JP2005526083A - Progesterone oral drug delivery system - Google Patents

Abstract

An oral dosage form suitable for delivery of a combined progesterone and estradiol formulation that provides a blood progesterone concentration of about 0.1 ng / ml to about 400 ng / ml when delivered through the gastrointestinal tract, said dosage form comprising: (A) a first solid dosage form having an average molecular weight of about 1000 to 10,000 and about 25 mg to about 25 mg in a solid polyethylene glycol carrier comprising at least about 30% of said first solid dosage form; An oral dosage form is provided comprising a combination comprising a first solid dosage form comprising about 500 mg micronized progesterone; and (b) a second solid dosage form comprising estrogen.

Description

FIELD OF THE INVENTION This invention relates to oral dosage forms of hormones and their delivery to patients in need of hormone therapy.
SUMMARY OF THE INVENTION In a first aspect, an oral dosage form suitable for delivery of a combined progesterone and estradiol formulation that provides a blood progesterone concentration of about 0.1 ng / ml to about 400 ng / ml when delivered through the gastrointestinal tract. Wherein the dosage form is (a) a first solid dosage form having an average molecular weight of about 1000 to 10,000 and comprising at least about 30% of the first solid dosage form A combination comprising a first solid dosage form comprising from about 25 mg to about 500 mg micronized progesterone in a solid polyethylene glycol carrier; and (b) a second solid dosage form comprising estrogen. In one embodiment, the polyethylene glycol carrier comprises about 45 to about 65% of the first solid dosage form. In a further embodiment, the second solid dosage form (b) contains about 0.25 mg to about 5 mg of estradiol.

  In a further embodiment, the solid polyethylene glycol carrier comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350, or polyethylene glycol 8000. In a preferred embodiment, an oral dosage form is provided that is suitable for delivery of a combined progesterone and estrogen formulation via the gastrointestinal tract and provides a blood progesterone concentration of about 0.1 ng / ml to about 400 ng / ml by oral administration; The dosage form is (a) a first solid dosage form containing from about 25 mg to about 500 mg of micronized progesterone, wherein the caplet is a solid that is a mixture of polyethylene glycol 1450, polyethylene glycol 3350, or polyethylene glycol 8000 Derived from the extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a polyethylene glycol carrier, said micronized progesterone being first dispersed in molten polyethylene glycol, cooled to a solid dosage form and then extruded, The mixture is before A first solid dosage form comprising about 45% to about 65% of the first solid dosage form; and (b) a second solid dosage form containing about 0.25 mg to about 5 mg of estradiol Comprising a combination. In a preferred embodiment, the oral dosage form is provided as a first solid dosage form as a caplet and the second solid dosage form as a tablet.

  In a second aspect of the invention, a method is provided for providing a combination therapy of progesterone and estradiol by oral administration, which method is suitable for delivery of a combined progesterone and estrogen formulation via the gastrointestinal tract. Administering to a patient an oral dosage form that provides a blood progesterone concentration of 0.1 ng / ml to about 400 ng / ml, said dosage form containing (a) about 25 mg to about 500 mg of micronized progesterone A first solid dosage form, wherein the caplet is from an extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a solid polyethylene glycol carrier that is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000. Being guided The micronized progesterone is first dispersed in molten polyethylene glycol, cooled to a solid dosage form and then extruded, the mixture comprising a first about 45% to about 65% of the first solid dosage form. And (b) a combination comprising a second solid dosage form containing from about 0.25 mg to about 5 mg estradiol.

  The present invention relates to a solid oral dosage form of progesterone comprising a therapeutically effective amount of micronized progesterone and a solid polymeric carrier, the dosage form providing a patient with a therapeutically effective amount of progesterone by oral administration. A preferred solid polymer carrier is a mixture of polyethylene glycols having a molecular weight in the range of about 1,000 to about 10,000. Preferably, the progesterone dosage forms of the present invention can be manufactured by injection molding techniques. In addition, the dosage form can be manufactured for immediate release or controlled release. The dosage form can be a tablet, capsule, caplet, encapsulated pellet, encapsulated granule, powder, or encapsulant. These dosage forms can be provided as unit dosage forms.

  In some preferred aspects, the polyethylene glycol is polyethylene glycol 1450, polyethylene glycol 3350, or polyethylene glycol 8000, or mixtures thereof.

  In some aspects, the cellulose ether is a hydroxyalkyl cellulose, a carboxyalkyl cellulose, or a mixture thereof. In some preferred aspects, the cellulose ether is hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, hydroxypropyl methyl cellulose, trimellitic acid cellulose acetate, or mixtures thereof.

  In one specific aspect, an oral progesterone unit dosage form is provided. The dosage form comprises micronized progesterone and a solid polymer carrier, the dosage form providing a patient with a therapeutically effective amount of progesterone by oral administration, the dosage form being from about 25 mg to about 500 mg micronized progesterone per dose. including. The solid polymer carrier comprises about 45% to about 65% of the weight of the dosage form and comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000.

  In another specific aspect, a combination dosage form is provided. The combination dosage forms include oral progesterone dosage forms and estrogen dosage forms, which are capsules encapsulating progesterone dosage forms and estrogen dosage forms.

  An oral progesterone dosage form is a caplet comprising micronized progesterone and a solid polymer carrier. The progesterone dosage form provides a patient with a therapeutically effective amount of progesterone by oral administration, wherein the progesterone dosage form contains from about 25 mg to about 500 mg micronized progesterone per dose. The solid polymer carrier then comprises about 45% to about 65% of the weight of the progesterone dosage form and comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000. A therapeutically effective amount of progesterone exhibits a blood concentration of about 0.1 ng / ml to about 400 ng / ml. Oral estrogen dosage forms are estradiol tablets containing from about 0.25 mg to about 5 mg of estradiol.

The present invention further provides hormone replacement therapy by administering the aforementioned dosage forms to patients in need of progesterone or a combination of progesterone and estrogen. The methods of the present invention can be used for the treatment or prevention of various conditions. For example, infertility related to the non-receptive uterus, premenstrual tension, ovulation, primary dysmenorrhea and endometriosis, habitual abortion, respiratory depression of Pickwick syndrome, secondary amenorrhea, functional uterine bleeding, Examples include, but are not limited to, preeclampsia and preeclampsia, sexual childhood, and postmenopausal syndrome.
Detailed Description of the Invention
A. Those skilled in the art will readily appreciate that the pharmaceutical formulations described herein can be prepared by applying known pharmaceutical procedures. Such formulations can be administered to patients by methods well known in the pharmaceutical art. Thus, the practice of the present invention will employ conventional pharmaceutical science and technology such as pharmaceutical dosage form design, drug development, and pharmacology, and organic chemistry, including polymer chemistry, unless otherwise noted. . These techniques are therefore within the abilities of those skilled in the art and are well described in the literature (in general, see, for example, Remington: The Science and Practice of Pharmacy, 19th edition, Alfonso R. Gennaro (ed. ): Mack Publishing Co., Easton, Pennsylvania (1995), hereinafter REMINGTON, incorporated herein by reference in its entirety).
B. Definitions Certain terms used herein may have the following clearly defined meanings:

  As used in the specification and claims, the singular forms a, an, and the include the plural meanings unless the context clearly dictates otherwise. For example, the term pharmaceutical agent described in the singular can also refer to one or more pharmaceutical agents used in the presently disclosed formulations and methods.

  The term pharmaceutical generally refers to any known pharmacologically active agent, as well as pharmaceutically acceptable salts, prodrugs such as esters or ethers, or salts of prodrugs, or ethanolates (ethanol additions). Solvate, or other derivatives of such pharmacologically active agents. These salts, prodrugs, prodrug salts, solvates and derivatives are well known in the art.

The present invention further contemplates the use of polymorphs, isomers (including stereoisomers, geometric isomers and optical isomers) and anomers of the medicaments described herein. The terms medicine and drug are used interchangeably as they have the same meaning.

  As used herein, the term pharmaceutical carrier or simply carrier refers to a composition that contains and / or delivers a pharmacologically active agent and is generally otherwise pharmacologically ineffective. It is considered active.

  By solid polymer carrier is meant a carrier comprising a polymer or mixture of polymers that is substantially free of oil. A formulation is substantially free of oil if the formulation is primarily free of an oil or mixture of oils for dissolving or dispersing a given drug in the formulation. The inclusion of any combination of polymers or oils that destroy the solid nature of the first dosage form is excluded from the scope of the present invention.

  A formulation is a pharmaceutical technical term that includes a carrier and a medicament. Formulation is a broad term and includes compositions that may or may not be processed into a dosage form that is ultimately administered to a patient. For example, a formulation includes a composition that is formulated to produce a dosage form.

  As used herein, a dosage form is a preparation that is ready for administration to a patient. In the present specification, it refers to a solid dosage form, and examples thereof include, but are not limited to, tablets, capsules, caplets, powders, pellets, and granules. The term also includes multilayer tablets, where a given layer can represent a different drug. The term also includes encapsulated powders, pellets and granules. The powders, pellets, and granules can be coated with a suitable polymer or conventional coating material, for example, to achieve greater stability in the gastrointestinal tract or to achieve a desired release rate. Furthermore, capsules containing the powder, pellets or granules can be further coated. Tablets or caplets may be scored to facilitate dosing. Alternatively, the dosage form of the invention may be a unit dosage form intended for delivery of a therapeutic amount per administration.

  The term pharmaceutically acceptable means that an ingredient that is recognized as being compatible is compatible with the other ingredients of the formulation and not harmful to the patient. Several pharmaceutically acceptable ingredients are known in the art and public publications. For example, the American Pharmacopoeia describes analytical criteria for assessing the pharmacological tolerance of a number of components of interest. Unless stated otherwise, the ingredients used in the present invention are pharmaceutically acceptable.

  Injection molding refers to a method for producing an oral solid dosage form, in which a predetermined amount of a preparation containing a carrier and a medicine (optionally together with an adjuvant) is injected into a mold at a certain temperature and pressure. In which the oral solid dosage form is recovered. Optionally, an additional amount of formulation material can be packed into the mold during the cooling cycle. In some aspects, the dosage form is a tablet or caplet.

  A therapeutically effective blood concentration is the patient's blood drug concentration that is necessary to provide a therapeutic benefit to the patient. The therapeutically effective blood concentration may vary depending on the desired therapeutic benefit as well as other variables such as the patient's age, weight, metabolism, physiological conditions such as gastrointestinal motility, renal clearance. A therapeutically effective blood concentration can be achieved by one or more administrations, applications or dosages. The determination of the dose necessary to achieve a therapeutically effective blood concentration for a given therapy or treatment is well within the skill of those in the pharmaceutical arts.

  In the context of hormone replacement therapy, a therapeutically effective amount of progesterone is an amount of progesterone that is effective in one or more of the following. For example, prevention of estrogen-induced endometrial hyperplasia in postmenopausal women, induction of bleeding in secondary amenorrhea, and reduction of such abnormal bleeding in women with endometrial hyperplasia and functional bleeding is there.

  Various therapeutically effective blood concentrations for various treatments are known in the art. For example, de Lignieres, B.M. Oral Micronized Progesterone (oral micronized progesterone), Clin. Ther. , 21 (1): 41-60 (1999) (incorporated herein by reference). The therapeutically effective blood concentration varies depending on the condition being treated and variables associated with the individual patient, such as age, weight, metabolic activity, etc., but is in the range of about 0.1 ng / ml to about 100 ng / ml or more. sell. See, for example, US Pat. No. 5,543,150 (incorporated herein by reference). This describes several therapeutic serum concentrations.

  The term blood level refers to blood concentration, plasma level, plasma concentration, serum level, serum concentration, and serum blood level. , serum blood concentration).

Cmax refers to the maximum serum progesterone concentration after oral administration of a solid oral dosage form to a patient.
Normalized Cmax is the value obtained by dividing Cmax by the dosage strength of a solid oral dosage form of progesterone. For example, after oral administration of a solid oral dosage form containing 200 mg micronized progesterone, if the maximum serum concentration of progesterone is 14 ng / ml, Cmax is 14 ng / ml and standardized Cmax is 0.07 ng / ml / mg is there.

AUC is the area under the curve that followed the serum concentration (ng / ml) of progesterone over a given time after oral administration of a solid oral dosage form to a patient. AUC can be measured 0-12 hours or 0-24 hours after administration, in which case it is described as AUC _(0-12) or AUC _(0-24) , respectively.

Standardized AUC is obtained by dividing AUC by the dosage titer of a solid oral dosage form of progesterone. For example, after oral administration of a solid oral dosage form containing 200 mg micronized progesterone, AUC _(0-12) is 160 hr. In the case of ng / ml, the standardized AUC _(0-12) is 0.8 hr. ng / ml / mg.

The term administration refers to a method of delivering the formulation to the desired site. Specifically, oral administration is taking a drug by swallowing or chewing.
As used herein, a patient refers to both male and female humans or animals (preferably mammals) that can benefit from administration of a progesterone formulation of the invention.

The concentrations, amounts, and other parameters of the various components of the present invention are often presented in a range format throughout the application. The description in range format is merely for convenience and brevity and should not be taken as a rigid limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, the description of the range such as 0.1-100 is 0.1-1, 0.4-10, 1-25, 10-50, 25-60, 40-65, 60-80, 70-100. As well as individual numbers within that range, such as 0.1, 0.4, 1, 5, 7, 11, 15, 19, 22, 28, 35, 39, 44, 60, 65, 78, 84, 89, 95, etc. should be considered as specifically disclosed. This applies regardless of the range width and regardless of the unit under consideration.
C. Dosage Form The present invention provides an oral progesterone dosage form comprising micronized progesterone and a solid polymer carrier. The dosage form provides a therapeutically effective amount of blood progesterone to the patient by oral administration. Currently available oral progesterone dosage forms containing micronized progesterone are oil based and do not contain a solid polymer carrier.

  The oral dosage form of the present invention can be processed into an immediate release dosage form or a sustained release dosage form. The immediate release dosage form can release progesterone in a fairly short time, for example within minutes to hours. Sustained release dosage forms can release progesterone over several hours, for example up to 24 hours or longer if desired. In either case, delivery can be controlled by having a substantially predetermined rate during delivery.

  The oral dosage forms of the present invention can be processed into dosage forms such as tablets, capsules, caplets, powders, encapsulated pellets, encapsulated granules, or encapsulated powders. These dosage forms are coated with a polymeric material or other coating material known in the art, for example, to achieve greater stability during storage or in the gastrointestinal tract, or to achieve control over drug release. be able to. Such coating techniques and materials used therein are well known in the art. For example, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, cellulose acetate trimellitate (cellulose trimellitic acid cellulose acetate), carboxymethylethylcellulose, and hydroxypropylmethylcellulose acetate succi Nates can be used to achieve enteric coatings. A mixture of waxes, shellac, zein, ethylcellulose, acrylic resin, cellulose acetate, silicone elastomer can be used to achieve a sustained release coating. For example, see Remington, Chapter 93 above for other types of coatings, techniques and equipment.

  In addition, the tablet or caplet dosage form can be scored so that it can be easily broken to adjust the dosage as needed. Tablets may be multi-layered, with each layer representing a different drug or different concentration of the same drug. Alternatively, the dosage forms of the invention can be manufactured as unit dosage forms intended for delivery of one therapeutically effective amount per administration.

General methods and equipment for making tablets, capsules, pellets, and powders are well known in the art. See Remington, 91 and 92 above.
The progesterone dosage forms contain pharmaceutical excipients commonly used to form stable natural progesterone products and do not use allergenic ingredients such as peanut oil. Furthermore, the dosage forms of the present invention deliver natural progesterone as opposed to synthetic progestins, thus avoiding the undesirable effects of synthetic progestins on liver function and carbohydrate metabolism. Other benefits of these dosage forms include administration flexibility, convenience, patient compliance in clinical settings (where the drug is used), and the accompanying improved clinical results (outcomes). is there.

Various aspects of the invention are described in detail below.
a) Progesterone Progesterone is a steroid hormone secreted mainly from the ovary corpus luteum during the latter half of the menstrual cycle. Chemically, progesterone is pregn-4-ene-3,20-dione. Progesterone can exist in two crystalline forms with equal bioactivity and readily interconvert. The α form is orthorhombic (a prism shape from a dilute alcohol) of a: b: c = 0.750: 1.0: 0.905. These crystals are reported to have a melting point of 127-131 ° C. The β form is orthorhombic (acicular) with a: b: c = 0.563: 1.0: 0.275. These β-form crystals are reported to have a melting point of 121 ° C. Merck Index, 12th edition, pp 1335-1336, Merck & Co. , Inc. White House Station, New Jersey (1996). The present invention contemplates the use of progesterone in either the alpha or beta form or mixtures thereof. Thus, the term progesterone as used herein refers to either the α form or the β form or mixtures thereof.

  The pharmaceutical dosage form according to the present invention comprises micronized progesterone. Micronized progesterone is a substantially water-insoluble white or creamy white (creamy white) crystalline particle powder in which almost all (ie, greater than 90%) individual progesterone particles are less than about 25 μm in diameter. The size has been reduced. Alternatively, in the case of non-circular particles, the maximum diameter is reduced to less than about 25 μm. In some aspects, almost all (greater than 90%) micronized progesterone particles have a particle size of less than 10 μm, and the majority of these particles (eg, 78%) have a particle size of less than 5 μm.

  Micronized progesterone is commercially available from sources such as Berlichem, a division of Schering AG, and from Upjohn Company. Alternatively, micronized progesterone can be produced from bulk progesterone with a radiator mill (jet air micronizer) by techniques well known in the art. See, for example, US Pat. Nos. 2,032,827 and 4,018,388 for a description of micronization techniques and equipment.

In a preferred embodiment, the dosage form contains about 50 mg to about 500 mg of progesterone per dose. In another preferred embodiment, the dosage form contains from about 10% to about 70% by weight (more preferably from about 15% to about 60%) micronized progesterone.
b) Carrier The dosage form comprises a solid polymeric carrier for delivering micronized progesterone. The solid polymer carrier may comprise at least 30% by weight of the first solid dosage form made from micronized progesterone and the solid polymer carrier. About 1% to about 80% by weight of the dosage form. In a preferred embodiment, the polymeric carrier comprises about 20% to about 70% by weight of the dosage form. In an even more preferred aspect, the polymeric carrier comprises from about 30% to about 65% by weight of the first solid dosage form.

  Polyethylene glycol is available in various grades under several trade names. For example, Carbowax® PEG 200, 300, 400, 540 Blend, 900, 1000, 1450, 3350, 4000, 4600, 8000 and Compound 20M from United Carbide, USA, and Dow Chemical Co. Poly Glycols (registered trademark) E series from the company. Various grades available under a given trade name show different molecular weights and viscosities.

  In one aspect, the carrier is a mixture of polyethylene glycols having a molecular weight of about 100 to about 20,000. In another aspect, the carrier is a mixture of polyethylene glycols having a molecular weight of about 1000 to about 10,000. In some aspects, the polyethylene glycol is polyethylene glycol 1450, polyethylene glycol 3350, or polyethylene glycol 8000, or mixtures thereof.

  The addition of additional ingredients to the polymer can also be considered if it has no adverse effect on the overall composition and effective treatment delivery of drug therapy, and it is considered to be within the scope of the present invention. Should be understood. Thus, in another aspect, the carrier can comprise a mixture of polyvinyl pyrrolidones having an average molecular weight in the range of 2,500 to 3,000,000 or more. Many polyvinylpyrrolidone polymers suitable for the purposes of the present invention are commercially available. In another aspect, the carrier is a cellulose ether. Some exemplary cellulose ethers include hydroxyalkyl celluloses (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate trimellitate, etc.), and carboxyalkyl celluloses (eg, carboxymethyl cellulose, carboxyethyl cellulose, etc.) or Can be included. In some aspects, the carrier may include adjuvants such as opacifiers, bulking agents, sweeteners, stabilizers. Examples of opacifiers are titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol and the like. Examples of bulking agents are starch, microcrystalline cellulose, calcium sulfate, calcium phosphate, and lactose. Examples of sweeteners are aspartame, saccharin, sodium cyclamate and xylitol. Examples of stabilizers include glyceryl alginate monostearate, hydroxypropyl cellulose, magnesium, aluminum silicate, propylene glycol, and the like.

  The carrier can be used to produce dosage forms of the invention that can release progesterone immediately, ie within minutes to hours, or continuously, ie over 24 hours or longer if desired. . The dissolution rate of a progesterone dosage form can be affected by the inclusion of an adjuvant such as a surfactant in the dosage form. Such surfactants include sodium lauryl sulfate, glyceryl monooleate, sorbitan esters, docusate sodium, cetrimide and the like. The surfactant may comprise from about 0.1% to about 5% by weight of the dosage form. In one aspect, for example, the inventive polyethylene glycol dosage forms described herein can include about 2.5% by weight sodium lauryl sulfate to provide an immediate release dosage form.

For sustained release dosage forms, an additional solid carrier may be used. For example, rubber, acrylic resin, or a mixture thereof is not limited thereto.
c) Combination dosage forms comprising progesterone and estrogen In a further aspect, the present invention provides a combination dosage form comprising an oral progesterone dosage form and an oral estrogen dosage form as described above. Such combination dosage forms can be tablets, capsules, caplets, powders, encapsulated pellets, encapsulated granules, or encapsulated powders. For example, the combination dosage form can be a capsule encapsulating a progesterone dosage form and an estrogen dosage form. The progesterone dosage form and the estrogen dosage form can now be independently tablets, capsules, caplets, powders, encapsulated pellets, encapsulated granules, or encapsulated powders. Alternatively, progesterone and estrogen can be formulated together in a single dosage form such as a powder or tablet, which may be further encapsulated or coated.

  Accordingly, in one aspect, the combination dosage form is a capsule encapsulating progesterone tablets and estrogen tablets. In another aspect, the combination dosage form is a capsule encapsulating a progesterone tablet and an estrogen powder. The desired dosage form can be selected according to the treatment to be performed and according to the desired order of release of progesterone and estrogen. For example, by choosing a progesterone caplet and an estrogen powder to make a combination capsule, rapid estrogen release (because estrogen is a powder) and slow release of progesterone (because the progesterone caplet must first dissolve) can be achieved. . The selection of the appropriate usage and dosage form for a given treatment is well within the skill of the art.

  Such a combined oral dosage form is feasible by developing an oral progesterone dosage form of the present invention that includes a solid polymer carrier. Solid polymer carriers, unlike existing dosage forms based on oil, allow for the production of oral progesterone dosage forms that are small enough to be included in capsule-like dosage forms along with estrogen oral dosage forms. A dosage form for hormone therapy can be created. Thus, for example, a combination of estradiol and progesterone can now be obtained in a single oral dosage form by placing one progesterone caplet and one estradiol tablet in a capsule such as a size # 1 gelatin capsule.

The estrogen that can be used in the combination dosage form described above may be any one or more estrogens known in the art. For example, the estrogen may be a natural estrogen or a congener of estrogen, such as estradiol, estrone, estropipete, ethinyl estradiol, quinestrol, or conjugated estrogens. Synthetic estrogens that can be used are dienestrol (diene estrol), diethylstilbesterol, and mestranol. Preferably, the estrogen is estradiol. The dose of estrogen can be from about 0.1 mg to about 10 mg per unit dosage form. Determination of the appropriate dose for a given treatment is within the skill of the art. See Remington, chapter 64 above for further details.
D. Manufacturing method
a) Injection Molding--Method of Producing Progesterone Oral Dosage Form Containing Micronized Progesterone and Solid Polymer Carrier An oral solid dosage form of progesterone is produced using a technique known as injection molding. For a general description of this technology, see, for example, U.S. Pat. Nos. 3,432,592, 4,801,460, 4,806,337, 5,004,601, and 5,082,655, And Cuff, G .; And Raouf, F .; , Pharmaceutical Technology, 96-106 (1998). All of which are incorporated herein by reference in their entirety.

  Briefly, polyethylene glycol is melted and micronized progesterone is dispersed in the molten polyethylene glycol carrier. Micronized progesterone constitutes at least 30% of the mixture. After dispersion of progesterone, a small amount of adjuvant, such as titanium dioxide (as an opacifier) or pregelatinized starch (as a bulking agent) may be added to the mixture. The molten mixture is cooled through a lentilizing device to form lentil flakes. Wentle or larger size intermediate flakes can be produced by melt granulation, lentiling and / or milling. The lentils and intermediate flakes are passed through a screen of suitable sieve size into smaller lentil pieces. These lentils are made into oral solid dosage forms such as tablets and caplets using techniques such as injection molding known to those skilled in the art.

  During injection molding, the mold is closed and clamped to prevent it from opening. A preparation containing a medicine and its carrier is injected into a mold cavity through a nozzle. The amount of material injected into the mold is controlled by moving the screw to a predetermined distance within the mold. When the screw is removed, it becomes easier to pack additional material into the mold cavity, so that the void created when the mold is cooled after the first injection can be filled. Various parameters of the injection and filling process, such as filling time, filling pressure, injection speed, and injection pressure can be adjusted. Cool the mold and return the screw to the position before injection. Open the mold and take out the molded product (in this case, solid unit dosage form). See Cuff and Raouf above.

The molded dosage form can be scored using conventional techniques. Alternatively, the mold can be set so that scoring is achieved during the molding process.
Other techniques known in the art can also be used to produce solid dosage forms. Examples include, but are not limited to, compression molding, tableting, and extrusion. For example, see Remington, chapters 91-94 above.
b) Combination of progesterone and estrogen in one dosage form A combination dosage form comprising progesterone and estrogen dosage forms can be prepared by first preparing the progesterone and estrogen formulations or dosage forms separately and then combining them. In one aspect, the progesterone and estrogen formulations can be compressed together into a single dosage form, such as a multi-layered tablet (each layer represents a progesterone or estrogen formulation). Alternatively, the progesterone dosage form and the estrogen dosage form can be encapsulated in one capsule. For example, one progesterone caplet and one estradiol tablet may be placed into a size # 1 hard gelatin capsule using an MG encapsulation device with custom-made parts.

  Methods for producing estrogen formulations are well known in the art. See Remington, chapters 91-93 above. For example, estrogen formulations can be produced by a direct compression method. In this method, the required amount of estrogen and some anhydrous lactose are mixed together in a blender. The remaining anhydrous lactose and possibly different types of colored aluminum lakes are premixed through a size 20 screen. Other ingredients such as microcrystalline cellulose and polacriline potassium can also be added to the mixture. Granulation can be lubricated with magnesium stearate. The granules are then tableted on a rotary tablet machine. The tablet machine is equipped with appropriate kneading and dies to achieve the desired tablet diameter, thickness and hardness.

  Estrogens comprise about 0.5% to about 5% by weight of the tablet, depending on the type of estrogen and the therapeutically effective blood estrogen concentration required for a given treatment. In one example, estradiol constitutes about 1.29% of the weight of the mixture. Then, a tablet containing 1 mg estradiol weighs about 80 mg and has a diameter of about 7/32 inches. The thickness of a tablet weighing 80 mg is about 0.107 inches.

  In one example, the progesterone formulation is a caplet, the estrogen formulation is an estradiol tablet, and the combination dosage form is a capsule. Thus, one caplet of progesterone and one tablet of estradiol may be filled into a size # 1 capsule using an MG encapsulation device with custom parts. As noted above, individual progesterone and estrogen formulations can vary, such as, but not limited to, tablets, powders, granules, and pellets. Thus, in other examples, the combination dosage form can be a capsule containing a progesterone tablet and an estradiol powder.

Progesterone formulations containing solid polymer carriers have allowed different progesterone and estrogen formulations. For example, it is now feasible to produce a compounded dosage form using standard size 1 capsules. Size 1 capsules have an inner diameter of about 0.253 inches and an internal length of about 0.748 inches when fully sealed. With the present invention, progesterone caplets up to a length of about 0.545 inches and estradiol tablets up to a thickness of about 0.115 inches can be placed end to end within a size 1 capsule.
E. Administration The pharmaceutical dosage forms of the present invention can be administered to patients in need of hormonal therapy requiring progesterone as a compensation or supplement. The effective progesterone amount per dosage form can vary widely depending on the needs of the patient, but is a dose of about 50 to about 500 mg per dosage form. Administration is generally performed by swallowing, aspirating or chewing the dosage form of the invention. Alternatively, the dosage form can be held in the mouth, sublingually or beside the cheek for a time sufficient to release an effective amount of progesterone from the dosage form. Other methods of administering oral dosage forms are well known in the art.

  The dosage forms of the present invention can be administered for the treatment or prevention of various conditions. Such conditions include infertility associated with the non-receptive uterus, premenstrual tension, ovulation, primary dysmenorrhea and endometriosis, habitual abortion, respiratory depression in Pickwick syndrome, secondary amenorrhea, function Sexual uterine bleeding, preeclampsia and pregnancy toxemia, sexual childhood, and postmenopausal syndrome.

The invention described herein is further illustrated by the following non-limiting examples.
Example
Example 1: Progesterone oral caplet, 200 mg
The composition for producing progesterone oral caplets composed of 200 mg progesterone per caplet is shown in Table 1 below.

  The required amounts of polyethylene glycol 1450, polyethylene glycol 3350 and polyethylene glycol 8000 were melted in an appropriately sized hot kettle. The molten mixture was mixed for 5-10 minutes. Titanium dioxide was passed through the size 20 mesh into the molten mixture and the mixture was stirred for an additional 10 minutes. Micronized progesterone was dispersed in the kettle with mixing. After all the micronized progesterone was added, the mixture was continuously stirred for about 50 minutes with the turbine speed on. The material was transferred to a lentilizer to form flakes or lentils. The flakes or lentils were passed through a fine grinder (Fitzpatrick) to obtain lentil pieces.

  The couplet was molded using an injection molding technique. Injection molding methods, required equipment, and operating conditions are well known in the art. See, for example, U.S. Pat. Nos. 4,629,621, 4,474,976, 4,774,074, 4,806,337, and 5,082,655. These are incorporated herein by reference.

  The method was carried out using a fully electrified 50 ton model ACT-50 injection molding machine. The lentil was supplied to the hopper of an injection molding machine (ACT-50D Cincinnati Milacorn). The couplets were manufactured using a 0.68 "x 0.23" capsule-type cold runner mold and mold insert. The barrel temperature was set to a temperature range of 130-150 ° F. The shot size was set to 0.8 to 0.9 inches. The mold cooler was set to a temperature of 8 to 10 ° C.

The mold was then closed in a semi-automatic mode and the selected mold cavity was filled with material flowing at 0.1-0.4 inches / second at an injection pressure of 1000-1200 pounds per square inch. At the end of the injection time of 8-12 seconds and 100-500 pounds per square inch of filling pressure of 1-3 seconds, there is a mold cooling time of 10-14 seconds, during which time the extruder is 0.8-0. Retreated to the starting shot size position of 9 inches. When the cooling timer timed out, the mold could be opened 8 inches and the injection cycle was rhythmed 2-4 times at a rate of 5-12 inches / second. At the same time, the protruding cycle was operated. A 40-80 psi air blast was fired into the spray to ensure it (spray) was removed from the mold before the start of the next cycle. After several cycles of operation in semi-automatic mode, all couplet parts were injected into the collection bin, so automatic cycle mode could be activated. Cycle stability will be achieved after about 5 minutes of operation.
Example 2: Progesterone oral caplet, 200 mg
The composition for producing progesterone oral caplets composed of 200 mg progesterone per caplet is shown in Table 2 below.

An oral caplet composed of 200 mg progesterone per caplet was prepared according to the process described in Example 1. However, a 0.545 "x 0.240" mold cavity was used during the injection molding process.
Example 3: Progesterone oral caplet, 200 mg
The composition for producing progesterone oral caplets composed of 200 mg progesterone per caplet is shown in Table 3 below.

The procedure for producing 200 mg of progesterone oral caplet was as in Example 2 above.
Example 4: Progesterone oral caplet, 150 mg
The composition for producing progesterone oral caplets composed of 150 mg progesterone per caplet is shown in Table 4 below.

The procedure for producing 150 mg progesterone oral caplet was as described in Example 2.
Example 5: Progesterone oral caplet, 150 mg
The composition for producing progesterone oral caplets composed of 150 mg progesterone per caplet is shown in Table 5 below.

The procedure for producing 150 mg progesterone oral caplet was as described in Example 2.
Example 6: Progesterone oral caplet, 75 mg
The composition for producing progesterone oral caplets composed of 75 mg progesterone per caplet is shown in Table 6 below.

The procedure for preparing 75 mg of progesterone oral caplet was as described in Example 2, except that in Example 6, pregelatinized starch was added as an additional ingredient.
Example 7: Progesterone oral caplet, 200 mg
The composition for producing progesterone oral caplets composed of 200 mg progesterone per caplet is shown in Table 7 below.

The above listed amounts of polyethylene glycol 1450, polyethylene glycol 3350 and polyethylene glycol 8000 were melted in a suitably sized hot kettle. The molten carrier was mixed for 5-10 minutes. Titanium dioxide was added to the molten mixture through a size 20 mesh and the mixture was stirred for an additional 10 minutes. Micronized progesterone was dispersed in the kettle with mixing. Stirring was continued for an additional 30 minutes after all the micronized progesterone had been added. The material was then poured into a sheet of aluminum foil and allowed to cool and harden. The hard sheet was then passed through screen # 20. The ground material was encapsulated using size 0 capsules.
Example 8: Progesterone oral caplet, 100 mg
The composition for producing progesterone oral caplets composed of 100 mg progesterone per caplet is shown in Table 8 below.

The required amount of micronized progesterone, lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate and microcrystalline cellulose were transferred to a suitably sized mixer and mixed for 10 minutes. Povidone was dissolved in ethyl alcohol while the powder was mixed. The powder was granulated with povidone solution and mixing continued until a wet granule mass was formed. Add additional ethyl alcohol if necessary to reach granulation and point. The granules were transferred to a drying oven tray and dried at 55 ° C. for 10-15 hours or until loss on drying was 2.0% or less. The dried granules were passed through a size 20 mesh screen with colloidal silicon dioxide. The milled granules were then lubricated (fluidized) by mixing with the required amount of magnesium stearate in a suitable blender. The granules were then compressed to 190 mg per tablet using a 1/4 inch flat chamfer (cut the edges diagonally) tool on a rotary tablet machine. To produce a 200 mg progesterone capsule, two tablets of 100 mg progesterone were filled into a size 0 hard gelatin capsule.
Example 9: Production of Estradiol Tablets, USP, 1 mg The composition for producing estradiol tablets composed of 1 mg estradiol per tablet is shown in Table 9 below.

Size 20 of partial amount of anhydrous lactose (eg about 17%), required amount of D & C Red # 30 (27%) aluminum lake, FD & C Blue # 1 (13%) aluminum lake, D & C Yellow # 10 (18%) aluminum lake Through a mesh screen. The required amount of estradiol and the remaining amount of anhydrous lactose were transferred to an appropriately sized mixer and mixed for 10 minutes. The required amount of microcrystalline cellulose, polacrilin potassium and ground color mixture were added to the lactose / estradiol mixture and the composition was mixed for 10 minutes. The granules were then lubricated by mixing with the required amount of magnesium stearate in the same mixer. The granules were then compressed to 80 mg per tablet using a 7/32 "circular flat chamfering tool on a rotary tablet machine. Tablet thickness range was 0.104" to 0.112 ", tablet hardness The range was 2-6 Kp.
Example 10: Progesterone caplet bioavailability Preliminary, single dose, two-period, randomized crossover studies were performed in healthy postmenopausal women to determine the relative oral bioavailability of two progesterone products under fasting conditions. It was measured. Methodologies for performing randomized crossover tests are well known in the medical and pharmaceutical fields.

  FIG. 1 shows the result of the experiment. In FIG. 1, “A” indicates data of a capsule preparation of 200 mg of progesterone of the present invention (hereinafter referred to as Watson progesterone), and “B” indicates data of a commercial preparation of Prometrium (registered trademark) 100 mg (× 2). The formulation was the same as Example 1, except that the lentil was passed through a size 20 mesh and encapsulated in a size 0 capsule.

  FIG. 1 shows that the average peak progesterone concentrations (Cmax) reached after administration of Watson progesterone and Prometrium® were 20.04 ± 14.09 and 19.60 ± 17.89 ng / ml, respectively. ing. When evaluated by ANOVA (Analysis of Variance), it was not recognized that there was a statistical difference in average. The time to reach the peak progesterone concentration (Tmax) was 2.31 ± 1.71 hours for Watson progesterone and 1.44 ± 0.32 hours for Prometrium®. It was not recognized that the p value was 0.05 or less and the average was not statistically different. The area under the curve (AUC) (0-t) after Watson progesterone and Prometrium® administration was not found to be statistically different as assessed by ANOVA (ANOVA). The area under the curve of drug concentration versus time from AUC (0-t) or time zero to the last measured concentration (12 hours) was calculated by the linear trapezoidal method.

According to this study, the average peak progesterone concentration (Cmax) after a single dose to healthy postmenopausal women between the Watson solid oral progesterone formulation and the FDA-approved oil-based oral progesterone formulation Prometrium®, It was shown that there was no statistically significant difference in mean time to reach peak progesterone concentration (Tmax) and area under the curve (AUC).
Example 11: Progesterone caplet bioavailability when administered with estradiol Preliminary, single dose, three-period, randomized crossover studies were performed on 12 healthy postmenopausal women, The relative oral bioavailability of progesterone products was measured. In the study, one progesterone caplet (300 mg), one estradiol tablet (1 mg) or a combination of estradiol tablets and progesterone caplets were administered.

The results of progesterone couplets showed that plasma Cmax of progesterone was 75.78 ± 5.3 ng / mL, Tmax was 2.62 ± 1.5 hours, and AUC _(0-24) was 211.1 ± 127 ng. hr / ml. Standardized Cmax is 0.25 ng / mL and standardized AUC is 0.7 ng. hr / ml / mg. Normalization data was obtained by dividing the corresponding data by the dose.

The results of the combination capsule showed that the plasma progesterone Cmax was 122.98 ± 157.9 ng / mL, the Tmax was 1.88 ± 0.98 hours, and the AUC _(0-24) was 276.6 ± 251.4 ng. hr / ml. Standardized Cmax is 0.41 ng / mL and standardized AUC _(0-24) is 0.9 ng. hr / ml / mg.

  The above data indicate that the normalized Cmax (0.41 ng / ml) of the progesterone in the combination capsule is about 60% higher than the normalized Cmax (0.25 ng / ml) of the caplet of progesterone only. Similarly, the standardized AUC (0.9 ng.hr/ml/mg) of the progesterone in the combination capsule is about 30% higher than the AUC of progesterone-only caplet progesterone (0.7 ng.hr/ml/mg). These are surprising results and show that higher progesterone Cmax and AUC levels can be achieved by providing a solid oral dosage form of progesterone with a solid polymer carrier and estrogen.

Claims (7)

  An oral dosage form suitable for delivery of a combined progesterone and estradiol formulation that provides a blood progesterone concentration of about 0.1 ng / ml to about 400 ng / ml when delivered through the gastrointestinal tract, said dosage form comprising: (A) a first solid dosage form having an average molecular weight of about 1000 to 10,000 and about 25 mg to about 25 mg in a solid polyethylene glycol carrier comprising at least about 30% of said first solid dosage form; An oral dosage form comprising a combination comprising a first solid dosage form comprising about 500 mg micronized progesterone; and (b) a second solid dosage form comprising estrogen.   The oral dosage form of claim 1, wherein the polyethylene glycol carrier comprises about 45% to about 65% of component (a).   The oral dosage form of claim 1, wherein the second solid dosage form (b) contains from about 0.25 mg to about 5 mg of estradiol.   The oral dosage form of claim 1, wherein the solid polyethylene glycol carrier comprises a mixture of polyethylene glycol 1450, polyethylene glycol 3350, or polyethylene glycol 8000.   An oral dosage form suitable for delivery of a combined progesterone and estrogen formulation via the gastrointestinal tract, which provides a blood progesterone concentration of about 0.1 ng / ml to about 400 ng / ml by oral administration, the dosage form comprising: (A) a first solid dosage form containing from about 25 mg to about 500 mg of micronized progesterone, wherein the first solid dosage form is a solid which is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000 Derived from the extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a polyethylene glycol carrier, said micronized progesterone being first dispersed in molten polyethylene glycol, cooled to a solid dosage form and then extruded, The mixture is in the first solid dosage form. An oral dosage form comprising a combination comprising a first solid dosage form comprising 45% to about 65%; and (b) a second solid dosage form containing about 0.25 mg to about 5 mg of estradiol .   The oral dosage form of claim 5, wherein the first solid dosage form is a caplet and the second solid dosage form is a tablet.   A method of providing a combination therapy of progesterone and estradiol by oral administration, suitable for delivery of a combined progesterone and estrogen formulation via the gastrointestinal tract, in blood of about 0.1 ng / ml to about 400 ng / ml by oral administration Administering to a patient an oral dosage form that provides a progesterone concentration, wherein the dosage form is (a) a first solid dosage form containing from about 25 mg to about 500 mg micronized progesterone, The solid dosage form is derived from extrusion of a polymer matrix extruded from a mixture comprising micronized progesterone in a solid polyethylene glycol carrier, which is a mixture of polyethylene glycol 1450, polyethylene glycol 3350 or polyethylene glycol 8000. Progesterone first melts A first solid dosage form dispersed in reethylene glycol, cooled to a solid dosage form and then extruded, wherein the mixture comprises about 45% to about 65% of the first solid dosage form; and ( b) A method comprising a combination comprising a second solid dosage form containing from about 0.25 mg to about 5 mg estradiol.