HK1158092A - Progestin-containing drug delivery system - Google Patents

Description

Progesterone-containing drug delivery system

Technical Field

The present invention relates to a drug delivery system in the form of a thin water-soluble film (wafers) comprising particles comprising at least one progestin and at least one protective agent. The protective agent provides effective taste masking of the progesterone due to the limited release of the progesterone in the mouth. The progesterone is thus not absorbed by the buccal route but rather by the enteral (oral) route. Thus, the wafers provided by the present invention can be readily modified into unit dosage forms substantially bioequivalent to corresponding standard Immediate Release (IR) oral tablets or capsules.

Background

Although drugs such as progesterone and/or estrogen can be included in conventional standard oral tablets or capsules to provide accurate and consistent dosages, such delivery forms have several deficiencies in both the administration and preparation of the drug. For example, it is estimated that about 50% of the population has difficulty swallowing tablets (see, Seager, J.Pharmacol.Pharm.1998; 50; 375-. The pharmaceutical industry has attempted to address this challenge by developing many different drug delivery systems, including tablets that disintegrate rapidly in the mouth, tablets that disintegrate in liquid prior to ingestion, liquids and syrups, gums (gums), and even transdermal patches. However, each of these delivery systems may have their own problems.

Transdermal patches can be inconvenient, uncomfortable and expensive to produce. Furthermore, drug flux (drug flux) through the skin can also cause very complex dosing problems. Liquid preparations are particularly useful for children. However, liquid agents can be inconvenient for adults and can be relatively expensive to formulate, package, and ship. Tablets which dissolve in liquid prior to ingestion may also be used. They can also be very inconvenient because they require the provision of liquid and drinking containers. Moreover, even when effervescent tablets are used, disintegration and/or dissolution takes time. Finally, these drug delivery systems can be very cumbersome because they typically leave particles and/or dregs in the glass. Intraorally rapidly disintegrating tablets, such as chewable tablets or self-disintegrating tablets, provide great convenience. However, chewing tablets or self-disintegrating tablets often create practical taste masking problems, as the chewing action can disrupt the protective coating. Furthermore, chewable tablets or self-disintegrating tablets are often associated with an unpleasant mouthfeel. Moreover, the fear of swallowing, chewing or choking on such solid shaped objects remains a concern for some people. In addition, the friability/fragility of such porous and low pressure molded tablets makes them difficult to carry, store, handle, and administer to patients, particularly children and elderly patients.

Accordingly, there is a need for a reliable delivery system with improved patient compliance, i.e. easy to administer and allowing patients to take their medication discontinuously, whenever and wherever they need it. Water-soluble films (wafers) offer a number of advantages over the drug delivery systems described above. Typically, such wafers rapidly dissolve in the saliva in the mouth, thereby releasing the active ingredient which can then be at least partially absorbed via the buccal route, thus reducing or even avoiding liver metabolism ("first pass metabolism"). While such wafers represent an interesting alternative to the above-described drug delivery systems in many cases, rapid dissolution of the drug in the mouth (and thus buccal administration) is not necessarily desired in some cases.

For example, many active ingredients have an unpleasant taste (e.g. bitter taste), such as the synthetic hormone drospirenone. When such active ingredients are rapidly dissolved from the wafer, this can result in a product that is not acceptable to the patient due to an unpleasant taste. Thus, taste masking of such active ingredients represents a problem. In addition, buccal administration via a wafer may require dosage adjustments as compared to approved and marketed oral tablets or capsules. This in turn means that in such cases regulatory agencies will typically require complete clinical trials to demonstrate the safety and efficacy of such improved products. Thus, where there is a need for a bioequivalent replacement for an approved and marketed oral tablet or capsule, it may still be desirable to utilize wafer technology due to the many advantages provided by this particular drug delivery system (without the need to swallow, chew, etc.). However, this drug delivery system must be modified so that absorption by the buccal route is avoided and it must be ensured that the active ingredient does not dissolve efficiently until it reaches the stomach or optionally the small intestine. As mentioned above, there is clearly also a need for effective taste masking.

In summary, there is a need for a drug delivery system in which the unpleasant taste of the active ingredient is effectively masked. Additionally, or alternatively, there is a need for a drug delivery system that is bioequivalent to a standard IR oral tablet or capsule, but at the same time does not suffer from the disadvantages of such a standard oral IR tablet or capsule.

The inventors provide a drug delivery system which on the one hand takes advantage of the beneficial properties of wafers, and on the other hand ensures that the unpleasant taste of the active ingredient is effectively masked. This is achieved by: ensuring that once the wafer matrix (rapidly) dissolves in saliva, the progesterone is not dissolved in the mouth (and thus not administered by the buccal route) but rather transported by normal swallowing into the stomach and/or intestine where it is effectively released, due to the presence of a suitable protective agent. The drug delivery system of the present invention is very flexible in the sense that it can easily accommodate systems bioequivalent to standard IR oral tablet or capsule references.

Flavored chewable pharmaceutical compositions are described in US 4,800,087.

Flavored Orally Disintegrating Tablets (ODT) are described in US 2006/0105038.

A taste modifying coating system is described in WO 00/30617.

WO 03/030883 describes a flavored wafer.

EP 1787640 describes taste-modifying powders and granules.

Particles comprising a drug and solid formulations comprising these particles are described in US 2007/0148230.

WO 2008/040534 describes Non-mucoadhesive film (Non-mucoadhesive film) dosage forms and techniques for delaying absorption of a drug from an orally disintegrating film through the oral mucosaAnd a method. According to this document, donepezil is mixed with EudragitThe EPO incorporation results in an immediate release profile of the active compound.

Solid dosage forms comprising an edible alkaline agent as a flavouring agent are described in WO 2007/109057.

Compositions and methods for mucosal delivery are described in WO 00/42992. This document also discloses dosage units in which the active substance is encapsulated in a polymer.

WO 2006/055142 describes a modified pharmaceutical composition prepared by coacervation.

Compositions comprising sustained release particles are described in US 7,225,876.

WO 2007/074472 teaches that filler particles, for example with a particle size > 100 μm, give a rough, gritty or gritty mouthfeel when ingested as an orally dissolving tablet. Furthermore, this document discloses a method of improving mouthfeel.

Xu et al, Int J Pharm 2008; 359; 63 describes taste-modifying microspheres for orally disintegrating tablets. However, the active agent is released from these particles relatively quickly and complete taste masking is not achieved.

US 2007/0292479 describes a film-like system for transmucosal buccal administration. Furthermore, this film-like system described in US 2007/0292479 comprises a large amount of cyclodextrin.

SI Pater, MJ Rathbone and S Senel, Expert Opin Drug Deliv 2008; 5; 531 review the current state and future of buccal drug delivery systems and provide insight into the difficulties and challenges encountered in developing buccal dosage forms.

In view of these prior art documents, the problems to be solved by the present invention include, but are not limited to:

● formulating the flavor particles so that they are of a size suitable for drug delivery systems in the form of thin films (wafers);

● the flavor particles are formulated so that they do not produce any rough, gritty or gritty mouthfeel when they are released from the drug delivery system into the mouth.

● the flavor particles are uniformly incorporated into the unit dosage form in the form of a thin film (wafer).

● the flavor particles are incorporated into a water-soluble film comprising a water-soluble matrix polymer during manufacture and/or storage without the need to dissolve or extract the flavor particles.

Summary of The Invention

In a first aspect, the present invention relates to a unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

Other aspects of the invention will be apparent from the following description and the appended claims.

Detailed Description

In this context, the term "progestin" (also sometimes referred to as "progestagens" or "progestogens") includes synthetic hormonal compounds which are agonists of the progesterone receptor. The term is also intended to include all isomeric and physical forms of progesterone, including hydrates, solvates, salts and complexes, for example with cyclodextrins. Specific examples of progestins include, but are not limited to, progestins selected from the group consisting of levonorgestrel, norethindrone (nordehydrohydroxyprogesterone), dienogest, norethindrone acetate (norethindrone acetate), norethindrone diacetate, dydrogesterone, medroxyprogesterone acetate, norethindrone, allylestrenol, linegestrol, quinigestrol acetate, medrogesterone, norgestrel, demegestone, ethisterone acetate, megestrol, promgestrel, 3-ketodesogestrel, norgestimate, gestodene, tibolone, cyproterone acetate, dienogone, and drospirenone. Preferred progestins are gestodene, dienogest and drospirenone, especially drospirenone. As discussed above, progesterone can be complexed with cyclodextrin.

The term "estrogen" is intended to include all compounds (natural or synthetic steroidal or non-steroidal compounds) that exhibit estrogenic activity. Such compounds include especially conjugated estrogens and phytoestrogens. The term is also intended to include all isomeric and physical forms of estrogens, including hydrates, solvates, salts and complexes, such as with cyclodextrins. More particularly, the estrogen may be selected from ethinylestradiol, estradiol including therapeutically acceptable derivatives (including esters) of estradiol, estrone, mestranol, estriol succinate, and conjugated estrogens including equine conjugated estrogens such as estrone sulfate, 17 β -estradiol sulfate, 17 α -estradiol sulfate, equilenin sulfate, 17 β -dihydroequilenin sulfate, 17 α -dihydroequilenin sulfate. Of particular interest are estrogens selected from the group consisting of ethinyl estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol, and estrone sulfate. More preferably, the estrogen is ethinyl estradiol or estradiol. The most preferred estrogen is ethinyl estradiol. As discussed above, the estrogen may be complexed with the cyclodextrin.

As used herein, the term "therapeutically acceptable derivative of estradiol" refers to an ester of estradiol; salts of estradiol and estradiol esters, such as sodium salts; and other derivatives known in the art. Typically, the ester of estradiol is in the 3-or 7-position of estradiol. Specific examples of representative esters of estradiol include estradiol valerate, estradiol acetate, estradiol propionate, estradiol heptanoate, estradiol undecanoate, estradiol benzoate, estradiol cypionate, estradiol sulfate, estradiol sulfamate, and salts thereof. Of the estradiol esters, estradiol valerate is particularly preferred.

The term "estradiol" is intended to mean estradiol which may be in the form of 17-alpha-estradiol or 17-beta-estradiol. Preferably, the estradiol is in the form of 17-beta-estradiol. The term "estradiol" also covers hydrated forms of estradiol, in particular semi-hydrated estradiol.

The term "estrogen-cyclodextrin complex" or "estrogen complexed with cyclodextrin" is intended to mean a complex of estrogen and cyclodextrin in which the estrogen molecule is at least partially inserted into the lumen of the cyclodextrin molecule. The molar ratio of estrogen to cyclodextrin can be adjusted to any desired value. In an interesting embodiment of the invention, the molar ratio of estrogen to cyclodextrin is from about 2: 1 to 1: 10, preferably from about 1: 1 to 1: 5, most preferably from about 1: 1 to 1: 3, e.g. 1: 1 or 1: 2. Furthermore, the estrogen molecule may be at least partially inserted into the lumen of two or more cyclodextrin molecules, e.g., a single estrogen molecule may be inserted into two cyclodextrin molecules to give a 1: 2 ratio of estrogen to cyclodextrin. Similarly, the complex may comprise more than one estrogen molecule at least partially inserted into a single cyclodextrin molecule, e.g., two estrogen molecules may be at least partially inserted into a single cyclodextrin molecule to give a 2: 1 ratio of estrogen to cyclodextrin. Complexes of estrogen and cyclodextrin can be obtained according to methods known in the art as described, for example, in US 5,798,338 and EP 1353700.

The term "ethinylestradiol-beta-cyclodextrin complex" is intended to mean a complex of ethinylestradiol and beta-cyclodextrin in any molar ratio. However, ethinylestradiol- β -cyclodextrin complexes are typically complexes of one molecule of ethinylestradiol and two molecules of β -cyclodextrin, i.e., 1: 2 ethinylestradiol- β -cyclodextrin complexes.

The term "progesterone-cyclodextrin complex" or "progesterone complexed with cyclodextrin" is intended to mean a complex of progesterone and cyclodextrin, wherein the progesterone molecule is at least partially inserted into the lumen of the cyclodextrin molecule. The molar ratio of progesterone to cyclodextrin can be adjusted to any desired value. In an interesting embodiment of the invention, the molar ratio of progesterone to cyclodextrin is from about 2: 1 to 1: 10, preferably from about 1: 1 to 1: 5, most preferably from about 1: 1 to 1: 3. Furthermore, the progesterone molecule can be at least partially inserted into the lumen of two or more cyclodextrin molecules, e.g., a single progesterone molecule can be inserted into two cyclodextrin molecules to give a ratio of progesterone to cyclodextrin of 1: 2. Similarly, the complex may comprise more than one progesterone molecule at least partially intercalated into a single cyclodextrin molecule, e.g., two progesterone molecules may be at least partially intercalated into a single cyclodextrin molecule to provide a 2: 1 ratio of progesterone to cyclodextrin. Complexes of progesterone and cyclodextrin can be obtained according to methods known in the art, for example as described in US 6,610,670 and references herein.

The term "drospirenone- β -cyclodextrin complex" is intended to mean a complex of drospirenone and β -cyclodextrin in any molar ratio as described in US 6,610,670. However, the drospirenone- β -cyclodextrin complex is typically a complex of one molecule of drospirenone and three molecules of β -cyclodextrin complex, i.e. a 1: 3 drospirenone- β -cyclodextrin complex.

The term "cyclodextrin" is intended to mean cyclodextrin or its derivatives and mixtures of cyclodextrins, mixtures of cyclodextrin derivatives and mixtures of cyclodextrins and their derivatives. The cyclodextrin may be selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and derivatives thereof. Cyclodextrins can be modified such that some or all of the primary or secondary hydroxyl groups of the macrocycle are alkylated or acylated. Methods of modifying these hydroxyl groups are well known to those skilled in the art, and many such modified cyclodextrins are commercially available. Thus, some or all of the hydroxyl groups of the cyclodextrin may be substituted with O-R groups or O-C (O) -R groups, where R is optionally substituted C_1-6-alkyl, optionally substituted C_2-6-alkenyl, optionally substitutedC_2-6-alkynyl, optionally substituted aryl or heteroaryl. Thus, R may be methyl, ethyl, propyl, butyl, pentyl or hexyl, i.e. O-C (O) -R may be acetate. Furthermore, it is possible to perhenzylate, perhalogenate, benzylate or benzoylate only one side of the macrocycle, i.e. to benzylate or benzoylate only 1, 2, 3, 4, 5 or 6 hydroxyls. Naturally, it is also possible to peralkylate or peracylate (e.g. peracylate or peracylate), alkylate or acylate (e.g. methylate or acetylate) only one side of the macrocycle, i.e. to alkylate or acylate only 1, 2, 3, 4, 5 or 6 hydroxyls, e.g. methylate or acetylate. Commonly used cyclodextrins are hydroxypropyl-beta-cyclodextrin, DIMEB, RAMEB and sulfoalkyl ether cyclodextrins, e.g. sulfobutyl ether cyclodextrin (available under the trade name Captisol)Purchased). Although active ingredients complexed with cyclodextrins are indeed contemplated, in one embodiment of the invention, the composition does not comprise any cyclodextrin.

In this context, the term "C_1-6-alkyl "is intended to denote a linear or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms, such as methyl; an ethyl group; propyl groups such as n-propyl and isopropyl; butyl groups such as n-butyl, isobutyl, sec-butyl and tert-butyl; pentyl, such as n-pentyl, isopentyl and neopentyl, and hexyl, such as n-hexyl and isohexyl. Similarly, the term "C_1-4-alkyl "is intended to denote a linear or branched saturated hydrocarbon chain having from 1 to 4 carbon atoms, such as methyl; an ethyl group; propyl groups such as n-propyl and isopropyl; and butyl groups such as n-butyl, isobutyl, sec-butyl, and tert-butyl.

Although various cyclodextrin complexes of progestin and estrogen are described above, it is presently preferred that neither progestin nor estrogen be complexed with cyclodextrin. Thus, in a preferred embodiment, the unit dosage form of the present invention does not comprise a cyclodextrin.

As indicated above, the progesterone-containing particles should be prepared in such a way that as little progesterone as possible is released in the mouth, while as much progesterone as possible is released in the stomach or optionally in the small intestine. This can be achieved by combining progesterone with a protective agent as will be discussed below.

As will be appreciated by those skilled in the art, typical residence times of a disintegrating dosage form in the mouth are generally less than 3 minutes. The same applies to (micro) particles when they are released from such dosage forms in the mouth. Thus, the typical residence time of these (micro) particles in the mouth is about 3 minutes (this is intended to include the time from ingestion of the dosage form until disintegration). Thus, effective taste masking can be studied by performing in vitro dissolution tests in small volumes of liquid simulating saliva, and it can be reasonably assumed that effective taste masking is achieved when the drug in 10ml of dissolution medium (typically an aqueous solution of pH 6) is not detectable at an early time point of 0 to 3 minutes or the detected amount is below a threshold at which its taste is discerned. It is clear that the absolute threshold for discriminating the taste of a drug depends on the nature and dose of the drug. For drospirenone, said threshold is higher than about 25% (w/w) when drospirenone is administered at a dosage level of 3 mg.

Thus, in order to effectively mask the unpleasant taste of progesterone, the protective agent must ensure that no or only very little progesterone is dissolved out under conditions that mimic the conditions prevailing in the mouth. More specifically, preferably less than 25% (w/w) (e.g. less than 20% (w/w)), more preferably less than 15% (w/w) (e.g. less than 10% (w/w)), most preferably less than 5% (w/w) of the progesterone is dissolved from the unit dosage form within 3 minutes as determined in an in vitro dissolution test representative of conditions in the mouth. A suitable in vitro dissolution test is described in example 8A herein. Briefly, the dosage forms were placed on the bottom of a glass beaker. 10ml of simulated saliva at 37 ℃ pH6.0 as dissolution medium (composition: 1.436g of disodium hydrogen phosphate dihydrate, 7.98g of potassium dihydrogen phosphate and 8.0g of sodium chloride dissolved in 950ml of water, adjusted to pH6.0 and made up to 1000ml) were then added to the beaker. The test is usually carried out without any stirring or shaking (except for slight shaking within the first 5 seconds of the test to ensure complete wetting of the dosage form) provided that the dosage form is formulated to take advantage of this operation to allow complete disintegration within 3 minutes. If the dosage form is not formulated in this manner, stirring or shaking may be used to ensure that the dosage form is completely disintegrated within 3 minutes. After 3 minutes, the contents of the beaker were visually inspected and a liquid sample was aspirated, filtered and analyzed for drug content.

To study and evaluate the taste-masking properties of the protected particles prior to incorporation into the unit dosage form of the present invention, Xu et al, Int J Pharm 2008; 359; 63, dissolution test described in (a). In a preferred embodiment of the invention less than 20% (w/w), more preferably less than 15% (w/w), most preferably less than 10% (w/w) of the progesterone is dissolved from the protected particles within 5 minutes as determined by a type II dissolution apparatus using distilled water at 37 ℃ as dissolution medium and 100rpm as stirring rate.

As indicated above, a fast and efficient release of progesterone in the stomach and/or intestine is of primary importance. As will be appreciated by those skilled in the art, this effect may also be simulated by in vitro dissolution testing and it is reasonable to assume that an effective release of progesterone in the stomach and/or intestine is achieved if at least 70% (w/w), more preferably at least 80% (w/w), most preferably at least 90% (w/w) of the progesterone is dissolved from the unit dosage form within 30 minutes as determined by the United States Pharmacopeia (USP) XXXI paddle method (apparatus 2) using 900-. Alternatively, the unit dosage form may be tested under similar conditions over a shorter period of time. In such cases, preferably at least 70% (w/w), more preferably at least 80% (w/w), most preferably at least 90% (w/w) of the progesterone is dissolved from the unit dosage form within 20 minutes (more preferably within 15 minutes), as determined by the USP XXXI paddle method (apparatus 2) using 900-1000ml of a suitable dissolution medium at 37 ℃ as dissolution medium and 50-100rpm (preferably 50rpm, 75rpm or 100rpm) as agitation rate.

A typical in vitro dissolution test is described in example 8B. Suitable dissolution media may be selected to reflect the physiological conditions of the stomach and/or intestine and the specific properties of the unit dosage form. Thus, suitable dissolution media may be selected from, for example, water, aqueous buffer solutions at pH 1-8 (e.g., pH1.0, 1.2, 1.3, 2.0, 4.5, 6.0, and 6.8) with the addition of 0.1-3% (w/v) sodium lauryl sulfate, simulated gastric fluid, simulated intestinal fluid (fasting or fed state).

In one embodiment, suitable dissolution media are selected from the group consisting of 900-1000ml of 0.05M phosphate buffer pH 6.0; 0.05M phosphate buffer pH6.0 containing 0.5% (w/v) sodium lauryl sulfate; and 0.05M phosphate buffer pH6.0 containing 1% (w/v) sodium lauryl sulfate. Most preferably, a suitable dissolution medium is 1000ml of 0.05M phosphate buffer pH6.0 containing 0.5% (w/v) sodium dodecyl sulfate.

In another embodiment, suitable dissolution media are selected from 900ml 0.05M acetate buffer pH 4.5; 0.05M acetate buffer pH 4.5 containing 0.5% (w/v) sodium lauryl sulfate; and 0.05M acetate buffer pH 4.5 containing 1% (w/v) sodium lauryl sulfate. In a preferred embodiment, when the protective agent is a wax, a suitable dissolution medium is 900ml of 0.05M acetate buffer pH 4.5 containing 0.5% (w/v) sodium lauryl sulfate; when the protective agent is a cationic polymethacrylate, a suitable dissolution medium is 900ml of 0.05M phosphate buffer pH 4.5.

The dissolution tests discussed above are described in more detail in examples 8B, 8C and 8D herein.

Examples of simulated gastric and simulated intestinal fluids are described in USP XXXI. But there are other compositions known in the pharmaceutical literature that mimic body fluids. As noted above, the exact composition of the dissolution medium should be selected to reflect the physiological conditions of the stomach and/or intestine as well as the specific properties of the unit dosage form.

A variety of materials known to those skilled in the art can be used as the protective agent of the present invention. Specific examples of such protective agents include cationic polymethacrylates and waxes.

In a preferred embodiment of the invention, the protective agent is based on di-C_1-4-alkyl-amino-C_1-4Alkyl methacrylates with neutral methacrylic acid C_1-6Cationic polymethacrylate copolymers of alkyl esters. In a more preferred embodiment of the invention, the cationic polymethacrylate is based on dimethylaminoethyl methacrylate and neutral methacrylic acid C_1-4Copolymers of alkyl esters, for example based on dimethyl-aminoethyl methacrylate, methyl methacrylate and butyl methacrylate. Particularly preferred cationic polymethacrylates are poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1: 2: 1. The above cationic polymethacrylates generally have an average molecular weight of from 100,000Da to 500,000Da, for example an average molecular weight of from 100,000Da to 300,000Da, for example an average molecular weight of from 100,000Da to 250,000Da, preferably an average molecular weight of from 100,000Da to 200,000Da, for example an average molecular weight of from 125,000Da to 175,000Da, for example an average molecular weight of about 150,000 Da.

Such cationic polymethacrylates may be under the trade name EudragitE was purchased from Degussa, Germany. Particularly preferred is EudragitE 100。

In another preferred embodiment of the present invention, the protective agent is a wax. Examples of the wax include animal waxes such as beeswax, chinese wax, shellac wax, spermaceti wax and wool wax; vegetable waxes such as carnauba wax, bayberry wax, candelilla wax, castor wax, esparto wax, ouricury wax, rice bran wax, and soybean wax; mineral waxes such as ozocerite (ceresin wax), montan wax, ozocerite (ozocerite wax), and peat wax; petroleum waxes, such as paraffin wax and microcrystalline wax; and synthetic waxes such as polyethylene waxes, Fischer-Tropsch waxes, esterified and/or saponified waxes, substituted amide waxes, and polymerized alpha-olefins. A particularly preferred wax is carnauba wax.

The weight ratio of progesterone to wax is typically from 1: 1 to 1: 4, for example about 1: 1, about 1: 2, about 1: 3 or about 1: 4.

As discussed above, the particles comprising progesterone and a protective agent should release as little progesterone as possible in the mouth, while dissolving as much progesterone as possible in the stomach and/or intestine. This can be achieved, for example, by embedding the progesterone in the protective agent, for example in such a way that the progesterone is present in the protective agent in the form of a solid dispersion. This embodiment is particularly preferred when the protecting agent is a cationic polymethacrylate.

Alternatively, progesterone may be coated with a protective agent. This embodiment is particularly preferred when the protective agent is a wax.

In this context, the term "solid dispersion" is used in its generally accepted sense, i.e. as a dispersion in which the dispersed phase consists of amorphous or crystalline particles or individual molecules (molecular dispersion). Thus, as used herein, the term "solid dispersion" means any solid system in which component a (e.g. progesterone) is dispersed in another component B (e.g. a protective agent) at the level of small particles or even at the molecular level (molecular dispersion).

In this context, the term "molecularly dispersed" or "molecular dispersion" is used in its generally accepted sense, i.e. as a dispersion in which the dispersed phase consists of individual molecules. Thus, as used herein, the term "molecularly dispersed" or "molecular dispersion" means any solid, semi-solid or liquid system in which component a (e.g. progesterone or estrogen) is dispersed at the molecular level in another component B (e.g. protective agent) such that component a is neither detectable in crystalline form by X-ray diffraction analysis nor in particulate form by any microscopic technique. It is also understood that component a is soluble in component B regardless of the nature and physical state of B. Thus, the term "molecularly dispersed" is used interchangeably with the term "molecularly dissolved".

As can be seen from the examples provided herein, the particle size of the particles comprising progesterone and a protective agent depends, at least to some extent, on the protective agent used. When carnauba wax is used as a protectant, d in some cases₉₀Particle size measurements give incredibly high values due to the formation of secondary aggregates or agglomerates. Such aggregates and agglomerates can be easily separated in the production of wafers. The particle size values specified in detail below refer to the particle size of the primary particles rather than aggregates and agglomerates.

As indicated above, the particle size of the particles comprising progesterone and the protective agent is 280 μm or less, for example 250 μm or less, such as 200 μm or less. In an interesting embodiment of the invention, d of said particles₉₀Particle size of 175 μm or less, e.g. d₉₀Particle size of 150 μm or less, e.g. d₉₀The particle size is less than or equal to 100 mu m.

In other words, d of the particles comprising progesterone and the protective agent₉₀The particle size is typically in the range 30 to 280 μm, for example 40 to 250 μm, such as 50 to 200 μm or 50 to 150 μm. d₉₀Specific examples of the particle size include the following values: about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about 100 μm, about 110 μm, about 120 μm, about 130 μm, about 140 μm, and about 150 μm. Similarly, d₅₀The particle size is generally from 5 to 80 μm, more typically from 10 to 75 μm. d₅₀Specific examples of the particle size include the following values: about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, and about 80 μm.

As used herein, the term "d" is used₉₀Particle size "is intended to mean the particle size distribution: according to the assumption of spherical particles, at least 90% of the particles have a particle size smaller than the nominal value, calculated from the volume distribution curve. Similarly, the term "d₅₀Particle size "is intended to mean the particle size distribution: according to the assumption of spherical particles, at least 50% of the particles have a particle size smaller than the nominal value, calculated from the volume distribution curve.

Thus, it is important to note that the terms "particle size", "particle size distribution", "particle size", "d" are used herein whenever possible₉₀”、“d₅₀"isochronal, it is to be understood that the specific values or ranges used therewith always mean as determined from the volume distribution curve on the assumption that spherical particles are present. The particle size distribution can be determined by a variety of techniques, such as laser diffraction, and is known to those skilled in the art. The particles may be spherical, substantially spherical or non-spherical, for example irregularly shaped particles or ellipsoidal particles. Because ellipsoidal particles or ellipsoids tend to precipitate to a lesser extent than spherical particles, they can be desirable because of the uniformity maintained in the film-forming matrix. When the granules containing progesterone and a protective agent are contained in the wafer, the particle size distribution can be determined by the following steps: the membrane-forming matrix is dissolved, the protected particles are isolated, and the protected particles are dried. The particle size distribution of the resulting particles can be determined, for example, by laser diffraction, as described above. For example, a Sympatec Helos laser diffractometer (focal length 125mm, gas flow volume 2.5 m) with a Sympatec rhodods module gas dispersion system (Sympatec rhodods module atmospheric dispersion system) may be used³H, prepressing for 2bar, dispersing pressure for 34bar, optical concentration for 0.8-20%, measuring time: 2 seconds, optical model: fraunhofer according to the hypothesis of spherical particles).

For particles comprising progesterone and a protective agent, these particles typically constitute less than 60% by weight of the unit dosage form, preferably less than 50% by weight of the unit dosage form, more preferably less than 40% by weight of the unit dosage form. As will be appreciated, the amount of particles comprising progesterone and a protective agent depends on the efficacy of the progesterone chosen. Thus, the particles comprising progesterone and a protective agent typically constitute from 0.1 to 50%, preferably from 1 to 40%, for example from 2 to 40%, such as from 5 to 30% by weight of the unit dosage form. Specific values include about 12%, about 15%, about 20%, and about 30% by weight of the unit dosage form.

As will be appreciated, the particles comprising the therapeutically active agent and the protective agent may comprise other excipients. However, in a preferred embodiment of the invention, the particles consist essentially of the therapeutically active agent (i.e. progesterone, estrogen or a combination of progesterone and estrogen) and the protective agent.

As can be appreciated from the examples provided herein, the encapsulation efficiency (encapsulation efficiency) is high and typically higher than 80%, for example higher than 85%, such as higher than 90%. Thus, the encapsulation efficiency is typically 80-100%, e.g. 85-100%, such as 90-100%. As used herein, the term "encapsulation efficiency" refers to the ratio of the amount of therapeutically active agent incorporated into the protected particle to the amount of active agent used to produce the protected particle.

As used herein, the term "water-soluble film matrix" refers to a film that comprises or consists of: water-soluble polymers, particles comprising at least one progestin and at least one protective agent, and optionally other auxiliary ingredients dissolved or dispersed in the water-soluble polymers.

The term "water-soluble polymer" as used herein refers to a polymer that is at least partially soluble in water, and preferably completely or mostly soluble in water or absorbs water. The water-absorbing polymers are generally referred to as "water-swellable polymers". The materials used in the present invention may be water soluble or water swellable at room temperature (about 20℃.) and other temperatures such as temperatures above room temperature. Also, the material may be water soluble or water swellable at pressures less than atmospheric pressure. Desirably, the water soluble polymer is water soluble, or is a water swellable polymer having at least 20 wt.% moisture absorption. Water swellable polymers having moisture absorption of 25 wt.% or more are also useful. The unit dosage forms of the present invention formed from such water-soluble polymers desirably have sufficient water solubility to dissolve upon contact with body fluids, particularly saliva.

The water-soluble matrix polymer of the invention (which typically constitutes the major part of the water-soluble film matrix) may be selected from cellulosic materials, synthetic polymers, gums, proteins, starches, dextrans and mixtures thereof.

Examples of cellulosic materials suitable for the purposes described herein include carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose, and combinations thereof. Particularly preferred cellulosic materials are hydroxypropyl methylcellulose and hydroxypropyl cellulose, especially hydroxypropyl methylcellulose.

Examples of synthetic polymers include polymers commonly used as Immediate Release (IR) coatings for drugs, such as may be available under the trade name KollicoatIR different grades of polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymers are commercially available. Other examples of synthetic polymers include polyacrylic acid and polyacrylic acid derivatives. Another advantage of using the above synthetic polymers (in particular PVA-PEG copolymers) is: they provide a stabilizing effect on the therapeutically active agent present in the unit dosage form by limiting the oxidative degradation of progesterone and estrogens, which are unsubstituted in position 6 and/or 7. This effect is particularly pronounced when the therapeutically active agent (typically an estrogen) is dispersed (particularly molecularly) in the membrane matrix. Such degradation is well known in the art and is often a problem with shelf life of the final solid formulation (see, e.g., T. Hurley et al, Steroids 2002; 67; 165-. The following estrogens, as well as the following progestins, stabilizing effects can be observed in particular: ethinyl estradiol, estradiol including therapeutically acceptable derivatives of estradiol, estrone, mestranol, estriol succinate, and conjugated estrogens (including equine conjugated estrogens such as estrone sulfate, estradiol 17 β -sulfate, and estradiol 17 α -sulfate); the progesterone is: levonorgestrel, norgestrel, norethindrone (nordehydrohydroxyprogesterone), dienogest, norethindrone acetate (norethindrone acetate), norethindrone diacetate, norethindrone, allylestrenol, lynestrenol, norgestrel, ethisterone, promeggestrelKetones, desogestrel, 3-keto-desogestrel, norgestimate, and gestodene.

Examples of water-soluble gums include gum arabic (gum arable), xanthan gum, tragacanth gum, acacia gum (acacia), carageenan, guar gum, locust bean gum, pectin, alginates, and combinations thereof.

Useful water-soluble protein polymers include gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, levin, collagen, and combinations thereof.

Examples of useful starches include gelatinized starches, modified starches or unmodified starches. The source of the starch can vary and includes amylopectin, tapioca, rice, corn, potato, wheat, and combinations thereof.

Other water-soluble polymers useful in the present invention include dextrins, dextrans, and combinations thereof; and chitin, chitosan (chitosin) and combinations thereof, polydextrose, and fructooligosaccharides.

The amount of progesterone incorporated into the unit dosage forms of the present invention will, of course, also depend on the potency of the progesterone chosen, but will generally be in the range of 0.1-30% (w/w) (based on the unit dosage form). Typically, the progesterone is incorporated in the unit dosage form of the present invention in an amount of 0.5-25% (w/w), such as 1-20% (w/w), preferably 1-15% (w/w), such as 2-10% (w/w), e.g. about 6% (w/w) or about 7.5% (w/w).

As discussed above, the unit dosage form preferably comprises drospirenone as the progestin component. Thus the unit dosage form typically comprises 0.25-5mg drospirenone, e.g. 1-4mg drospirenone, such as 2-4mg drospirenone, preferably 2.5-3.5mg drospirenone, most preferably about 3mg drospirenone. As discussed above, drospirenone may be complexed with a cyclodextrin.

Although the preferred progestin is drospirenone, it is within the scope of the invention to incorporate other progestins. More specifically, the unit dosage form may comprise desogestrel in an amount of 0.05 to 0.5mg, preferably 0.075 to 0.25mg, such as 0.1mg, 0.125mg or 0.15 mg; norethindrone diacetate in an amount of 0.25-2mg, preferably 0.75-1.5mg, e.g. 1 mg; levonorgestrel in an amount of 0.025 to 0.3mg, preferably 0.075 to 0.25mg, for example 0.1mg or 0.15 mg; norethindrone (nordehydrohydroxyprogesterone) in an amount of 0.2 to 1.5mg, preferably 0.3 to 1.25mg, e.g. 0.4mg, 0.5mg or 1 mg; norethindrone acetate (norethindrone acetate) in an amount of 0.5-2mg, preferably 1-1.5mg, e.g. 1mg or 1.5 mg; norgestrel in an amount of 0.1 to 1mg, preferably 0.25 to 0.75mg, e.g. 0.3mg or 0.5 mg; norgestimate in an amount of 0.1-0.5mg, preferably 0.15-0.3mg, e.g. 0.18mg, 0.215mg or 0.25 mg; cyproterone acetate in an amount of 0.5 to 3mg, for example 1 to 2mg, preferably 2 mg; dienogest in an amount of 0.25-4mg, such as 1-4mg, preferably 2-3mg, more preferably 2 mg; gestodene in an amount of 0.01-0.1mg, e.g. 0.025-0.1mg, such as 0.05-0.1mg, preferably 0.06-0.075mg, e.g. 0.060mg or 0.075 mg; and tibolone in an amount of 2-3mg, for example 2.5 mg. As indicated above, the most preferred progestins are gestodene, dienogest and drospirenone, in particular drospirenone.

In addition to the water-soluble matrix polymer and the particles comprising progesterone and the protective agent, the unit dosage form of the present invention may also comprise various auxiliary ingredients, such as taste-masking agents; organoleptic agents (organoleptic agents), such as sweeteners, taste modifiers (tast modifiers) and flavoring agents; anti-foaming and defoaming agents; a plasticizer; a surfactant; an emulsifier; (ii) agents to improve wetting of the particles (agents); a thickener; a binder; a coolant; saliva stimulating agents (saliva-stimulating agents), such as menthol; an antimicrobial agent; colorants, and the like. In a preferred embodiment of the invention, the unit dosage form does not comprise an absorption enhancer.

Suitable sweeteners include natural sweeteners and artificial sweeteners. Specific examples of suitable sweeteners include, for example:

a) water-soluble sweeteners such as sugar alcohols, monosaccharides, disaccharides, oligosaccharides and polysaccharides such as maltitol (maltit), xylitol, mannitol, sorbitol, xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monellin, stevioside, and glycyrrhizin;

b) water-soluble artificial sweeteners, such as the soluble saccharin salts, i.e., saccharin sodium or saccharin calcium salts; a cyclic acid salt; sodium, ammonium or calcium salts of 3, 4-dihydro-6-methyl-1, 2, 3-oxathiazin-4-one-2, 2-dioxide; potassium salt of 3, 4-dihydro-6-methyl-1, 2, 3-oxathiazin-4-one-2, 2-dioxide (acesulfame potassium); free acid forms of saccharin and the like;

c) dipeptide-based sweeteners, such as L-aspartic acid-derived sweeteners, e.g., L-aspartyl-L-phenylalanine methyl ester (aspartame), L- α -aspartyl-N- (2, 2, 4, 45 tetramethyl-3-thietanyl) -D-alaninamide hydrate, methyl esters of L-aspartyl-L-phenylglycerol and L-aspartyl-L-2, 5-dihydrophenylglycine, L-aspartyl-2, 5-dihydro-L-phenylalanine, L-aspartyl-L- (1-cyclohexene) -alanine, and the like;

d) water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, e.g. according to sucraloseDescription of the known products, chlorinated derivatives of common sugars (sucrose); and

e) protein-based sweeteners, such as thaurnatoccous danielli (Thaurnatin I and II).

Generally, an effective amount of sweetener is used to provide the desired level of sweetness for a particular unit dosage form, and this amount will vary with the sweetener selected. This amount is generally from about 0.01% to about 20% by weight of the unit dosage form, preferably from about 0.05% to about 10% by weight of the unit dosage form. These amounts can be used to achieve the desired sweetness level regardless of the flavor level achieved by any optional flavor oil used.

Useful flavoring agents (or flavors) include natural and artificial flavors. These flavouring agents may be selected from synthetic flavouring oils and spices, and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits etc., and combinations thereof. Non-limiting examples of flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and bitter almond oil. Artificial, natural or synthetic fruit flavors are also useful, such as vanilla, chocolate, coffee, cocoa and lemon oil, including lemon, orange, grape, lime (lime) and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavoring agents may be used alone or in combination. Commonly used flavors, whether used alone or in combination, include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors. Flavoring agents such as aldehydes and esters may also be used, including cinnamyl acetate, cinnamaldehyde, citral, acetal, dihydrocarvyl acetate, eugenyl formate, p-methylanisole, and the like. Other examples of aldehyde flavorings include, but are not limited to, acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamaldehyde (cinnamon); citral, i.e. alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropine (heliotropine), i.e. piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamic aldehyde (flavoured fruity flavour); butyraldehyde (butter, cheese); pentanal (butter, cheese); citronellal (modified, many types); decanal (citrus fruits); c-8 aldehyde (citrus fruit); c-9 aldehyde (citrus fruit); c-12 aldehyde (citrus fruit); 2-ethylbutyraldehyde (berry fruit); hexenal, i.e., trans-2 (berry fruit); tolualdehyde (cherry, almond); veratraldehyde (vanilla); 12, 6-dimethyl-5-heptenal, i.e., melonal (melon); 2-dimethyloctanal (greenfruit); and 2-dodecenal (citrus, orange); cherry; grapes; essential oils, such as menthol; mixtures thereof and the like.

The amount of flavoring agent used will generally depend on preference, as determined by factors such as the type of flavor, the individual taste, and the desired intensity. The amount can be varied to achieve the desired effect in the final product. Such variations are also within the ability of those skilled in the art without undue experimentation. Typically, amounts of about 0.01% to about 10% by weight of the film matrix are used.

As discussed above, the unit dosage form may also contain one or more surfactants, one or more emulsifiers, and/or other agents that help improve particle wetting. This is particularly preferred when the membrane matrix comprises particles comprising an estrogen, in particular ethinylestradiol, and the protective agent is a wax, in particular carnauba wax.

Examples of surfactants include nonionic, anionic, cationic and amphoteric surfactants. Nonionic surfactants are particularly preferred.

Examples of nonionic surfactants include, but are not limited to, the following:

reaction products of natural or hydrogenated castor oil with ethylene oxide. The natural or hydrogenated castor oil may be reacted with ethylene oxide in a molar ratio of about 1: 35 to about 1: 60, optionally with the PEG component removed from the product. Cremophor with trade nameThe PEG-hydrogenated castor oil obtained is particularly suitable, in particular CremophorS9 (polyoxyethylene-400-monostearate) and CremophorEL (polyethylene glycol 35 castor oil).

Polyoxyethylene sorbitan fatty acid esters, also known as polysorbates, for example under the trade name TweenKnown and commercially available types of mono-and trilaurates (mono-and tri-lauryl ester), palmitates (palmityl ester), stearates (stearyl ester) and oleates (oleyl ester) include the following products:

-Tween20[ polyoxyethylene (20) sorbitan monolaurate]

-Tween40[ polyoxyethylene (20) sorbitan monopalmitate]

-Tween60[ polyoxyethylene (20) sorbitan monostearate]

-Tween65[ polyoxyethylene (20) sorbitan tristearate]

-Tween80[ polyoxyethylene (20) sorbitan monooleate]

-Tween81[ polyoxyethylene (5) sorbitan monooleate]

-Tween85[ polyoxyethylene (20) sorbitan trioleate]

Although PEG does not function as a surfactant by itself, many PEG-fatty acid esters have useful surfactant properties. Among the PEG-fatty acid monoesters, lauric acid, oleic acid esters, and stearic acid esters are most useful.

Sorbitan fatty acid esters, also known as spans, such as sorbitan monolaurate (span20), sorbitan monostearate (span 60) and sorbitan monooleate (span 80).

Polyoxyethylene fatty acid esters, for example under the trade name MyrjPolyoxyethylene stearates of the type are known and commercially available.

Polyoxyethylene-polyoxypropylene copolymers and block copolymers, e.g. under the trade name Pluronic、EmkalyxAnd PoloxamerKnown and commercially available types of polyoxyethylene-polyoxypropylene copolymers and block copolymers.

-dioctyl sulfosuccinate or di- [ 2-ethylhexyl ] -succinate.

Phospholipids, in particular lecithins. Suitable lecithins include in particular soya lecithin.

PEG mono-and di-fatty acid esters, e.g. also under the trade name Miglyol840 known and commercially available PEG dicaprylate, PEG dilaurate, PEG hydroxystearate, PEG isostearate, PEG laurate, PEG ricinoleate, and PEG stearate.

Polyoxyethylene alkyl ethers, under the trade name BrijCommercially available polyoxyethylene alkyl ethers such as Brij92V and Brij35。

Fatty acid monoglyceride, e.g. glyceryl monostearate and glyceryl monolaurate

Sucrose fatty acid esters.

-cyclodextrin.

Tocopheryl esters, such as tocopheryl acetate and tocopheryl succinate.

Succinic acid esters, such as dioctyl sulfosuccinate or related compounds, such as di- [ 2-ethylhexyl ] -succinate.

Examples of anionic surfactants include, but are not limited to, sulfosuccinates, phosphates, sulfates, and sulfonates. Specific examples of the anionic surfactant are sodium lauryl sulfate, ammonium stearate, alpha-olefin sulfonate, ammonium laureth sulfate, ammonium stearate, sodium laureth sulfate, sodium octyl sulfate, sodium sulfonate, sodium sulfosuccinate, sodium trideceth sulfate, and triethanolamine lauryl sulfate.

The amount may be varied to achieve the desired result in the final product. Such variations are within the ability of those skilled in the art without undue experimentation. Typically, an amount of about 0.01% to about 10% by weight of the film substrate is used, preferably an amount of about 0.05% to 5% by weight of the film substrate is used.

As discussed above, the unit dosage form may also contain an anti-foaming and/or defoaming agent, such as simethicone (simethicone), which is a combination of methicone and silicon dioxide. The simethicone acts as an anti-foaming or defoaming agent that reduces or eliminates air from the film composition. The anti-foaming agent helps to prevent air from entering the composition, while the defoaming agent helps to remove air from the composition.

The unit dosage form of the present invention is most preferably in the form of a thin film which dissolves rapidly, primarily due to the large surface area of the film, which wets rapidly when exposed to the moist oral environment. In contrast to fast dissolving tablets, which are generally soft, brittle and/or friable, the film is solid and strong, but still flexible and does not require special packaging. As indicated above, the film is thin and can be carried in a patient's pocket, purse, or small notebook.

The film may be administered to the female mammal sublingually or lingually, to the palate, to the inner cheek, or to any oral mucosal tissue. The membrane may be rectangular, oval, circular, or a membrane cut to the specific shape of the tongue, palate or inner cheek may be applied as desired. The film hydrates rapidly and will adhere to the application site. Then, the film rapidly disintegrates.

Regarding the size of the unit dosage form of the present invention, the water-soluble film forming matrix is formed as a dry film having a thickness of 300 μm or less, preferably 250 μm or less, more preferably 200 μm or less, most preferably 150 μm or less, for example 120 μm or less, such as 100 μm or less. As can be appreciated from the above discussion of the particle size of the particles comprising progesterone and the protective agent, the particle size and thus to some extent the thickness of the membrane matrix is dependent to some extent on the protective agent actually selected. However, it is generally preferred that the thickness of the membrane matrix is in the range 10 to 150. mu.m, for example 20 to 125. mu.m, such as 30 to 100. mu.m. More preferably, the thickness of the membrane matrix is 35-90 μm, especially 40-48 μm. Specific and preferred examples include a thickness of about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about 100 μm, about 110 μm, or about 120 μm.

Thus, in some embodiments of the invention, the membrane matrix has a thickness of ≦ 300 μm, and comprises d of the particles of progesterone and the protective agent₉₀The particle size is less than or equal to 250 mu m; the thickness of the membrane matrix is 250 [ mu ] m or less and the d of the particles containing progesterone and the protective agent₉₀The granularity is less than or equal to 200 mu m; film matrix having a thickness of 200 [ mu ] m or less and comprising particles of progesterone and a protective agent₉₀The particle size is less than or equal to 175 mu m; film matrix having a thickness of 200 [ mu ] m or less and comprising particles of progesterone and a protective agent₉₀The particle size is less than or equal to 150 mu m; film matrix having a thickness of 150 [ mu ] m or less and comprising particles of progesterone and a protective agent₉₀The granularity is less than or equal to 100 mu m; or the thickness of the membrane matrix is less than or equal to 120 mu m, and the d of the particles containing the progesterone and the protective agent₉₀The granularity is less than or equal to 100 mu m;

the surface size (surface area) of the membrane substrate is typically 2-10cm²E.g. 3-10cm²E.g. 3-9cm²More preferably 4 to 8cm². Specific and preferred examples of the surface area include the following surface areas: about 4cm²、4.5cm²、5cm²、5.5cm²、6cm²、6.5cm²、7cm²、7.5cm²Or 8cm². Most preferably, the surface area is about 5cm²、5.5cm²、6cm²、6.5cm²Or 7cm²。

The total weight of the membrane matrix is typically from 5 to 200mg, for example from 5 to 150mg, such as from 10 to 100 mg. More preferably, the total weight of the membrane matrix is 10-75mg, for example 10-55 mg. Specific and preferred examples of the weight of the membrane substrate include the following weights: about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, or about 50 mg.

The unit dosage form may be prepared and attached to a second layer, a support layer or backing layer (liner), which is removed from the second layer prior to use, i.e., prior to entering the oral cavity. Preferably, the support or backing material is non-water soluble and may preferably be composed of polyethylene-terephthalate (pet) or other suitable materials known to the skilled person.

In one embodiment of the invention, the unit dosage form comprises progesterone as the only therapeutically active agent. However, in an interesting embodiment of the invention, the unit dosage form further comprises an estrogen.

In one embodiment of the invention, estrogen is incorporated into the unit dosage form, similar to progesterone, such that estrogen is not absorbed by the buccal route, i.e., so that as little estrogen as possible is dissolved in the mouth and as much estrogen as possible is dissolved in the stomach and/or intestine. This can be achieved by combining the estrogen with the protective agent in a similar manner as discussed above with respect to the progesterone component.

In a particular embodiment of the invention, the estrogen is incorporated into particles already comprising progesterone, i.e. according to this embodiment of the invention, the particles comprising at least one progestin and at least one protective agent further comprise at least one estrogen. Thus, in another aspect, the present invention relates to a unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin, at least one estrogen, and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

In another embodiment of the invention, the estrogen is incorporated in a different particle, i.e. in a particle comprising the protective agent but no progesterone. Thus, in another aspect, the present invention relates to a unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m;

c) the membrane matrix comprises particles, wherein the particles comprise at least one estrogen and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

d) The thickness of the film matrix is less than or equal to 300 mu m.

The estrogen may be selected from ethinyl estradiol, estradiol including therapeutically acceptable derivatives of estradiol, estrone, mestranol, estriol succinate and conjugated estrogens. More preferably, the estrogen is selected from the group consisting of ethinyl estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate. In a very preferred embodiment of the invention, the estrogen is ethinyl estradiol or estradiol, in particular ethinyl estradiol.

When ethinyl estradiol is present in a unit dosage form, the unit dosage form typically comprises 0.01 to 0.05mg of ethinyl estradiol, preferably 0.02 to 0.03mg of ethinyl estradiol. Specific amounts of ethinyl estradiol include about 0.01mg, about 0.015mg, about 0.020mg, about 0.025mg, or about 0.030 mg. Most preferably, the amount of ethinylestradiol is about 0.02mg of ethinylestradiol or about 0.03mg of ethinylestradiol. As discussed above, ethinyl estradiol may be complexed with a cyclodextrin. Thus, in a particularly interesting embodiment of the invention, the unit dosage form comprises about 3mg drospirenone and about 0.02mg ethinylestradiol, wherein the ethinylestradiol is optionally complexed with a cyclodextrin. In another particularly interesting embodiment of the present invention, said unit dosage form comprises about 3mg drospirenone and about 0.03mg ethinylestradiol

When estradiol is present in a unit dosage form, the unit dosage form typically contains 1-3mg estradiol, e.g., about 1mg estradiol, about 2mg estradiol, or about 3mg estradiol. Most preferably, the unit dosage form contains about 1mg estradiol. Thus, in a particularly interesting embodiment of the present invention, said unit dosage form comprises about 0.5mg, 1mg or 2mg drospirenone and about 1mg estradiol.

It is to be understood that all other statements above regarding particles comprising progestin and protective agent apply mutatis mutandis to aspects and embodiments in which such particles comprise at least one estrogen (irrespective of the presence or absence of progestin), except for the specific amount of estrogen incorporated in the particles. In other words, it is to be understood that all statements regarding protective agents, dissolution properties, water-soluble matrix polymers, etc. apply equally to estrogen-containing particles, and that this is to be understood irrespective of whether the particles contain progesterone and estrogen or whether the particles contain estrogen as the only therapeutically active agent.

As mentioned above, preferably, according to this embodiment of the invention, if the protective agent is a wax, a surfactant is included in the film matrix. The weight ratio of estrogen to wax is typically 1: 1 to 1: 4, for example about 1: 1, about 1: 2, about 1: 3, or about 1: 4.

In another embodiment of the invention, estrogen is incorporated into the unit dosage form, as opposed to progesterone, allowing the estrogen to be absorbed by the buccal route, i.e., so that as much of the estrogen as possible is dissolved in the mouth and thus absorbed by the oral mucosal route. This can be achieved by dissolving the estrogen (not in combination with any protective agent) in the water-soluble matrix polymer. Thus, in another aspect, the present invention relates to a unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer, wherein the water-soluble matrix polymer has dispersed therein, preferably molecularly dispersed therein, at least one estrogen;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

The estrogen may be selected from ethinyl estradiol, estradiol including therapeutically acceptable derivatives of estradiol, estrone, mestranol, estriol succinate and conjugated estrogens. More preferably, the estrogen is selected from the group consisting of ethinyl estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol and estrone sulfate. In a very preferred embodiment of the invention, the estrogen is ethinyl estradiol or estradiol, in particular ethinyl estradiol.

It will be appreciated that when the estrogenic component is incorporated into the unit dosage form of the above-described embodiments of the present invention (buccal administration), the bioavailability of the estrogen is improved as compared to embodiments of the present invention in which the estrogen is combined with a protective agent. This again has the result that significantly lower doses of estrogen than those described above can be used.

Thus, if estradiol is incorporated into the unit dosage form of this embodiment of the invention, the unit dosage form comprises from 5 to 1000 μ g estradiol, for example from 10 to 750 μ g estradiol, such as from 25 to 500 μ g estradiol. Typically, the unit dosage form comprises 10-200 μ g estradiol, e.g. 10-60 μ g estradiol or > 60-200 μ g estradiol.

In a preferred embodiment, the unit dosage form comprises an "ultra low" amount of estradiol, i.e. 10-60 μ g estradiol, e.g. 25-60 μ g estradiol, preferably 30-50 μ g estradiol, more preferably 40-50 μ g estradiol, e.g. about 40 μ g, 45 μ g, 46 μ g or 50 μ g estradiol. Alternatively, the "ultra low" amount is 10-60 μ g estradiol, for example 10-50 μ g estradiol, preferably 20-40 μ g estradiol, more preferably 25-35 μ g estradiol, e.g. about 30 μ g estradiol.

The unit dosage form may also contain a "very low" amount of estradiol, i.e. > 60-200. mu.g estradiol, e.g. 70-160. mu.g estradiol, such as 70-150. mu.g estradiol, preferably 80-150. mu.g estradiol, e.g. 80-120. mu.g estradiol or 120-150. mu.g estradiol. Specific estradiol doses include 80 μ g, 85 μ g, 90 μ g, 100 μ g, 115 μ g, 120 μ g, 130 μ g, 150 μ g, and 160 μ g estradiol.

The unit dosage form may also comprise an "intermediate" amount of estradiol, i.e. > 200-.

In another embodiment, the unit dosage form may comprise a "low" amount of estradiol, i.e., a dosage of about > 500-.

Specific examples of dosages of estradiol that may be incorporated into the unit dosage form include the following dosages: about 10. mu.g, 12.5. mu.g, 15. mu.g, 20. mu.g, 30. mu.g, 40. mu.g, 45. mu.g, 46. mu.g, 50. mu.g, 60. mu.g, 70. mu.g, 80. mu.g, 85. mu.g, 90. mu.g, 100. mu.g, 115. mu.g, 120. mu.g, 130. mu.g, 150. mu.g, 160. mu.g, 180. mu.g, 200. mu.g or 270. mu.g of estradiol.

The above-mentioned doses preferably correspond to daily doses. It is to be understood that the above dosages are the dosages indicated for anhydrous estradiol. If estradiol hydrates such as estradiol hemihydrate are used, or pharmaceutically acceptable esters of estradiol such as estradiol valerate are used, it is to be understood that dosages should be used which are therapeutically equivalent to the prescribed dosage of anhydrous estradiol. Determining pharmacologically/therapeutically equivalent dosages of such other forms is routine to those skilled in the art when effective dosages of anhydrous estradiol are known.

If ethinyl estradiol is incorporated into the unit dosage form of this embodiment of the invention, the unit dosage form typically comprises 10-20 μ g of ethinyl estradiol, for example about 15 μ g or 20 μ g of ethinyl estradiol.

Preparation of

The unit dosage forms of the present invention may be prepared by the processes and methods as shown in the examples and as described in WO 2007/073911.

The protected particles are typically prepared by dissolving the protective agent in a suitable organic solvent after addition of the progestin. Depending on the choice of protective agent, it is possible to deposit the protective agent on the surface of the progesterone particles (for example in the case of carnauba wax as protective agent) or to incorporate the progesterone in the form of a solid dispersion into particles comprising the protective agent and progesterone (for example in the case of cationic polymethacrylate copolymers as protective agent).

After removal of the organic solvent, the resulting microparticles are dried and optionally milled and sieved. The grinding equipment is selected according to the nature of the particles and the desired particle size, and for example, a rotary mill (rotor mill) or a jet mill (air jet mill) may be used. Alternatively, the progesterone can be dissolved together with the protective agent and spray dried at a suitable temperature (e.g., 30-50 ℃, such as at a temperature of about 35 ℃). In general, d of protected particles prepared by spray drying₅₀The particle size is about 5-50 μm.

The matrix polymer solution (coating solution) is generally prepared by adding a water-soluble matrix polymer to a suitable solvent (e.g., water or a mixture of an alcohol and water). As mentioned above, preferably, a surfactant is added if the protected particles contain an estrogen (especially ethinyl estradiol) and the protective agent is a wax (especially carnauba wax). It will be appreciated that the time and conditions required to dissolve the water-soluble matrix polymer will depend on the polymer and solvent used. Thus, in some cases, the water-soluble matrix polymer can be readily dissolved at room temperature and with only mild agitation, while in other cases, heat is applied to the system and vigorous agitation is applied. In a representative embodiment, the mixture is stirred for 1-4 hours, preferably about 2 hours, or until a solution is obtained. The solution is generally stirred at a temperature of 60-80 c, for example about 70 c. After cooling to room temperature, the protected particles are optionally dispersed in a small amount of solvent or solvent mixture, then poured into the matrix polymer solution and mixed thoroughly. The final mixing step and optional pre-dispersion step may also be performed by any method known to the skilled person, for example by using a pestle and mortar, or by stirring with a suitable stirrer (e.g. a propeller stirrer), or by high shear mixing, or by using a rotor-stator mixing device such as an ultra-turrax and/or using ultrasound. The resulting solution (coating solution) can be used for coating immediately or within a few days, preferably within a day. The various amounts of solvent, matrix polymer, etc. are adjusted to achieve a coating solution solids content of about 5-50 wt.%, preferably 10-40 wt.%, particularly 20-40 wt.%, for example about 25 wt.%, about 30 wt.%, about 33 wt.%, about 35 wt.%, and about 40 wt.%.

Other excipients, auxiliary ingredients and/or active drugs may be added during any of the above steps.

As discussed above, the unit dosage form of the present invention may comprise an estrogen dispersed (preferably molecularly dispersed) in a water-soluble film matrix. In this case, the estrogen is dissolved in a suitable solvent (e.g., ethanol and/or propylene glycol). The solution may be added to the solvent used to coat the solution prior to the addition of the water-soluble polymer. Alternatively, the solution may also be added after the water-soluble matrix polymer has dissolved. In this case, the solution may be added before, simultaneously with, or after the addition of the protected particles and before the final mixing step is performed.

If desired, the coating solution is degassed before being spread on a suitable support or backing layer (liner). Examples of suitable gaskets include, but are not limited to, polyethylene terephthalate (PET) gaskets, such as PerlasicLF75 (supplied by Perlen Converting), LoparexLF2000 (supplied by Loparex BV) and Scotchpack9742 (supplied by 3M Drug delivery Systems). In one embodiment of the invention, the coating solution is spread on a suitable liner by means of a spreading box and dried at room temperature for 12-24 hours. An opaque film is then produced which is subsequently cut or die-cut into pieces of the desired size and shape. Alternatively, the coating solution is used asThe film is coated onto a suitable liner and dried in-line at a drying temperature of 40-100 c using an automated Coating and drying apparatus (e.g., supplied by Coatema Coating Machinery GmbH, Dormagen, germany). An opaque film is then produced which is subsequently cut or die-cut into pieces of the desired size and shape.

Therapeutic uses and administration

As is apparent from the disclosure herein, the unit dosage form of the present invention is suitable for inhibiting ovulation in a female mammal, i.e. for providing contraception in a female mammal.

In another interesting embodiment, the present invention relates to a pharmaceutical formulation or kit consisting essentially of 21, 22, 23 or 24 (especially 21 or 24) individually removable unit dosage forms (wafers) and 7, 6, 5 or 4 (especially 7 or 4) individually removable unit dosage forms (wafers) not comprising any therapeutically active agent placed in a packaging unit. In another embodiment of the invention, the pharmaceutical formulation or kit does not comprise any placebo wafers, i.e. the invention relates to a pharmaceutical formulation or kit consisting essentially of 21, 22, 23 or 24 (especially 21 or 24) individually removable unit dosage forms (wafers) of the invention placed in a packaging unit. The unit dosage forms may be packaged separately (e.g., in a single pouch, in a multiple unit blister pack), or the unit dosage forms (wafers) may be packaged together, e.g., in a multiple unit dispenser.

The formulation (or kit) may be a monophasic formulation, i.e. a formulation in which the amount of progesterone and estrogen is maintained constant over the entire 21, 22, 23 or 24 day period. Alternatively, the amount of each or both of the active agents (i.e. progesterone and estrogen) may be varied over a period of 21, 22, 23 or 24 days to produce a multi-phasic formulation (e.g. a biphasic or triphasic formulation), such as the one described in US 4621079.

In another aspect, the present invention relates to a unit dosage form according to the invention for use in the treatment, alleviation or prevention of a physical disorder in a female mammal caused by insufficient endogenous estrogen levels, such as osteoporosis, headache, nausea, depression, vasomotor symptoms, urogenital atrophy symptoms, decreased bone mineral density or increased risk or incidence of bone fracture. In a preferred embodiment of the invention, the female mammal to be treated according to the invention is a postmenopausal woman, in particular a postmenopausal woman without removal of the uterus.

In another aspect, the invention relates to a unit dosage form of the invention for use in both inhibiting ovulation in a female animal (i.e. for providing contraception in a female mammal) and treating, alleviating or preventing a physical condition in a female mammal caused by insufficient endogenous estrogen levels, such as osteoporosis, headache, nausea, depression, vasomotor symptoms, urogenital atrophy symptoms, reduced or increased bone mineral density fracture risk or morbidity. The group of women who may benefit particularly from this treatment are women in the perimenopause (sometimes also referred to as "perimenopausal transition", see the North American Menopause Society: Menopause Practice: A Clinician's Guide, 3.Edition, 2007), who require hormone replacement therapy but still require contraceptive protection. According to this embodiment of the present invention, it is preferred that the wafers containing the therapeutically active agent are administered for 23 days or 24 days (particularly 24 days) in a 28 day administration cycle, followed by 5 days or 4 days (particularly 4 days) of wafers not containing any therapeutically active agent.

In another aspect, the invention relates to a unit dosage form of the invention for use in the treatment, alleviation or prevention of acne.

In another aspect, the invention relates to a unit dosage form of the invention for use in the treatment, alleviation or prevention of hypertension.

In another aspect, the present invention relates to a unit dosage form according to the invention for use in the treatment, alleviation or prevention of premenstrual syndrome (PMS) and/or premenstrual dysphoric disorder (PMDD).

Other embodiments

1. A unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

2. The unit dosage form according to embodiment 1, wherein said progestin is embedded in said protective agent.

3. The unit dosage form according to embodiment 2, wherein the progestin is present in the protective agent in the form of a solid dispersion.

4. The unit dosage form according to embodiment 1, wherein said progesterone is coated with said protective agent.

5. The unit dosage form according to any of the preceding embodiments, wherein the protective agent is a cationic polymethacrylate.

6. The unit dosage form of embodiment 5 wherein the cationic polymethacrylate is di-C based_1-4-alkyl-amino-C_1-4Alkyl methacrylates with neutral methacrylic acid C_1-6-copolymers of alkyl esters.

7. The unit dosage form of embodiment 6, wherein the cationic polymethacrylate is based on dimethylaminoethyl methacrylate with neutral methacrylic acid C_1-4-copolymers of alkyl esters.

8. The unit dosage form according to embodiment 7, wherein the cationic polymethacrylate is a copolymer based on dimethyl-aminoethyl methacrylate, methyl methacrylate and butyl methacrylate.

9. The unit dosage form according to embodiment 8, wherein the cationic polymethacrylate is poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1: 2: 1.

10. The unit dosage form according to any of embodiments 1-4, wherein the protective agent is a wax.

11. The unit dosage form of embodiment 10, wherein the wax is carnauba wax.

12. The unit dosage form according to any of the preceding embodiments, wherein the d of the particles₉₀Particle size of 250 μm or less, e.g. d₉₀Particle size of 200 μm or less, preferably d₉₀Particle size of 175 μm or less, e.g. d₉₀Particle size of 150 μm or less, e.g. d₉₀The particle size is less than or equal to 100 mu m.

13. The unit dosage form according to any of the preceding embodiments, wherein the d of the particles₉₀The particle size is in the range of 30 to 280. mu.m, such as 40 to 250. mu.m, such as 50 to 200. mu.m or 50 to 150. mu.m.

14. The unit dosage form according to any of the preceding embodiments, wherein the progestin is selected from the group consisting of levonorgestrel, norethindrone (nordehydrohydroxyprogesterone), dienogest, norethindrone acetate (norethindrone acetate), norethindrone diacetate, dydrogesterone, medroxyprogesterone acetate, norethindrone, allylestrenol, linegestrol, quinigestrol acetate, medrogestone, norelgestromine, demegestone, ethisterone acetate, megestrol, desogestrel, 3-ketodesogestrel, norgestimate, gestodene, telolone, cyproterone acetate, dienogest, and drospirenone.

15. The unit dosage form according to embodiment 14, wherein the progestin is selected from the group consisting of drospirenone, gestodene, and dienogest.

16. The unit dosage form according to embodiment 15, wherein said unit dosage form comprises 0.25-5mg drospirenone, e.g. 1-4mg drospirenone, such as 2-4mg drospirenone, preferably 2.5-3.5mg drospirenone, most preferably about 3mg drospirenone.

17. The unit dosage form according to any of the preceding embodiments, wherein said water-soluble matrix polymer is selected from the group consisting of cellulosic materials, gums, proteins, starches, synthetic polymers, dextrans and mixtures thereof.

18. The unit dosage form according to embodiment 17, wherein the water-soluble matrix polymer is cellulosic.

19. The unit dosage form of embodiment 18, wherein said cellulosic material is selected from the group consisting of carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose and hydroxypropylmethyl cellulose.

20. The unit dosage form according to embodiment 19, wherein the cellulosic material is hydroxypropyl methylcellulose or hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose.

21. The unit dosage form according to embodiment 17, wherein the water-soluble matrix polymer is a synthetic polymer.

22. The unit dosage form of embodiment 21, wherein the synthetic polymer is a polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymer.

23. The unit dosage form according to any of the preceding embodiments, wherein said film matrix has a thickness of 250 μm or less, preferably 200 μm or less, such as 150 μm or less, more preferably 120 μm or less, such as 100 μm or less.

24. The unit dosage form according to embodiment 23, wherein the thickness of the film matrix is 10-150 μm, such as 20-125 μm, e.g. 30-100 μm, preferably 35-90 μm, more preferably 40-80 μm.

25. The unit dosage form according to any of the preceding embodiments, wherein said unit dosage form further comprises at least one estrogen.

26. A unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin, at least one estrogen, and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

27. A unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m;

c) the membrane matrix comprises particles, wherein the particles comprise at least one estrogen and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

d) The thickness of the film matrix is less than or equal to 300 mu m.

28. A unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer, wherein the water-soluble matrix polymer has dispersed therein, preferably molecularly dispersed therein, at least one estrogen;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

29. The unit dosage form according to any of embodiments 25-28, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol including therapeutically acceptable derivatives of estradiol, estrone, mestranol, estriol succinate and conjugated estrogens

30. The unit dosage form according to embodiment 29, wherein said estrogen is selected from the group consisting of ethinyl estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, mestranol, and estrone sulfate.

31. The unit dosage form according to embodiment 30, wherein the estrogen is ethinyl estradiol or estradiol.

32. The unit dosage form of embodiment 31, wherein the estrogen is ethinyl estradiol.

33. The unit dosage form of embodiment 31, wherein the estrogen is estradiol.

34. The unit dosage form according to any of embodiments 25-33, wherein said unit dosage form comprises at least one surfactant.

35. The unit dosage form according to any of embodiments 26-34, wherein said film matrix comprises at least one surfactant.

36. The unit dosage form according to any of the preceding embodiments, wherein less than 25% (w/w), preferably less than 20% (w/w), more preferably less than 15% (w/w), most preferably less than 5% (w/w) of the progesterone is dissolved from the unit dosage form within 3 minutes when said unit dosage form is placed in a beaker containing 10ml of simulated saliva pH6.0 at 37 ℃ as dissolution medium.

37. The unit dosage form according to any of the preceding embodiments for use as a medicament.

38. The unit dosage form of any of embodiments 25-36 for use in inhibiting ovulation in a female mammal.

39. The unit dosage form of any of embodiments 25-36 for use in providing contraception in a female mammal.

40. A method of inhibiting ovulation in a female mammal, said method comprising administering a unit dosage form as defined in any one of embodiments 25 to 36 to a female mammal in need thereof.

41. A method of providing contraception in a female mammal, said method comprising administering to a female mammal in need thereof a unit dosage form as defined in any one of embodiments 25-36.

42. A unit dosage form as defined in any of embodiments 25 to 36 for use in the treatment, alleviation or prevention of a physical disorder in a female mammal that is caused by a deficiency in the level of endogenous estrogen.

43. The unit dosage form of embodiment 42, wherein said physical disorder is selected from the group consisting of osteoporosis, headache, nausea, depression, vasomotor symptoms, urogenital atrophy symptoms, decreased bone mineral density, and increased risk or incidence of bone fracture.

44. A method of treating, ameliorating or preventing a physical disorder in a female mammal caused by insufficient endogenous estrogen levels, the method comprising administering to a female mammal in need thereof a unit dosage form as defined in any one of embodiments 25 to 36.

45. The method of embodiment 44, wherein the physical disorder is selected from the group consisting of osteoporosis, headache, nausea, depression, vasomotor symptoms, urogenital atrophy symptoms, decreased bone mineral density, and increased risk or incidence of bone fracture.

The invention is further illustrated by the following non-limiting examples.

Examples

Example 1:

preparation of granules comprising protective agent

Example 1A: drospirenone/baraPalm wax

80g of carnauba wax (pharmaceutical grade) was dissolved in 1kg of n-heptane in a 2l double glass beaker at 60 ℃ while stirring at 400rpm until a clear solution was obtained.

To this solution was slowly added 80g of micronisation (d)₅₀＝2.2μm；d₉₀4.8 μm) to avoid clotting while adjusting the stirring rate to 600 rpm. The mixture was cooled to 20 ℃ at a cooling rate of 20 ℃/hour to obtain a drug containing microparticles coated with carnauba wax.

The particles containing drospirenone were filtered through a cellulose acetate filter and glass filter unit. The microparticles were then washed with 300ml ethanol (96%) to remove n-heptane residues and unencapsulated drospirenone.

The filtered microparticles were transferred to a glass bowl and dried at 30 ℃ for 2 hours.

The resulting batches of protected particles in which drospirenone was coated with a protecting agent had the following particle size. It can be seen that d is measured for certain batches₉₀The particle size is higher due to secondary agglomeration. Estimating the true d of the primary particle₉₀The particle size is from 40 μm to 60 μm.

The encapsulation efficiency is greater than 90%.

Example 1B: ethinyl estradiol/carnauba wax

80g of micronization (d) was used as described in example 1A₅₀＝1.5μm；d₉₀4.0 μm) instead of 80g of drospirenone.

The resulting batch of protected granules in which ethinylestradiol was coated with the protective agent had the following granulesAnd (4) degree. It can be seen that d is measured for certain batches₉₀The particle size is higher due to secondary agglomeration. Estimating the true d of the primary particle₉₀The particle size is from 30 μm to 75 μm.

The encapsulation efficiency is greater than 90%.

In a 300ml glass beaker, 20g drospirenone and 80g EudragitE100 was dissolved in 200ml of a mixture of ethanol and acetone 7+23(w + w) while stirring at 200rpm for 1 hour at room temperature. A clear solution was obtained.

The solution was then transferred to the siliconized disks. The solution was dried in a hood at ambient conditions for 3 days to remove the acetone. Sensory testing (sensory test) was used to indicate the absence of acetone. The rigid film thus obtained, having a thickness of a few millimeters, was broken up by hand into about 10cm²Part (c) of (a). These fractions were then ground using a rotary mill (Retsch ultra centrifugation mill ZM200) with cooling on dry ice. The ground product was sieved through a 100 μm sieve. D of the resulting protected particles in which drospirenone is present in the form of a solid dispersion in the protective agent₅₀Particle size 34 μm, and d₉₀The particle size was 100. mu.m. The protected particles are stored insulated (e.g., in a refrigerator) until the next use. The encapsulation efficiency is greater than 90%.

As described in example 1C, 10g ethinylestradiol/90 g Eudragit was usedE100 instead of 20g drospirenone/80 g EudragitE100 to prepare microparticles containing ethinyl estradiol. Ethinyl estradiol was found to be molecularly dispersed in the protective agent as a solid dispersion, as verified by X-ray analysis. D of the resulting protected particles in which ethinyl estradiol is present in molecularly dispersed form in the protective agent₅₀Particle size 48 μm, and d₉₀The particle size was 136 μm. The protected particles are stored insulated (e.g., in a refrigerator) until the next use. The encapsulation efficiency is greater than 90%.

The experiment as described in example 1D was repeated and the following particle size distribution was obtained: d₅₀The particle size is 46 mu m; d₉₀The particle size was 122 μm. The encapsulation efficiency is greater than 90%.

The experiment as described in example 1C was repeated and the following particle size distribution was obtained: d₅₀The particle size is 40 mu m; d₉₀The particle size was 129 μm. The encapsulation efficiency is greater than 90%.

20g of drospirenone and 80g of EudragitE100 was dissolved in 1000ml of ethanol (96%) and spray-dried using a laboratory spray dryer (Buchi 190, Switzerland). D of the resulting protected particles in which drospirenone is present in the form of a solid dispersion in the protective agent₅₀Particle size 6.6 μm, and d₉₀The particle size was 57 μm. The protected particles are stored insulated (e.g., in a refrigerator) until the next use. The encapsulation efficiency is greater than 90%.

Ethinylestradiol-containing microparticles were prepared as described in example 1G, using ethinylestradiol instead of drospirenone. Ethinyl estradiol was found to be molecularly dispersed in the protective agent as a solid dispersion, as verified by X-ray analysis. D of the resulting protected particles in which ethinyl estradiol is present in molecularly dispersed form in the protective agent₅₀Particle size 10 μm, and d₉₀The particle size was 73 μm. The protected particles are stored insulated (e.g., in a refrigerator) until the next use. The encapsulation efficiency is greater than 90%.

As described in example 1H, 10g ethinylestradiol/90 g Eudragit was usedE100 instead of 20g ethinylestradiol/80 g EudragitE100 to prepare microparticles containing ethinyl estradiol. Ethinyl estradiol was found to be molecularly dispersed in the protective agent as a solid dispersion, as verified by X-ray analysis. D of the resulting protected particles in which ethinyl estradiol is present in molecularly dispersed form in the protective agent₅₀Particle size 5.5 μm, and d₉₀The particle size was 13.8. mu.m. The protected particles are stored insulated (e.g., in a refrigerator) until the next use. The encapsulation efficiency is greater than 90%.

Example 2:

preparation of a particulate-containing film matrix (coating) solution

In a glass beaker, 43.96g of Kollicoat are added at 60-80 deg.CIR was dissolved in 100ml of purified water while stirring at 100rpm for 2 hours. A clear solution (polymer solution) was obtained. After cooling, the evaporated water was replaced.

6g of the granulate prepared in example 1A (drospirenone) and 40mg of the granulate prepared in example 1B (ethinylestradiol) were slowly added to the polymer solution with stirring. The stirring speed and time were adjusted to obtain a uniform dispersion (coating solution).

A coating solution was prepared as described in example 2A, except that the mixture was homogenized by a high shear homogenizer after the addition of the particles.

In a high shear homogenizer (Becomix RW2.5), 88.9g of the particles prepared in example 1A (drospirenone) and 0.593g of the particles prepared in example 1B (ethinylestradiol) were homogeneously dispersed in 222g of purified waterAnd 116g of 96% ethanol. 1121g of purified water was added and mixed with the particle dispersion. The particle dispersion was warmed to 60-80 ℃. Adding 651g of KollicoatIR and dissolved to obtain a polymer solution (coating solution) containing uniformly dispersed protected particles. After cooling the coating solution to room temperature, it was degassed under vacuum overnight.

In a glass beaker, 43.96g of Kollicoat are added at 60-80 deg.CIR was dissolved in 80ml of purified water while stirring at 100rpm for 2 hours. A clear solution (polymer solution) was obtained. After cooling, the evaporated water was replaced.

6g of the granules prepared in example 1A (drospirenone) and 40mg of the granules prepared in example 1B (ethinylestradiol) were dispersed in a mixture of 8ml of ethanol and 12ml of water, and then added to the polymer solution while stirring. The stirring speed and time were adjusted to obtain a uniform dispersion (coating solution).

In a glass beaker, 42.96g of Kollicoat are added at 60-80 deg.CIR was dissolved in 77ml of purified water while stirring at 100rpm for 2 hours. A clear solution (polymer solution) was obtained. After cooling, the evaporated water was replaced.

1g of menthol was dissolved in 3ml of ethanol (96%) while stirring under ambient conditions (ethanol solution).

6g of the granules prepared in example 1A (drospirenone) and 40mg of the granules prepared in example 1B (ethinylestradiol) were dispersed in a mixture of 8ml of ethanol and 12ml of water, and then added to the polymer solution while stirring. The stirring speed and time were adjusted to obtain a uniform dispersion. Then, an ethanol solution (coating solution) was added.

222mg of ethinylestradiol were dissolved in 116.4g of ethanol (96%) in a high shear mixer (Becomix 2.5RW) with stirring under ambient conditions. Then 222g of purified water (ethanol/water solution) was added.

89g of the granulate prepared in example 1A (drospirenone) were dispersed in an ethanol/water solution. 1121g of purified water was then added, mixed with the dispersion and heated to 60-80 ℃. 652g of Kollicoat are addedIR and dissolved to obtain a solution (coating solution).

88.9g of the particles prepared in example 1A (drospirenone) were dispersed in a 1: 1 mixture of 474g of ethanol (96%) and purified water (dispersion) at ambient temperature in a high shear mixer (Becomix 2.5 RW).

1.39g of estradiol hemihydrate was dissolved in 46.3g of ethanol (96%) while stirring under ambient conditions (ethanol solution). The ethanol solution was then added to the dispersion and homogenized. A mixture of 155.6g of ethanol (96%) and 785g of purified water is then added dropwise and homogenized. The mixture was then heated to 60-80 ℃. 650g of Kollicoat are addedIR and dissolved to obtain a solution (coating solution).

In a glass beaker, 43.882g of Kollicoat were added at 60-80 deg.CIR was dissolved in 78ml of purified water while stirring at 100rpm for 2 hours. A clear solution (polymer solution) was obtained. After cooling, the evaporated water was replaced.

118mg of estradiol valerate are dissolved in 2ml of ethanol (96%) while stirring under ambient conditions (ethanol solution).

6g of the granulate prepared in example 1A (drospirenone) are dispersed in a mixture of 8ml of ethanol and 12ml of water and then slowly added to the polymer solution while stirring. The stirring speed and time were adjusted to obtain a uniform dispersion (coating solution). Then, an ethanol solution (coating solution) was added.

Example 2I: HPMC matrix/drospirenone granules/ethinylestradiol granules

37.5g of sorbitol and 37.5g of propylene glycol were dissolved in 750g of purified water in a high shear mixer (Becomix RW 2.5). 150g of the granulate prepared in example 1C (drospirenone) and 2g of the granulate prepared in example 1D (ethinylestradiol) were slowly added with stirring and homogenized until a homogeneous dispersion of the granules was obtained. 273g of Hydroxypropylmethylcellulose (HPMC) was sprinkled on the aqueous particle dispersion and dissolved by stirring and homogenizing for 2 hours without any further heating (coating solution).

Example 2J: HPMC matrix/drospirenone/ethinylestradiol granules containing menthol

In a glass beaker, 3.75g of sorbitol was dissolved in 58ml of purified water at 60-80 ℃. 26.3g of Hydroxypropylmethylcellulose (HPMC) was sprinkled on the aqueous solution and dissolved by stirring for 2 hours without any further heating (polymer solution).

3.75g of propylene glycol and 1g of menthol were dissolved in 2ml of ethanol (96%) while stirring under ambient conditions (ethanol solution).

15g of the granulate prepared in example 1C (drospirenone) and 200mg of the granulate prepared in example 1D (ethinylestradiol) were slowly added to the cooled (. about.20 ℃ C.) polymer solution with stirring. The stirring speed and time were adjusted to obtain a uniform dispersion. Then the ethanol solution was added and mixed (coating solution).

Example 2K: HPMC matrix/ethinylestradiol/drospirenone granules

375g of Hydroxypropylmethylcellulose (HPMC) were dissolved in 900g of purified water at 60-80 ℃ in a high shear mixer (Beomix RW 2.5). The solution was then cooled to 25-45 deg.C (polymer solution). To avoid the formation of bubbles, the polymer solution was degassed under vacuum for 15-20 hours.

181mg of ethinyl estradiol were dissolved in 45g of propylene glycol while stirring under ambient conditions (propylene glycol solution).

186g of the granulate prepared in example 1C (drospirenone) were slowly added to the cooled (. about.20 ℃ C.) polymer solution while stirring and homogenizing. The speed and time of stirring and homogenization are adjusted to obtain a uniform dispersion. The propylene glycol solution was then added and mixed (coating solution).

Example 2L: HPMC matrix/estradiol/drospirenone granules

353g of Hydroxypropylmethylcellulose (HPMC) were dissolved in 850g of purified water in a high shear mixer (Beomix RW2.5) at 60-80 ℃. The solution was then cooled to 25-45 deg.C (polymer solution). To avoid the formation of bubbles, the polymer solution was degassed under vacuum for 15-20 hours.

1.1g of estradiol hemihydrate was dissolved in 42.5g of propylene glycol while stirring under ambient conditions (propylene glycol solution).

170g of the granulate prepared in example 1C (drospirenone) were slowly added to the cooled (. about.20 ℃ C.) polymer solution while stirring and homogenizing. The speed and time of stirring and homogenization are adjusted to obtain a uniform dispersion. The propylene glycol solution was then added and mixed (coating solution).

Example 2M: HPMC matrix/estradiol valerate/drospirenone granules

In a glass beaker, 3.75g of sorbitol was dissolved in 58ml of purified water at 60-80 ℃. 27.382g of Hydroxypropylmethylcellulose (HPMC) were sprinkled onto the aqueous solution and dissolved by stirring for 2 hours without any further heating (polymer solution).

3.75g of propylene glycol and 118mg of estradiol valerate are dissolved in 2ml of ethanol (96%) while stirring under ambient conditions (ethanol solution).

15g of the granulate prepared in example 1C (drospirenone) were slowly added to the cooled (. about.20 ℃ C.) polymer solution while stirring. The stirring speed and time were adjusted to obtain a uniform dispersion. Then, an ethanol solution (coating solution) was added.

In a high shear homogenizer (Becomix RW2.5), 88.9g of the particles prepared in example 1A (drospirenone) and 0.593g of the particles prepared in example 1B (ethinylestradiol) were homogeneously dispersed in a solution containing 0.05% (w/w) Tween80 of a mixture of 460g of purified water. Adding a solution containing 0.05% (w/w) Tween80g of purified water, and mixed with the particle dispersion. The particle dispersion was warmed to 60-80 ℃. 651g of Kollicoat IR were addedAnd dissolved to obtain a polymer solution (coating solution) containing uniformly dispersed protected particles. After cooling the coating solution to room temperature, it was degassed under vacuum overnight.

Example 3

Preparation of wafers

Example 3A

The coating solution was degassed and spread onto a polyethylene terephthalate (PET) liner (permatic) with the aid of a coating knife (casting knife)LF75) and dried at room temperature for 24 hours. An opaque film having a thickness of about 70 μm was prepared. By punching (punch out)7cm²Size samples wafers containing a drospirenone content of 3mg were obtained.

Example 3B

The coating solution was degassed and applied as a film to a polyethylene terephthalate (PET) liner (Perlasic)LF75) and dried on-line using an automatic Coating and drying apparatus (Coatema Coating Machinery GmbH, Dormagen, germany). A drying temperature of 70 ℃ was applied. An opaque film having a thickness of about 70 μm was prepared. By punching 7cm²Size samples obtained wafers containing a drospirenone content of 3mg and a total weight of about 50 mg.

Example 3C

The coating solution was degassed and applied as a film to a polyethylene terephthalate (PET) liner (Perlasic)LF75) and dried on-line using an automatic Coating and drying apparatus (Coatema Coating Machinery GmbH, Dormagen, germany). A drying temperature of 70 ℃ was applied. An opaque film having a thickness of about 90 μm was prepared. By punching for 5cm²Size samples obtained wafers containing a drospirenone content of 3mg and a total weight of about 50 mg.

Example 3D

The coating solution was degassed and applied as a film to a polyethylene terephthalate (PET) liner (Perlasic)LF75) and dried on-line using an automatic Coating and drying apparatus (Coatema Coating Machinery GmbH, Dormagen, germany). A drying temperature of 70 ℃ was applied. An opaque film having a thickness of about 70 μm was prepared. By punching for 5cm²Size samples obtained wafers containing a drospirenone content of 3mg and a total weight of about 35 mg.

Example 4:

preparation of wafers containing polystyrene Standard particles

In a glass beaker, 3.75g of sorbitol and 3.75g of propylene glycol were dissolved in 60ml of purified water at 60-80 ℃. 27.3g of Hydroxypropylmethylcellulose (HPMC) was sprinkled on the aqueous solution and dissolved by stirring for 2 hours without further heating. Four solutions were prepared.

3.5g of four different Standard polystyrene particles (obtained from Polymer Standard Services) having diameters of 10 μm, 20 μm, 40 μm and 50 μm, respectively, were slowly added to the above four solutions while stirring. The stirring speed and time were adjusted to obtain a uniform dispersion (coating solution).

The coating solution was spread to a polyethylene terephthalate (PET) liner (Perlasic) by means of a film knifeLF75) and dried at room temperature for 24 hours. Four opaque films with a thickness of about 100 μm were produced, each film containing about 50% of polystyrene standard particles of different diameters. The film was cut into 5cm²Sample size.

The sensory mouthfeel of the wafers was evaluated in a test group consisting of five subjects. The wafers were completely randomized and all appeared similar. The subject was informed that the wafer did not contain any active compound, but did not know any other information about the formulation and composition of the wafer. Scores ranged from 1 (no sensation) to 5 (sandy and sandy mouthfeel). The results (average) obtained are summarized below:

from the above results, it can be inferred that the particle size is very important for the taste of the resulting wafer. Obviously, the smaller the particle size, the better the mouthfeel.

Example 5

Preparation of a wafer containing drospirenone and no protective agent

500mg of Hydroxypropylmethylcellulose (HMPC) was sprinkled onto 2ml of purified water and dissolved by stirring at 60-80 ℃ for 2 hours.

30mg of micronized drospirenone were slowly added to the solution while stirring at 200rpm for 1 hour at room temperature. A homogeneous dispersion (coating solution) was obtained.

The coating solution was formed into opaque wafers as described in example 3A.

Example 6:

taste evaluation

The taste panel evaluated the bitterness of wafers prepared from the coating solution as described in examples 2A, 2E, 2I and 5 (unprotected drospirenone) (drospirenone had a bitter taste). All wafers were prepared as described in example 3A. The wafers were completely randomized and all appeared similar. The subject was informed of the active drug and the dosage present in the wafer, but was not aware of any information about the specific prescription of the wafer. The subject was advised to place the wafer on the tongue and disintegrate it within three minutes without swallowing. The subject must then expectorate any residual material from the mouth and then rinse with water.

The wafer prepared according to example 5 had a bitter taste. No bitterness could be detected with any other wafers.

In addition, the subjects were asked to describe the sensory mouthfeel of the samples. All wafer recipes were rated as acceptable.

Example 7:

formulation of

Example 7A

Example 7B

Example 7C

Example 7D

Example 7E

^*As beta-cyclodextrin inclusion compounds; corresponding to 0.020mg of ethinylestradiol

Example 7F

Example 7G

^*As beta-cyclodextrin inclusion compounds; corresponding to 0.020mg of ethinylestradiol

Example 7H

Example 7I

Example 7J

Example 7K

Example 7L

^*As beta-cyclodextrin inclusion compounds; corresponding to 0.015mg of ethinylestradiol

Example 7M

^*Corresponds to 0.090mg of estradiol

Example 7N

^*Corresponds to 0.090mg of estradiol

Example 7O

^*Corresponds to 0.090mg of estradiol

Example 7P

^*Corresponds to 0.090mg of estradiol

Example 7Q

^*Corresponds to 0.090mg of estradiol

Example 7R

^*Corresponds to 0.090mg of estradiol

Example 7S

^*Corresponds to 0.090mg of estradiol

Example 7T

^*Corresponds to 0.090mg of estradiol

Example 7U

Example 7V

Example 7W

Example 7X

Example 7Y

^*Corresponds to 0.090mg of estradiol

Example 7Z

^*Corresponds to 0.090mg of estradiol

Example 7AA

Example 7AB

Example 7AC

Example 7AD

Example 7AE

Example 7AF

Example 7AG

Example 7AH

Example 7AI

Example 7AJ

Example 7AK

The 50mg and 35mg wafers described in this example each had a surface area of 7cm²And 5cm². Moreover, a wafer similar to the 50mg wafer described above, but having a total weight of 40mg or 45mg, can be similarly prepared by using a corresponding lower amount of the matrix polymer. It should be understood that the amount of therapeutically active agent is the same regardless of the total weight and surface size of the wafer.

Similarly, a wafer similar to those described in examples 7A to 7AK above but containing 2mg dienogest, 0.06mg gestodene or 0.075mg gestodene instead of 3mg drospirenone may be similarly prepared by using a corresponding higher amount of the matrix polymer.

Example 8:

in vitro dissolution test

Example 8A: in vitro dissolution test representing conditions in the mouth

The dosage form was placed in the bottom of a 100ml glass beaker. 10.0ml of simulated saliva at 37 ℃ pH6.0 (composition: 1.436g of disodium hydrogen phosphate dihydrate, 7.98g of monopotassium phosphate and 8.0g of sodium chloride dissolved in 950ml of water, adjusted to pH6.0 and made up to 1000ml) were then added to the beaker (dissolution medium). The test was performed without any stirring or shaking (except that slight shaking was performed within the first 5 seconds of the test to ensure complete wetting of the dosage form). After 3 minutes, the contents of the beaker were visually inspected and the sample was aspirated, filtered (Spartan 30B filter) and analyzed for drospirenone content.

The wafers prepared from the coating solution described in example 2A and prepared as described in example 3A were subjected to the in vitro dissolution test described above, which represents the conditions in the mouth. The experiment was performed in triplicate. All wafers completely disintegrated after 3 minutes. The respective drospirenone release after 3 minutes was 3.5%, 2.8% and 3.5% (average 3.3%).

The wafers prepared from the coating solution described in example 2I and prepared as described in example 3A were subjected to the in vitro dissolution test described above, which represents the intraoral conditions. The experiment was performed in triplicate. All wafers disintegrated completely after 3 minutes. The release of drospirenone was 21.2%, 20.4% and 12.5% respectively (average 18.0%) after 3 minutes.

Example 8B: in vitro dissolution test representing intestinal conditions

Drug release was studied by using 1000ml of 0.05M phosphate buffer containing 0.5% (w/v) sodium lauryl sulfate at 37 ℃ pH6.0 as dissolution medium and USP XXXI paddle method (apparatus 2) with 50rpm as stirring rate.

The wafers prepared from the coating solution described in example 2A and prepared as described in example 3A were subjected to the in vitro dissolution test described above, which represents the intestinal conditions. It was found that about 75% of the drospirenone was dissolved after 15 minutes and about 80% of the drospirenone was dissolved after 30 minutes.

The wafer prepared from the coating solution described in example 2I and prepared as described in example 3A was subjected to the in vitro dissolution test described above, which represents the intestinal conditions. About 95% of the drospirenone was found to dissolve after 15 minutes.

Example 8C: in vitro dissolution test representing conditions in the gastrointestinal tract

Drug release was studied by using 1000ml of 0.05M acetate buffer containing 0.5% (w/v) sodium lauryl sulfate at 37 ℃ pH 4.5 as dissolution medium and USP XXXI paddle method (apparatus 2) with 50rpm as stirring speed.

The wafers of examples 7D, 7K, 7P and prepared as described in example 3b were subjected to the in vitro dissolution test described above, which represents the conditions in the gastrointestinal tract. About 95% of the drospirenone was found to dissolve after 15 minutes.

Example 8D: in vitro dissolution test representing conditions in the gastrointestinal tract

Drug release was studied by USP XXXI Paddle method (Instrument 2) using 1000ml of 0.05M acetate buffer at 37 ℃ pH 4.5 as dissolution medium and 50rpm as agitation speed.

The wafers of examples 7W, 7X, 7Y and prepared as described in example 3b were subjected to the in vitro dissolution test described above, which represents the conditions in the gastrointestinal tract. It was found that about 90% of the drospirenone was dissolved out after 15 minutes.

Example 9

Uniformity of content

The wafers prepared according to examples 7A, 7D, 7K, 7P, 7X and as described in example 3b were tested for content uniformity according to the United States Pharmacopoeia (USP). The determination was carried out by HPLC. The following acceptable values were measured.

Claims (25)

1. A unit dosage form comprising a water-soluble film matrix, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

2. The unit dosage form according to claim 1, wherein said progesterone is embedded in said protective agent.

3. The unit dosage form according to claim 2, wherein the progesterone is present in the protective agent in the form of a solid dispersion.

4. The unit dosage form according to claim 1, wherein said progesterone is coated with said protective agent.

5. The unit dosage form according to any of the preceding claims, wherein said protective agent is a cationic polymethacrylate.

6. The unit dosage form according to any of claims 1-4, wherein the protective agent is a wax.

7. The unit dosage form according to claim 6, wherein the wax is carnauba wax.

8. The unit dosage form according to any of the preceding claims, wherein the d of said particles₉₀Particle size of 250 μm or less, e.g. d₉₀Particle size of 200 μm or less, preferably d₉₀Particle size of 175 μm or less, e.g. d₉₀Particle size of 150 μm or less, e.g. d₉₀The particle size is less than or equal to 100 mu m.

9. The unit dosage form according to any of the preceding claims, wherein the d of said particles₉₀The particle size is in the range of 30 to 280. mu.m, such as 40 to 250. mu.m, such as 50 to 200. mu.m or 50 to 150. mu.m.

10. The unit dosage form according to any of the preceding claims, wherein the progestin is selected from the group consisting of levonorgestrel, norethindrone (nordehydrohydroxyprogesterone), dienogest, norethindrone acetate (norethindrone acetate), norethindrone diacetate, dydrogesterone, medroxyprogesterone acetate, norethindrone, allylestrenol, linegestrol, quinigestrol acetate, medrogestone, norelgestromine, demegestone, ethisterone acetate, megestrol, desogestrel, 3-ketodesogestrel, norgestimate, gestodene, telolone, cyproterone acetate, dienogest, and drospirenone.

11. The unit dosage form according to claim 10, wherein said progestin is selected from the group consisting of gestodene, dienogest, and drospirenone.

12. The unit dosage form according to claim 11, wherein said unit dosage form comprises 0.25-5mg drospirenone, such as 1-4mg drospirenone, such as 2-4mg drospirenone, preferably 2.5-3.5mg drospirenone, most preferably about 3mg drospirenone.

13. The unit dosage form according to any of the preceding claims, wherein said water-soluble matrix polymer is selected from the group consisting of cellulosic materials, gums, proteins, starches, synthetic polymers, dextrans and mixtures thereof.

14. The unit dosage form according to any of the preceding claims, wherein said film matrix has a thickness of 250 μm or less, preferably 200 μm or less, such as 150 μm or less, more preferably 120 μm or less, such as 100 μm or less.

15. The unit dosage form according to claim 14, wherein said film matrix has a thickness of 10-150 μm, such as 20-125 μm, such as 30-100 μm, preferably 35-90 μm, more preferably 40-80 μm.

16. The unit dosage form according to any of the preceding claims, wherein said unit dosage form further comprises at least one estrogen.

17. The unit dosage form of claim 16, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin, at least one estrogen, and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

18. The unit dosage form of claim 16, wherein

a) The film matrix comprises at least one water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m;

c) the membrane matrix comprises particles, wherein the particles comprise at least one estrogen and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m;

d) the thickness of the film matrix is less than or equal to 300 mu m.

19. The unit dosage form according to any of claims 16-18, wherein said film matrix comprises at least one surfactant.

20. The unit dosage form of claim 16, wherein

a) The film matrix comprises at least one water-soluble matrix polymer, wherein at least one estrogen is dispersed in the water-soluble matrix polymer;

b) the membrane matrix comprises particles, wherein the particles comprise at least one progestin and at least one protective agent, and wherein the particles have a d₉₀The granularity is less than or equal to 280 mu m; and is

c) The thickness of the film matrix is less than or equal to 300 mu m.

21. The unit dosage form according to claims 16-20, wherein said estrogen is selected from the group consisting of ethinyl estradiol, estradiol including therapeutically acceptable derivatives of estradiol, estrone, mestranol, estriol succinate and conjugated estrogens.

22. The unit dosage form according to any of the preceding claims, wherein less than 25% (w/w), preferably less than 20% (w/w), more preferably less than 15% (w/w), most preferably less than 5% (w/w) of the progesterone is dissolved from the unit dosage form within 3 minutes when the unit dosage form is placed in a beaker containing 10ml of simulated saliva pH6.0 at 37 ℃ as dissolution medium.

23. The unit dosage form according to any of the preceding claims for use as a medicament.

24. The unit dosage form according to any of claims 16-22 for use in inhibiting ovulation in a female mammal.

25. The unit dosage form according to any of claims 16-22, for use in providing contraception in a female mammal.