used effectively but a progrestogen is specific for this condition. The treatment regimen is to administer small doses of the progestogen for four days and then to continue a maintenance dosage for a period of one to two weeks. Withdrawal bleeding at the end of the treatment will usually result in a normal menstrual flow. The optimal form of therapy is to combine a progestogen with an estrogen.

To prevent reoccurrence of functional bleeding, hormonal therapy is instituted and the medication is prescribed in single doses for a period of five days at monthly intervals beginning 20 to 25 days after the induced period, Regular menstrual periods can thus be induced as long as one chooses. This allows time to elapse for the young patient to mature; for the pre-menopausal patient to age, and for many of the patients to recover spontaneously from whatever caused the upset. Furthermore, it is well recognized that cyclic therapy may exert a favorable effect upon the establishment of a normal hormonal interplay between the ovary and the pituitary glands. By means of the present invention, reliance on memory is avoided. Cyclic therapeutic medication regimens may be prepared to contain active medication and placebo so that the patient receives the necessary hormonal medication for the exact five day period at the proper time interval of the cycle, while the intervening doses being placebo or inactive medication. Sufficient therapeutic sequential medication may be provided for as many cycles as is desired and in this manner, full and proper control of the menstrual irregularity is achieved.

The relief of dysmenorrhea by inhibiting ovulation is an important advance in the treatment of this disease. The treatment of dysmenorrhea is rendered difiicult by the delay in onset of withdrawal bleeding and if estrogen is not prescribed until this bleeding stops, some 10 days may elapse and ovulation in the next cycle will not be under therapeutic control. A progestogen is, therefore, used to advantage either with the estrogen from days to 25 of the cycle or added to the estrogen during the last 5 days of the cycle. In either case, menstruation is prompt and the treatment is resumed after a 5-day interval during which no active medication is prescribed. The therapeutic cycle must be repeated for a number of times in order to achieve a lasting effect and in many instances the cycle of sequential therapy may be repeated as long as is necessary even extending over a period of years. It is in the therapy of pathology such as this one that the method of the present invention is most advantageous. Through the use of methods described herein, there is no need to rely on memory to have sufficient drug available at the required time or to take the medication when in dicated. This is of particular advantage when repeated cyclic therapy is indicated since the omission of medication may negate the beneficial effects of therapy achieved in previous cycles.

Closely allied with the treatment of dysmenorrhea is the severe pain accompanying menstruation in the presence of endometriosis. In many instances, the suppression of ovulation with an estrogen is followed by a painless, estrogen-withdrawal period. In certain severe cases of endometriosis, the major problem becomes the development of painful extra-uterine masses and the treatment is aimed at causing regression of the ectopic endometrial growths. Prolonged treatment, designed to prevent menstruation for many months, relieves the major difficulty by preventing bleeding into these endometrial masses. Through the use of proestogens and estrogens, the actual legression of the endometrial growths has been observed. For this therapeutic regimen, recent evidence has shown that the use of an oral progestogen with low estrogenic potency or with minimal or no added estrogen causes the maximal regression. In the course of practice, an induced amenorrhea for intervals as long as 30 months is achieved by the administration of first a progestogen and then an estrogen. After the succession of therapy there were no adverse effects upon subsequent cycles and ovulation. Because of the prolonged period during which sequential cyclic therapy is required, the method of the present invention serves a particular advantageous function when used in the treatment of dysmenorrhea.

Pre-menstrual tension is an ill-defined condition of uncertain etiology. In general, it has been determined that a psychogenic pattern of symptomatology appears during the luteal phase of the ovarian cycle and pre-menstrual tension manifests itself as an exaggeration of the normal irritability of the patient. Despite the relationship between the onset of symptomatology and luteal activity, the administration of a progestogen has been found to be effective when given during the last 10 days preceding the onset of menstruation. This necessity of counting backward is a particularly hazardous one in view of the need to maintain careful records and the well known occurrence of a faulty memory. The omission of medication during the critical period results in a therapeutic failure thereby increasing the morbidity of the patient and since the beneficial effects of therapy are delayed for months to come, a complete abdication of therapy by the patient refusing to cooperate with the regimen may result. By means of the present method, for administering sequential therapy describing the subject invention, patient cooperation is enhanced and the relief of symptomatology may be achieved at a significantly earlier time. The need to count back is avoided and medication is begun at the proper time interval of the cycle. The patient obtains the full benefit of the medication and therapeutic success is thereby enhanced.

In combating the problem of threatened and habitual abortion, it is now well established that the administration of a progestogen is of value. Of critical importance in determining the value of therapy is the reliance upon a rigid adherence to the administration of the hormonal component. Thus, a method for the administration of these hormonal agents which does not rely upon memory and is simple for the patient to follow, will predispose toward a more favorable outcome.

The use of sequential therapy of hormonal agents is also of an advantage in evaluating ovarium function and in the diagnosis of pregnancy. In diagnosing the etiology of amenorrhea, some indication of the production of estrogen from the ovary may be derived from the response to the administration of progesterone or a non-estrogenic progestogen to determine whether withdrawal is followed by menstrual bleeding. When bleeding does not take place, it is presumed that secretion of estrogen is at a minimum level.

If a missed period occurs in an individual who has a reasonably normal menstrual cycle pattern, administra tion of a progestogen may be used as a test for pregnancy. In this instance, the orally active progestin is combined with an estrogen to be administered for a period of time and the occurrence of withdrawal bleeding at the termination of therapy is taken as proof that the patient is not pregnant. If the patient is pregnant, then withdrawal bleeding will not occur. This diagnostic technique has been found to be safe to both the fetus and the mother as well as being a reliable test. A particular advantage of this method is the normalizing effect on the menstrual cycle of a woman in the event that she is not pregnant. This diagnostic method has still another advantage in that it does not depend upon the need for an animal laboratory and trained technicians and therefore results in a lowered cost as well as being a test suitable for application to large numbers of people in developing areas.

The aforegoing discussion readily demonstrates the applicability and utility of the herein described methods for dispensing medication in a sequential order in accord with a previously determined regimen and dosage schedule. The following examples are given merely by the way of illustration of the preferred embodiments of this invention and it is not intended to be limited thereby.

EXAMPLE 1 When it is desired to administer a course of therapy involving a sequential dosage regimen, then a transparent strip film of foil packaging such as is in common use for pharmaceutical packaging is prepared which provides separate sealed pockets for each dosage unit, e.g., tablets, capsules, suppositories, powders, etc. and are of sufficient length to provide a continuous strip of 24 such separate and sealed pockets attached to and contiguous with each other. The line of demarkation between each of said pockets being a series of perforations which afford a ready means of detaching an individual dose of medication.

Into pockets number 1 to 4, inclusive, are placed inactive placebo agents formulated into the preferred unit dosage form, that is, tablets, capsules, suppositories, powders, etc.; pockets numbered 5 to 19, inclusive, contain active medication in unit dosage form, as for example, a therapeutically sufficient quantity of an estrogen, and pockets, numbered 20 to 24, inclusive, contain a combination of a therapeutically sufficient quantity of an estrogen and a therapeutically sufficient quantity of a progestogen, formulated in unit dosage form.

For purposes of color coding, the dosage form in pock-. ets numbered 1 to 4, inclusive, may be colored red; while those in pockets numbered 5 to 19, inclusive, may be colored white, and the units in pockets numbered 20 to 24, inclusive, may be colored yellow. The aforesaid colors are used only by way of illustration and any combination of distinctive colors may be used. The color may be applied to the finished dosage form as a coating or may be incorporated directly into the mixture of materials during manufacture of the appropriate dosage form.

A further method of distinguishing the particular medication used in therapy is to vary the shape of the unit dosage form, thus when tablets are inserted in pockets 1 to 4, inclusive, these may be square-shaped and the tablets in pockets 5 to 19, inclusive, may be round in shape, while the tablets in pockets 20 to 24, inclusive, may be triangular-shaped. Should capsules be utilized as the preferred dosage form, then both color and distinctive shape may be employed in the manner described above, for example, a colored capsule shell may be used and/or an elongated or a football-shaped capsule shape adopted for the respective medicaments contained therein.

Should it be desired to repeat a course of therapy, then two or more such strips as is described above, may be connected in a contiguous and serial manner to provide continued therapy for as many ovarian cycles as is required. However, when two or more strips are aflixed in a continuous series, than each film strip is prepared to contain 28 pockets and pockets number 25 to 28 contain placebo medication to correspond to the period of withdrawal bleedings.

EXAMPLE 2 In preparing the unit dosage forms for the respective pockets of the film strip described in Example 1, above, the placebo unit dosage form may be prepared from any inert pharmaceutically acceptable substance as, for example, corn starch, potato starch, dextrin, dextrose, glucose, sucrose, lactose and kaolin.

When it is required to utilize an estrogen as the active medicament, then such estrogenic compounds as estradiol, 0.1 mg. to 0.5 mg.; est-radi'ol benzoate, 0.1 mg. to 5 mg.; ethinyl estradiol, 20 meg. to 500 mcg.; ethinyl estradiol-3 methyl ether, 20 meg. to 500 mcg.; estrone 0.2 mg. to 1 mg.; piperazine estrone sulfate, 1 mg. to 5 mg.; estriol, 0.06 mg. to 0.12 mg.; and conjugated estrogenic substances, 1 mg. to 20 mg., may be utilized in the usual dosage range set forth.

The synthetic estrogenic compounds may also be used when estrogen therapy is required and examples of synthetic estrogenic substances which may be used together with their average dosage are benzestrol, 0.5 mg. to 5 mg.; chlorotrianisene, 12 mg. to 50 mg.; dienestrol, 0.1 mg. to 15 mg.; diethylstilbestrol, 0.25 mg. to 15 mg.; hexestrol, 0.2 mg. to 3 mg.; methallenestril, 6 mg. to 20 mg.; and promethestrol dipropionate, 1 mg. to 3 mg.

Any of the estrogenic substances described above may be used singly or in combination and the naturally derived estrogenic compounds may be mixed with the synthetic estrogenic compounds to achieve a particular hormonal effect suitable for the particular patient.

When it is desired to administer an estrogenic compound in combination with a progestogen compound then any of the aforesaid estrogenic agents or mixtures of these may be used. Examples of progestogen compounds which may be combined with an estrogen are ethisterone, 5 to mg.; medroxyprogesterone acetate, 2.5 mg. to 5 mg.; norethindrone, 10 mg. to 30 mg.; progesterone, 10 mg. to 50 mg.; norethinodrel, 2.5 mg. to 10 mg.; ethynodiol diacetate, 1 mg. to 5 mg.; dydrogesterone, 2 mg. to 10 mg.; chlormadinone acetate, 2 mg. to 10 mg.; dimethisterone, 1 mg. to 10 mg. The dose range set forth for the respective progestogens is the respective usually recommended dose and higher or lower doses may be used. When the progestogen is combined with an estrogen, the dosage range of the estrogen may be used as described above, or it may be varied according to the patients needs.

The sequence in which the medication is arranged within the film strip will vary with the intended purpose for which the medication is prescribed.

EXAMPLE 3 When it is desired to utilize the present method for administering sequential hormonal therapy for the control of ovulation, then a transparent film strip is prepared as described above to contain 24 individual pockets. This will provide a. single course of therapy for one ovarian cycle having an average 28 days duration. In each of pockets 1 to 4, inclusive, is placed an inactive placebo tablet, comprising of corn starch, potato starch, dextrine, lactose, or any of the placebo compounds prescribed in Example 2 above.

In each of pockets 5 to 19, inclusive, is placed a tablet of an estrogenic compound as, for example, ethinyl estradiol, each tablet containing 0.05 mg. of the active ingredient. Other estrogenic compounds as described in Example 2 above, may be utilized in therapeutically equivalent quantities in place of the ethinyl estradiol. In each of pockets 20 to 24, inclusive, is placed a tablet containing a mixture of an estrogen as, for example, ethinyl estradiol, 0.05 mg., and a progestogen, as, for example, ethisterone, 25 mg. In place of the ethinyl estradiol may be substituted any of the estrogenic compounds of Example 2, in therapeutically equally potent quantities, and in place of the ethisterone may be substituted any of the progestogen compounds described in Example 2, in therapeutically equivalent quantities. The patient is instructed to begin therapy with the first day of bleeding and to take one tablet each day. After theconclusion of a course of therapy, withdrawal bleeding will occur about two days after the last dose.

EXAMPLE 4 The combination of an estrogen and a progestogen may be utilized throughout the developing phases of the ovarian cycle and in this instance, the film strip is prepared as described above and pockets 1 to 4, inclusive, contain the inactive placebo. The tablets to be inserted in pockets to 24, inclusive, contain a combination of the estrogen and the progestogen. In this instance, a preferred formulation would be a tablet containing ethinyl estradiol, 0.05 mg. and ethisterone, 25 mg. The patient is instructed to begin medication on the first day of bleeding and to take one tablet each day. When the entire course of medication has been administered, the withdrawal bleeding will begin approximately two days after the last dose.

In place of the estrogen substance, ethinyl estradiol, may be substituted in therapeutically equivalent quantities any of the estrogenic compounds described in Example 2, and for the progestogen compound, ethisterone, there may be substituted any of the progestogen compounds described in Example 2, above, in therapeutically equivalent quantities.

EXAMPLE 5 The synthetic estrogenic compounds are utilized in the same manner as the naturally occurring substances and these may be used alone or in combination with a progestogen. Should it be desired to utilize the synthetic estrogens as the basis for a cyclic ovulation control, then tablets 1 to 4 would continue to be inactive placebo, while tablets 5 to 19, inclusive, would each contain diethylstilbestrol, 2 mg, and tablets to 24 would contain the combination of diethylstilbestrol, 2 mg., and ethisterone, mg.

Another illustration of the use of the synthetic extrogenic compounds is to prepare a film strip so that tablets 1 to 4, inclusive, contain the inactive placebo while tablets 5 to 24 contain the combination of diethylstilbestrol, 2 mg. and ethisterone, 25 mg.

EXAMPLE 6 Should it be desired to control ovulation for more than one cycle, then two or more film strips are attached in a contiguous manner, so as to provide the continued course of therapy for as long a duration as it is required. When such sequential tablet administration is required for more than one menstrual period, then an additional 4 pockets are created in the film strip to provide a daily dose of medication for each of the 28 days of the cycle. Thus, the pockets numbered 1 to 4, inclusive, would contain the inactive placebo substance as described above and tablets 5 to 19, inclusive, would contain an estrogenic substance, as for example, piperazine estrone sulfate, 2.5 mg, and the tablets for pockets 20 to 24, inclusive, would contain the combination of piperazine estrone sulfate, 2.5 mg., and hydroxyprogesterone acetate, 25 mg, while the newly added pockets numbered 25 to 28, inclusive, would contain the inactive placebo medication. The latter four days (25-28) provide for the menstrual interval which occurs after the last dose. In this manner, the entire 28-day period of one ovarian cycle is accounted for and is under direct therapeutic control at all times. The medication for the next cycle is affixed to the previous film strip and begins again with the placebo tablets of pockets 1 to 4, as the sequential distribution of medication is repeated. As many such film strips containing the required sequential medica-v tion may be affixed in continuous series, as is desired.

Other estrogenic substances as described in Example 2 above, may be substituted in therapeutically equivalent amounts for the estrogenic compound, piperazine estrone sulfate, and other progestogen substances as described in Example 2 above, may be substituted for the hydroxyprogesterone acetate in therapeutically equivalent amounts.

When it is desired to use combined estrogen-progestogen therapy for sequential administration for more than one cycle, then the film strip is prepared so that pockets 1 to 4, inclusive, contain an inactive placebo, and pockets 5 to 24 contain a combination of estrogen and progestogen, as for example, a tablet comprising norethindrone acetate, 10 mg, and ethinyl estradiol-3-methyl ether, 0.06 mg, while pockets numbered 25 to 28, inclusive,.contain an inactive placebo. Such strips are afiixed in a continuous series so as to provide sequential therapy for as many cycles as is desired. Any of the estrogens described in Ex ample 2, may be substituted for the ethinyl estradiol-3- methyl ether in therapeutically equivalent amounts and any of the progestogens of Example 2 may be substituted for the norethindrone.

EXAMPLE 7 The medication utilized in the Examples 1 to 6 above, is set forth in the dosage form of a tablet but any other pharmaceutically accepted solid dosage form, as for example, pills, capsules, suppositories and powders, may be utilized in .the method of the present invention to achieve the desired therapeutic effect. The preference of the specific dosage form will depend upon needs of the patient.

The particular dosage form may be colored to provide a distinctive identity to its contents. Such colors as are preferred may be used to designate a particular medication as well as the sequence for its administration. Appropriately shaped unit dosage forms may also be utilized to identify the nature of the medication contained in a particular preparation, as well as the sequence for its administration. Thus, square-shaped tablets may be alternated with round or triangular-shaped tablets and the oval-shaped capsules may be utilized in sequence with the conventional elongated capsules. Colored coated granules may be utilized as means of identifying the medication in powder dosage forms.

Although the medication may be administered in differing unit dosage forms, the concentration of active ingredient per unit dose remains the same. Thus, there is no difference in concentration of active ingredient utilized when either the tablet, pill, capsule, suppository, or powder is used.

EXAMPLE 8 When it is desired to treat functional uterine bleeding, then a film strip may be prepared as described in Example 1. In each of pockets 1 to 4, is placed a tablet containing 15 mg. of norethindrone and in each of pockets 5 to 19, is placed a tablet of norethindrone, containing 7.5 mg. of norethindrone, while pockets 20 to 24 contain placebo medication. A single course of therapy will generally provide excellent symptomatic relief, but repeated cyclic therapy is indicated in most instances and this may be readily obtained by providing a continuous film strip as described in Example 6 in sequential arrangement for the first strip to provide therapy for each of the 28 days of the menstrual cycle. Thus, after the bleeding has been interrupted and when normal withdrawal bleeding ,is instituted, the maintenance therapy cycle is begun. For continued sequential cyclic therapy, a film strip containing 28 pockets is prepared and placebo medication is placed in pockets numbered 1 through 19; pockets 20 to 25 contain norethindrone, 10 mg, and pockets 26 to 28 contain placebo medication. Two or more such strips may be afiixed in a contiguous manner to provide therapy for chooses.

and pockets numbered 1 menstrual periods can be induced for as long as one ,Any of the progestogen agents described Example 2, may be used in placeof, the norethindrone and combination s of estrogen and p rogestogen may also be employed in the manner described above, if desired.

' EXAMPLE 9 When it is desired to providcrelief for the patient with dysmenorrhea by inhibiting ovulation, thena progestogen and an estrogen combined. in a single unit dosage form may be administered in a sequential manner according to the preference of the physician and the need of patient. The film strip is prepared as is described in Example 1,

I l to 4 contain placebo medication. Pockets to, 24 contain tablets each containing chlormadinone acetate, 2 meg, and mestranol, 80 mcg. Withdrawal bleeding occurs promptly after the administration of the last dose. Should it be desired to vary the administration of the progestogen, then pockets 1 to 4 con- ,tain the inactive placebo and pockets 5 to 19 contain tablets each containing mestranol, 80 mcg., while pockets 20 to 24 contain tablets, each containing chlorrn'adinone acetate, 2 mcg.,. and mestranol, 80 mcg.

Should it be desired to continue medication for more than one cycle, then four additional pockets to provide for 28-d ay therapy are added to the film strip, and pockets 25 to 28, inclusive, contain inactive placebo medication. Two or more such strips are afiixed in series to provide continued therapy.

EXAMPLE When it is desired to suppress ovulation in the presence EXAMPLE 11 When it is'desired to control the symptoms of premenstrual tension, then a 'film strip is prepared as described above, to contain 24 pockets. Pockets numbered 1 to 14 contain inactive placebo medication and pockets 15 through 24'contain therapeutically active tablets, each containing norethindrone acetate, 10 mg. The course of therapy for a cycle is begun with the first day of bleeding.

In the course of the therapy of pre-menstrual tension it may, also be desired to control ovulation for one-cycle, in which case the film strip is prepared as described in Examples 1 through 6, and this strip is followed by a film strip containing placebo medication in pockets 1 to 10 and the progestogen compound in pockets 15 to 24. When such sequential therapy is repeated, it is usually not necessary to control ovulation a second time and only the progestogen is administered in successive cycles so that pockets 25 to 28 contain placebo medication.

EXAMPLE 12 When it is desired to control ovulation for prolonged periods, utilizing combined estrogen and progestogen medication, then a film strip is prepared as described above to contain 28 pockets in each unit. The strips are affixed in a contiguous manner to provide cyclic sequential therapy for as long a period as is desired. Pockets 1 to 4, inclusive, contain inactive placebo while in pockets 5 to 24, or 25 inclusive, is placed tablets each containing norethynodrel, 10 mg., (a progestogen) and mestranol, 0.15 mg., (an estrogen) and pockets numbered 24 or 25 to 28, inclusive, contain inactive placebo.

It should be noted that although the seven or eight placebos are distributed at the beginning and end of the sequence of hormonally active doses they may be located in sequence entirely at the beginning or end of the sequence of hormonally active doses. When the placebos event the continuation of the medication sequence provides continued protection during the full cycle.

In place of the progestogen compound (norethynodrel) and the estrogen (mestranol), which are described above, there may be substituted the following combinations of progestogen and estrogen compounds in the amounts set forth for each compound: V Y

Progestogen: Mg. Norethynodrel 5 Norethynodrel 2.5 Norethindrone 2 Norethindrone acetate 2.5

" Medroxyprogesterone acetate -10 Medroxyprogesterone acetate 5 'Medroxyprogesterone acetate 2 Ethynodiol diacetate 2 Ethynodiol diacetate A 1 6-dehydromedroxyprogesterone acetate 4 Estrogen: I Mg. Mestranol 0.075 Mestranol 0.1 Mestranol 0.1 Ethinyl estradiol 0.05 Ethinyl estradiol 0.05 Ethinyl estradiol 0.05 Ethinyl estradiol 0.02 Mestranol 0.1 Mestranol 0. 1 Ethinyl estradiol 0.05

While there have been illustrated and described preferred embodiments of the present invention, it is apparent that numerous alterations, omissions and additions may be made without departing from the spirit thereof. Although a specific type of package has been described and illustrated for effecting the sequential dispensing of the unit doses in accordance with the predetermined regimen, other sequential dispensing devices may be effectively employed. Examples of such devices are described and illustrated in' US. patents, No. 3,143,207 granted Aug. 4, 1964, No. 3,199,489 granted Aug. 10, 1965, No. 3,270,915 granted Sept. 6, 1966, No. 3,276,573, granted Oct. 4, 1966, No. 3,278,010, granted Oct. 11, 1966, and No. 3,283,885, granted Nov; 8, 1966, No.-2,652,149 granted September 15, 1953, No. 2,953,242 granted September 20, 1960, No. 3,057,473 granted October 9, 1962, No. 3,099,352 granted July 30, 1963, No. 3,182,791 granted May 11, 1965, No. 3,225,913 granted December 28, 1965, No. 3,227,127 granted January 4, 1966, and No. 3,261, 455 granted July 19, 1966.

While there have been described and illustrated preferred embodiments of the present invention, it is apparent that numerous alterations, omissions and additions may be made without departing from the spirit thereof.

1 claim:

1. In the method of providing an ovarian or menstrual cycle oral dosage regimen effective in the control of ovulation wherein drugs are administered orally to women during and for their effects upon their ovarlan or menstrual cycle as a single oral dosage daily during a consecutive sequence of at least 24 days, the improvement which consists essentially of:

(a) administering orally, once daily for four days,

starting on the first day of menstruation, endocrineinac-tive dosages or placebos during the menstrual phase which lasts four to five days in the average woman; and

(b) administering orally, once daily, in an uninterrupted consecutive sequence from the 5th day to the 19th day following the first day of menstruation, an individual dosage of a naturally occurring or synthetic estrogenic compound orally' effective in the control of ovulation; and e (c) administering orally once daily from the 20th day to the 24th day following the first day of menstruation, an individual unit dosage combination of a naturally occurring or synthetic estrogenic compound and a. compound having progestational activity orally effective in the control of ovulation.

2. The method of claim 1 in which the estrogenic compound is a compound selected from the group consisting of estradiol, estradiol benzoate, ethinyl estradiol, mestranol, piperazine estrone sulfate, estriol, conjugated estrogenic substances, benzestrol, chlorotrianisene, dienestrol, diethylstilbestrol, hexestrol, methallenestril, and. promethestrol dipropionate, and combinations of the same.

3. The method of claim 1 in which the compound hav' ing progestational activity in a compound selected from the group consisting of ethistrone, medroxy progesterone acetate, norethindrone, progesterone, norethinodrel, ethynodiol diacetate, didrogesterone, chlormadinone, chlormadinone acetate, dimethisterone, norethindrone acetate, and combinations of the same.

4. In the method of providing an ovarian or menstrual cycle oral dosage regimen effective in the control of ovulation wherein drugs are administered orally to women during and for their effects upon their ovarian or menstrual cycle as a single oral dosage daily during a consecutive sequence of at least 24 days, the improvement which consists essentially of:

(a) administering orally, once daily for four days,

starting on the first day of menstruation, endocrineinactive dosages or placebos during the menstrual phase which lasts four to five days in the average woman; and

(b) administering orally, once daily, in an uninterrupted consecutive sequence from the 5th day to the 19th day following the first day of menstruation, an indi vidual dosage of a naturally occurring or synthetic estrogenic compound orally effective in the control of ovulation; and

(c) administering orally once daily from the 20th day to the 24th day following the first day of menstruation, an individual unit dosage combination of a naturally occurring or synthetic estrogenic compound and a compound having progestational activity orally effective in the control of ovulation; and

(d) administering orally once daily from the 25th day to the 28th day following the first day of menstrua- '16 tion,endocrine-inactive dosages or placebos thus completing a 28-day dose regimen.

5. The method of claim 4 'and'(e) without interruption repeating a plurality of times' the steps of the dose regimen of (a), (b), (c) and (d) in that order.

6. The method of claim 4 the dose regimen starting at step (b) and proceeding through steps ,(c), (d) and (a), and repeating a plurality of times the steps of the dose regimen of (b), (c), (d) and (a) inthatordel'.

7. The method of claim 4 wherein in step (b) of said dose regimen there is included, along with said estrogenic compound, a compound having progestational activity orally effective in the control of ovulation. v

8. The method of claim 4 and (e) without interruption repeating a plurality of times the steps of the dose regimen of (a), (b), (c) and (d) in that order, wherein in step (b) of said dose regimen there is included along with said estrogenic compound, a compound having progestational activity orally effective in the control of :QVUIE; tion.

9. The method of claim 4, the dose regimen starting at step (b) and proceeding through steps (c), (d), and'(a) and repeating a plurality of times the steps of the dose regimen of (b), (c), (d) and (a) in that order, wherein in step (b) of said dose regimen there i included along with said estrogenic compound, a compound having progestational activity orally effective in the control of ovulation.

References Cited June 1958, Fertility Control With Oral Medication.

Pincus, Postgraduate Medicine 24 (6), 654-660, December 1958, The Hormonal Control of Ovulation and Early Development.

Pincus et al., Science (3367), 8l-83, July 10, 1959, Effectiveness of an Oral Contraceptive.

LEWIS GOTIS, Priinizry Examiner. SHEP K. ROSE, Assistant Examiner.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3182791 *Nov 13, 1962May 11, 1965Jenner MyronPackage
GB992160A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3502772 *Oct 16, 1967Mar 24, 1970OrganonMethod for stimulating anovulatory cycles and pharmaceutical packages
US3568828 *Mar 1, 1967Mar 9, 1971Squibb & Sons IncModified sequential oral contraceptive
US3656483 *Jan 15, 1970Apr 18, 1972Biolog Concepts IncIntrauterine medicator
US3835992 *Oct 24, 1972Sep 17, 1974J AdamsBandage dispensing package
US3892855 *Oct 10, 1973Jul 1, 1975Searle & CoMethod for fertile breeding control in female bovine
US3932635 *May 5, 1972Jan 13, 1976Syntex CorporationNovel cyclic progestogen-interrupted estrogen oral contraceptive regimens
US3942641 *Mar 24, 1975Mar 9, 1976Syntex CorporationDispensing packages containing novel cyclic progestogen-interrupted estrogen oral contraceptive regimens
US3969502 *Jul 9, 1974Jul 13, 1976Schering AktiengesellschaftMethod for contraception by the administration of sequential contraceptive preparations
US3995633 *Dec 2, 1975Dec 7, 1976The Procter & Gamble CompanyVaginal Medicament dispensing device
US4018919 *Jul 16, 1975Apr 19, 1977Eli Lilly And CompanySequential contraceptive method using two types of progestational agents
US4066757 *Mar 26, 1973Jan 3, 1978Ortho Pharmaceutical CorporationOral contraceptive regimen
US4076811 *Jun 23, 1976Feb 28, 1978Schering AktiengesellschaftNovel agents and methods for treatment of climacteric disturbances
US4292315 *Aug 24, 1979Sep 29, 1981Nichols VorysSequential pills for contraception, menstrual dysfunction
US4378356 *Mar 16, 1981Mar 29, 1983Akzon N.V.Multi-phase combination-type sequential preparation for oral contraception and method of oral contraception
US4610687 *Aug 6, 1984Sep 9, 1986Board Of Trustees Operating Michigan State UniversityMethod for breeding control in female bovines
US4860899 *Jan 11, 1988Aug 29, 1989Rna, IncorporatedMedication control system
US4994449 *Nov 27, 1989Feb 19, 1991Modulus Iii, Inc.Calendar-oriented regimen of estrogen, progesterone and calcium; postmenopausal treatment
US5005698 *Jan 5, 1984Apr 9, 1991Ameer Mikhail GIndividually wrapped cigarettes in cigarette pack or box
US5010070 *May 22, 1990Apr 23, 1991Warner-Lambert CompanySide effect reduction
US5108995 *Apr 26, 1990Apr 28, 1992Jencap Research Ltd.Repeating cycles of unit dosage of combination of estrogen and progestin; contraceptive
US5140021 *Oct 27, 1989Aug 18, 1992Genesis Systems CorporationOral administration of micronized progesterone in an oil vehicle high in glycerides of polyunsaturated fatty acids
US5276022 *Nov 5, 1991Jan 4, 1994Jencap Research Ltd.Combination of estrogen and progestin
US5908113 *Feb 19, 1998Jun 1, 1999Sanyo Electric Co., LtdPouches of wrapping paper for containing medicinal doses
US7062312 *Jan 17, 2001Jun 13, 2006Pediamed Pharmaceuticals, Inc.Combination and method including a visual marker for determining compliance with a medication regimen
US7493744 *Dec 12, 2003Feb 24, 2009Sanyo Electric Co., Ltd.Medicine wrapping machine, medicine wrapping sheet, and divided wrapping bag
US20110100863 *Sep 27, 2010May 5, 2011Edge Medical Properties, LlcDual dispensing tablet container
USRE35724 *Jan 6, 1995Feb 3, 1998Bio-Technology General Corp.Administering estrogen contraceptive orally to human female daily from day 3 or 4 through day 7 of menstrual cyle, then follow-up composition containing progestin
EP0397823A1 *Oct 19, 1989Nov 22, 1990Bio-Technology General Corp.Contraception system and method
WO2006013464A1 *Jul 26, 2005Feb 9, 2006Amistad Pharma SasHormone replacement therapy comprising a combination of 17-beta-oestradiol and chlormadinone acetate
Classifications
U.S. Classification514/170, 40/312, 206/820, 221/2, 206/532, 116/201, 206/538, 514/841
International ClassificationA61K31/567, A61J7/04, A61K31/568, A61K31/57, A61K31/565, A61J1/03, A61J1/00
Cooperative ClassificationA61J1/03, A61K31/565, Y10S206/82, A61K31/568, Y10S514/841, A61K31/567, A61J7/04, A61K31/57
European ClassificationA61J1/03, A61K31/565, A61K31/568, A61K31/57, A61K31/567