HK1002172B - Process of making dosage units by wet granulation - Google Patents

Description

Process for preparing dosage units by wet granulation

The present invention relates to a process for the preparation of dosage units containing at least desogestrel or Org30659 (17 alpha-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one) and present in an amount of about 0.005-1.0% by weight of each pharmaceutical dosage unit.

The preparation of tablets and other solid or dry pharmaceutical preparations is well known. The preparation of tablets, capsules and pills and their respective components is described, for example, in the standard english work Remington's Pharmaceutical Sciences of Gennaro et al (18 th edition, Mack Publishing Company, 1990, see especially part 8, Pharmaceutical preparations and their preparation).

The preparation method of the tablet comprises a wet granulation method, a dry granulation method and a direct compression method.

The wet granulation process involves weighing out the amounts of the ingredients (including solvent), mixing the ingredients, granulating them, masking their moisture, drying, dry sieving, lubricating and compressing the resulting mixture into tablets. These steps result in at least a suitably homogeneous tablet. A drawback of wet granulation is that some solvents are used which are undesirable when sometimes from an environmental and safety point of view.

Other problems arise when using some very potent pharmaceutical compounds in providing the desired tablet uniformity. For example, very potent steroids may require only a small dose of the compound per tablet (e.g., < 1.0mg/100mg tablet) and may not always be distributed completely throughout the tableting mixture, which may result in some tablets having a relatively high amount of steroid (i.e., "high potency tablets") while other tablets contain a lower amount of steroid or may not be present at all.

No solution to these problems in the dry mixing step is provided in european patent application 503,521.

The present invention provides a new solution to the problem of obtaining tablets of desogestrel or Org30659 with a very homogeneous content and containing a small dose of micronized or finely ground steroidal progestogen by wet granulation techniques, wherein the progestogen and optionally pharmaceutically acceptable excipients are mixed with water and granulated. The resulting granules may be optionally mixed with pharmaceutically acceptable adjuvants and compressed into tablets.

The process is well suited for tablets of desogestrel or Org30659 containing small doses of steroidal progestogens, wherein desogestrel or Org 30569 is present in an amount of 0.005-1.0%, preferably 0.01-0.5% by weight of each pharmaceutical dosage unit. Desogestrel is also understood to be its active metabolite 3-keto-desogestrel.

The progestogen desogestrel and Org30659 can be mixed with an estrogen selected from the group consisting of Ethinyl Estradiol (EE), estradiol and mestranol. Typically a mixture of progestin and estrogen is used. Most preferred are tablets containing a progestogen and ethinyl estradiol.

Since progestogen-containing tablets (and tablets also containing Org 30659) are known to be unstable to moisture, attempts have been made to remove the water by manufacturing methods such as dry granulation or wet granulation with anhydrous organic solvents. For example, marketed products (Marvelon)^R) Are contained in impermeable bags to prevent the tablets from coming into contact with the surrounding environment. More particularly, it has now been found that the process of the present invention, which comprises granulation in an aqueous medium, provides granules of desogestrel or Org30659 and ethinyl estradiol from which tablets are made that are more moisture stable than tablets made without water.

Wet granulation differs from dry granulation in that water or organic solvents are used in the wet granulation process to produce the chunks or granules.

The most widely used granulation processes in the pharmaceutical industry are the fluid bed granulation process and the wet mass granulation process, wherein a liquid is added to a powder or granulate in a container (which may provide a granulate or a mass) equipped with any type of stirrer. Various operations can be performed in wet (block) granulation, including: grinding the drug and excipients, mixing the ground powders to produce a binding solution, mixing the binding solution with the powder mixture to form a wet mass, coarse sieving the wet mass, drying the wet granulate, mixing the sieved granulate with a lubricant and a disintegrant, and finally filling the granulate into capsules or compressing the granulate into tablets. It will be apparent that some steps may be combined or eliminated or specific steps included, based on the excipients selected and the size of the pieces and the equipment selected. Common methods of granulation, see, for example, Pharmaceutical Dosage Forms: tablets (Volume 1), ED.H.A.Lieberman, L, Lachman, J.B.Schwartz (1989), Marcel Dekker Inc.New York and Basel pp.131-190.

The advantages of wet granulation include improved cohesiveness and compressibility of the powder, good distribution and uniformity of the content of micronized or milled drug in small doses, reduction of many dusts and air pollution and prevention of separation of the components.

Small-scale production can be achieved by a method of mixing and moistening agglomerates in a mortar or stainless steel vessel, while for large-scale production, double-walled kneaders, compound cone mixers, planetary mixers, rotary granulators, high-shear mixers, and fluidized bed granulation equipment can be used. General mixing methods are disclosed in Pharmaceutical Dosage Forms (second volume) Marcel Dekker inc. new York, written by h.a. lieberman, l.lachman, j.b. schwartz (1990) and Basel pages 1-71. The dry excipients and the micronized or ground active ingredient are mixed in a suitable mixer, preferably one capable of mixing and granulation, such as a Gral high shear mixer, after which an aqueous solution of a binder is added. Another preferred method is to suspend the active ingredient in an aqueous solution of a binder, add the suspension to a mixture of excipients and granulate.

Granules and tablets prepared by wet granulation consist of several inert substances which can generally be found in conventional solid oral dosage forms. These components can be divided into excipients which help the formulation produce satisfactory processing and tabletting characteristics, such as diluents, binders, glidants and lubricants, and excipients which give the finished tablet the desired physical characteristics, such as disintegrants and colorants. If a film coating is provided to the desired tablet, it is described, for example, in Pharmaceutical Dosage Forms (third volume) Marcel Dekker Inc. New York and Basel, pages 93-125, written by H.A. Lieberman, L.Lachman, J.B. Schwartz (1990).

Diluents (fillers) or fillers generally make up the major part of the tablet. The most commonly used diluent groups include water insoluble calcium phosphates (di-and tri-valent), calcium sulfate dihydrate, calcium carbonate, starch, modified starch and microcrystalline cellulose and water soluble lactose, sucrose, dextrose, mannitol and sorbitol.

The substance that binds the powders together and provides cohesiveness to the tablet is a binder or adhesive. The binder can be added dry and mixed with the diluent and drug. In this case, water or other solvent is added to activate the binder. In other production methods, the adhesive is soluble in or slurried in a liquid, and then added to the mixed powder in this form. Conventional binders include gelatin, water-soluble modified starches and sugars such as sucrose, glucose, dextrose, molasses and lactose. Natural and synthetic gums that have been used include: tragacanth, magnesium aluminum silicate, acacia, calcium ammonium alginate, sodium alginate, carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol and clays such as magnesium aluminosilicate. Depending on the solubility of the binder in the different liquids, a powder mixture of water, a water-solvent mixture and an organic solvent is added to make a solution.

We refer to the substance that enhances flow properties as glidant. Such as silicon dioxide, magnesium lauryl sulfate, magnesium aluminum silicate, magnesium oxide, talc or clay can be incorporated into the formulation to reduce inter-particle friction and solve problems associated with material flow from large to small pores in tableting.

Most lubricants are added to prevent friction and wear during the process before filling into capsules or sachets or tabletting. Some lubricants also have corresponding anti-stick properties when the compressed tablet particles adhere to the punch and die wall surfaces. Examples of lubricant groups are metal stearates (magnesium stearate), hydrogenated vegetable oils, high melting waxes and corn starch.

Disintegrants are a component incorporated into a tablet to aid disintegration and dissolution of the tablet to release the active ingredient. The total weight of disintegrant is added to the granulate prior to tableting, or it may be added to the total mass of powdered material prior to the start of wet granulation or it may simply be divided into a portion prior to wet granulation and a portion prior to drying the granulate. Examples of disintegrating agents that can be used are starch (starch 1500), microcrystalline cellulose (Avicel PH 101 and Avicel PH 102), purified lignocellulose, alginic acid, sodium starch glycolate, guar gum, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, and ion exchange resins.

The tablets made by the process of the present invention are free of organic solvents and contain a progestogen selected from desogestrel and Org30659, present in an amount of 0.005 to 1.0% by weight per pharmaceutical dosage unit, a minor amount of water of less than 20% (e.g., 0.5 to 20%) and preferably less than 10% by weight, and optionally an estrogen. The preferred progestogen is desogestrel and the estrogen is ethinyl estradiol. The water content can vary and depends on the drying conditions. However, there is always a minor amount of water in the tablet, generally less than 10% and preferably about 0.5 to 10% by weight water.

The following examples serve to illustrate the invention in further detail.Example I

Forming the active ingredient into a homogeneous granulate comprising (per tablet): desogestrel (micronized) 150. mu. gEE (micronized) 30. mu.g hydroxypropyl cellulose 1.95mg corn starch 6.50mg colloidal silicon dioxide 0.98mg magnesium stearate 0.33mg lactose to 65mg

To prepare a 1kg batch, lactose 200M and corn starch were charged to a Gral 10 high shear mixer. After mixing for 1 minute, a suspension of desogestrel and EE (acetylene glycol) in an aqueous solution of hydroxypropyl cellulose (125ml) was dosed to the mass. The beaker was then rinsed with 25ml of water, followed by addition of the mixture. The mixture was granulated with Gral 10 for 2.5 minutes. The resulting wet granules were dried in a Marius vacuum chamber at 40 ℃ under reduced pressure for 4 hours. After drying and screening with a 710 μm sieve using an Erweka apparatus, the particles were mixed with colloidal silicaAnd magnesium stearate. The granules are then compressed into tablets.Example II

Granules containing the composition of example I were prepared. Granulation was performed in the binder solution with ethanol instead of water.Example III

The tablets of example I and example II were stored at 40 ℃ with Relative Humidity (RH) of 10 and 95%, respectively. The degradation of desogestrel was calculated.

	Degradation (%)
		10％RH 95％RH
	Tablet of example II		1 4
Tablet of example I		0 1

Tablets made without aqueous binder solution had a sensitivity to humidity on storage (example II), while tablets made with aqueous binder solution had a lower sensitivity to humidity and improved stability (example I).Example IV

The active ingredient is formed into uniform granules containing (per tablet): org30659 (ground) 60. mu.g hydroxypropyl cellulose 1.95mg corn starch 6.50mg magnesium stearate 0.325mg lactose 56.165mg

To prepare a 1kg batch, lactose 200M and corn starch were charged to a Gral 10 high shear mixer. After mixing for 1 minute, a suspension of Org30659 (17 α -17-hydroxy-11-methylene-19-norpregna-4, 15-di-en-20-yn-3-one) in an aqueous granulation solution of hydroxypropyl cellulose (125ml) was dosed to the mass. The beaker was then rinsed with 25ml of water, followed by addition of the mixture. The mixture was granulated with Gral 10 for 2.5 minutes.

The wet mass obtained was dried for 4 hours in a Marius vacuum chamber at a low pressure of 40 ℃. After drying and sieving through a 710um sieve using an Erweka unit, the granules were mixed with magnesium stearate. The granules are then compressed into tablets.

Example V

Granules having the composition of example IV were prepared. Granulation was performed in the binder solution with ethanol instead of water.

Example VI

The tablets of example IV and example V were stored in open glass containers at 30 ℃ with Relative Humidity (RH) of 10 and 95%, respectively. The degradation of Org30659 was calculated.

	Degradation (%)
		10％RH 95％RH
	Tablet of example V		0 6
Tablet of example IV		0 0

Tablets made without aqueous binder solution had a sensitivity to humidity on storage (example V), while tablets made with aqueous binder solution had a lower sensitivity to humidity and improved stability (example IV).

Example VII

The active ingredient is formed into uniform granules containing (per tablet): desogestrel (micronized) 150. mu. gEE (micronized) 30. mu.g hydroxypropyl cellulose 1.95mg corn starch 6.50mg colloidal silicon dioxide 0.98mg magnesium stearate 0.33mg lactose to 65mg

To prepare a 1kg batch, lactose 200M and corn starch, desogestrel and EE (ethinyl estradiol) were charged into a Gral 10 high-speed shear mixer. After mixing for 1 minute, the suspension in the hydroxypropyl cellulose (125ml) aqueous granulation solution was dosed to the mass. The beaker was then rinsed with 25ml of water, followed by addition of the mixture. The mixture was granulated with Gral 10 for 2.5 minutes.

The resulting wet mass was dried in a Marius vacuum chamber at 40 ℃ under reduced pressure for 4 hours. After drying and sieving through a 710 μm sieve using an Erweka apparatus, the granules were mixed with colloidal silicon dioxide and magnesium stearate. The granules are then compressed into tablets.

Example VIII

The active ingredient is formed into uniform granules containing (per tablet): org30659 (ground) 60. mu.g polyvinylpyrrolidone 1.95mg corn starch 6.50mg magnesium stearate 0.325mg lactose to 65mg were granulated and compressed into tablets according to the method of example IV.

Example IX (comparative example)

Particles with the composition of example VIII were prepared with acetone instead of water. The tablets thus obtained were stored in open glass containers at 30 ℃ and 40 ℃ with a relative humidity of 75% for 12 months. The tablets of example VIII were stored under the same conditions and the percentage of starting content at zero time was calculated:

	30℃	40℃
			tablet of example VIII	94.4％	73.6％
Tablet of example IX	64.1％	44.5％

Example XI

A tablet was prepared containing the following components: org30659 (ground) 7.5. mu.g estradiol 2mg hydroxypropyl cellulose 1.95mg corn starch 30% colloidal silicon dioxide 0.98mg magnesium stearate 0.325mg lactose to 65mg granules were granulated with 280ml granulation solution according to the method of example IV. Tabletting on a rotary press.

Claims (7)

1. A process for the preparation of pharmaceutical dosage units comprising at least one steroidal progestogen selected from desogestrel and Org30659, present in an amount of 0.005 to 1.0% by weight of each pharmaceutical dosage unit, characterized in that water is mixed with the progestogen and optionally pharmaceutically acceptable excipients and granulated.

2. A process according to claim 1, wherein the granulate, optionally in admixture with pharmaceutically acceptable adjuvants, is compressed into tablets.

3. The method according to claim 1 or 2, wherein the progestogen is present at 0.01 to 0.5% by weight of each pharmaceutical dosage unit.

4. A method according to any one of claims 1-3 wherein the progestogen is mixed with an estrogen.

5. A method according to any one of claims 1-4 wherein the progestogen is desogestrel or wherein desogestrel is mixed with ethinyl estradiol.

6. An organic solvent free tablet comprising at least one steroidal progestogen selected from desogestrel and Org30659, a minor amount of water less than 20% by weight and optionally an estrogen, wherein desogestrel and Org30659 are present in an amount of 0.005 to 1.0% by weight of each pharmaceutical dosage unit.

7. A tablet according to claim 6 wherein the progestogen is desogestrel and the estrogen is ethinyl estradiol.