Steroid hormone products and methods for preparing them   

This application is a divisional of U.S. application Ser. No. 10/022,138, filed on Dec. 13, 2001, which claims the benefit of U.S. Provisional Application No. 60/255,669, filed on Dec. 14, 2000, which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to steroid hormone products comprising at least one steroid active ingredient mixed with an excipient and having improved dissolution and release rate properties. More particularly, the invention provides an oral contraception product having an improved dissolution profile. The invention further relates to methods for making such steroid hormone products, either with or without the use of solvents.

As used herein, the term “steroid hormone product” is a physically discrete unit suitable as a unitary dosage for a human host. The product contains a predetermined quantity of at least one steroid active ingredient effective to produce a desired effect. Examples, of such products are tablets, capsules, caplets, pills or discrete quantities of powder.

BACKGROUND OF THE INVENTION

Oral contraceptives first became available in the early 1960\'s. Since then, a number of regimens for controlling ovulation and contraception by the administration of hormones have become known and are readily available. Oral contraceptive formulations typically contain an estrogen and a progestin. In addition to these steroid active ingredients, the formulation may contain an excipient including various grades of lactose, additives and fillers such as pregelatinized starch and magnesium stearate, and a colorant such as an aluminum oxide lake.

Solvent-based processes, referred to herein as “wet processing” have been commonly employed for many years to make commercial quantities of steroid hormone products, such as oral contraceptives containing steroid active ingredients, According to one well-known process, an active ingredient, such as a steroid hormone, is dissolved in an appropriate volatile solvent and sprayed onto a bed of a pharmaceutically acceptable excipient powder until a desired concentration of the active ingredient per unit weight of powder is achieved. In general, the solvent employed is compatible with the active ingredient and the chosen excipient and can be removed under conditions that will not result in the degradation of the active ingredient. Particularly suitable solvents for use with steroid hormone active ingredients include alcohols such as methanol, ethanol and propanol, ketones such as acetone, hydrocarbons such as ethylene chloride and chloroform, and mixtures of one or more of these solvents with water. The solution is typically sprayed onto the bed of excipient powder in a suitable processor, such as a V-blender with an intensifier bar or a fluid bed processor. The solution and powder are then thoroughly mixed in the processor to ensure uniform dispersion of the active ingredient in the excipient. After mixing, the solvent is removed by the application of heat and/or vacuum to provide a dry mixture.

In an alternative wet processing technique, referred to by those skilled in the art as high sheer wet granulation, the solvent is not sprayed onto the excipient but is, instead, mixed directly with the excipient powder in a high shear blender. Subsequent to mixing, the solvent is removed as described above to provide a dry mixture.

Wet processing provides a number of advantages, including powder blends that have a uniform distribution of active ingredient and that suffer only minimal segregation under usual conditions of storage and handling. Steroid hormone products prepared from these blends typically exhibit excellent content uniformity.

A major disadvantage of these solvent-based processes is that environmentally objectionable organic solvents are generally required in those cases where the steroid active ingredient has poor water solubility. Such solvents often pose safety hazards during handling, in addition to the hazards they present when they are released into the environment. Increasingly, health regulatory authorities are objecting to the use of such solvents due to their toxicity and mutagenicity.

Accordingly, a dry granulation or direct compression process would be preferable for active ingredients that would generally otherwise require the use of an organic solvent. Such dry granulation or direct compression processes will be referred to herein as “dry processing”. Dry processing generally involves fewer steps than solvent-based wet processing and does not require elevated temperatures that can reduce the potency of temperature-sensitive active ingredients. Dry processing is also especially suitable for products that include steroid hormones sensitive to the moisture associated with wet processing via aqueous granulation. The absence of expensive organic solvents and the required evaporation steps also makes dry processing economically more attractive.

U.S. Pat. No. 5,382,434 has proposed pharmaceutical preparations containing steroids (e.g., progestin and/or estrogen) and an excipient (e.g., lactose) made without the use of solvents. According to the \'434 patent, at least 80% of the steroid must be bound to the excipient and the excipient must have a low “demixing potential,” which is a measure of content uniformity. The excipient is mixed with the steroid until a uniform mixture is obtained. However, the \'434 patent is silent as to release characteristics of these compositions and teaches only a mechanical interaction during the mixing operation.

As those skilled in the art recognize, known steroid hormone products present a number of disadvantages that are not addressed by either wet or dry processing techniques. Steroids exist in various polymorphic forms, defined here to include crystalline, amorphous and solvate forms. In the case of wet processing, the inability to identify the polymorphic form(s) of the potent steroid(s) that exists in a steroid hormone product following removal of the deposited organic solvent is a potential concern both from a physical/chemical stability prospective and from a biopharmaceutical prospective. Unfortunately, known methods of dry processing do not completely eliminate the potential existence of polymorphic forms.

In addition, steroid hormone products prepared by either wet or dry processing methods may present bioavailability problems. Before a drug that is orally administered as a solid can be absorbed, it must first dissolve in the gastrointestinal medium, and then it must be transported in the dissolved state across the gastrointestinal mucosa into the blood stream. As a surrogate test to predict bioavailability prior to commercial release of a drug product, regulatory authorities routinely require that at least 80% of the active ingredient in the product dissolve within 60 minutes in a “physiologically relevant” medium, i.e., a dissolution medium for in-vitro testing. Low dose steroid formulations prepared by known methods of either wet or dry processing have exhibited an undesirable variability in release rate, as measured by dissolution rate techniques in an aqueous medium containing a surfactant. Notably, upon scale up, formulations containing low dose steroids manufactured by dry processing and intended for use as oral contraceptives routinely had slower dissolution rates or at least suffered from a poorly reproducible dissolution profile.

Steroid hormones such as estrogen and progestin are also employed for hormone replacement therapy (HRT). Steroid hormone products used for HRT may contain up to a ten fold higher amount of estrogen and, typically, a lesser amount of progestin than oral contraceptives. Consequently, it is anticipated that such products may experience similar problems related to dissolution. Accordingly, it would also be desirable to reduce or eliminate such problems in the case of HRT steroid hormone products.

SUMMARY

In accordance with the invention, a steroid hormone product having an improved dissolution profile and release rate profile is provided. The product comprises at least one steroid hormone in substantially non-crystalline form in admixture with primary excipient, wherein the excipient stabilizes the steroid in its substantially non-crystalline form. The hormone products taught by the invention are characterized by highly favorable dissolution properties. The preferred excipient is lactose, although it should be understood that the invention is in no way limited in this regard and other excipients well-know in the art may be utilized, including dextrose, fructose, sorbitol, xylitol, sucrose, mannitol, dextrate, cellulose, starch and combinations of two or more of the foregoing.

The steroid hormone products of the invention are particularly useful as either oral contraceptives or HRT products. In a preferred embodiment of this aspect of the invention, the steroid hormone product is an oral contraceptive comprising from about 10 μg to about 50 μg of an estrogen and/or from about 50 μg to about 300 μg of a progestin. The progestin is preferably either norgestimate, norgestrel, levonorgestrel, norethindrone or desogestrel, and the estrogen is preferably either ethinyl estradiol, estradiol, estopipate or mestranol.

In a second aspect, the invention provides a method of preparing such a steroid hormone product, which method comprises preparing a mixture of at least one steroid hormone and an excipient, preferably lactose, and imparting to said mixture mechanical energy sufficient to yield an excipient/steroid powder blend in which the steroid is stabilized by the excipient in a substantially non-crystalline form. Preferably, at least about 0.1 hp-min/kg of mechanical energy is imparted to the mixture. Any method of high energy processing may be employed to impart sufficient mechanical energy to carry out the process of the invention. One preferred method of imparting sufficient mechanical energy involves high energy blending of the lactose and steroid, but other high energy mixing processes known in the art may be employed such as co-grinding or milling the mixture.

Preferably, the mixture is prepared with a steroid hormone to excipient ratio in the range of from about 1/1 to about 1/10. However, it should be understood that the invention is in no way limited in this regard and other hormone/excipient ratios may be employed depending on the desired concentration of hormone in the final product. Typically, the ratio of steroid to excipient in the mixture is the same as that required for the final product. However, it should be understood that an initial mixture of steroid hormone and excipient may be prepared, with additional excipient added subsequently to produce a final mixture. The final mixture is then subjected to high energy processing to impart sufficient mechanical energy to carry out the invention.

In one preferred embodiment of the invention, the steroid/excipient mixture is formed by standard wet processing. For example, a solution of at least one steroid hormone dissolved in an appropriate solvent is prepared and then sprayed onto the excipient powder. The solution and excipient are mixed in a suitable processor to ensure uniform distribution of the solvent in the excipient. The resulting mixture is then dried by removing the solvent via the application of heat and/or vacuum. Mechanical energy is then imparted to the mixture as described above to provide the steroid/excipient powder blend. In another preferred embodiment of the invention, the steroid and excipient are mixed by standard dry processing and mechanical energy is then imparted to the mixture as described above to provide the steroid/excipient powder blend.

DETAILED DESCRIPTION

As used herein, the following terms shall have the meaning ascribed to them below, except when the context clearly indicates differently:

“Poor” or “low” solubility refers to substances that are very slightly soluble to insoluble according to the following USP definitions.

Part of Solvent USP Descriptive Required for 1 Equivalent Term Part of Solute mg/mL Sparingly Soluble From 30 to 100 33.3 mg/mL-10 mg/mL  Slightly Soluble From 100 to 1000 10 mg/mL-1 mg/mL Very Slightly Soluble From 1000 to 10000   1 mg/mL-0.1 mg/mL Practically Insoluble, 10000 and over ≦0.1 mg/mL or Insoluble

“Content uniformity” means a relative standard deviation in active ingredient content of ±1.5%, preferably ±1.0% and most preferably ±0.5%.

As stated above, it is known that steroid hormones such as estrogens and progestins can exist in various solid state forms and that the particular form of the steroid may significantly effect properties such as dissolution rate and physical/chemical stability. An increase in dissolution rate and the extent of dissolution, as well as a decrease in physical/chemical stability are two potential consequences of modifying the stable crystalline form of these steroid hormones. In general, the higher energy, non-crystalline solid state form will exhibit an increase in dissolution rate over the more stable, lower energy crystalline form.

This is also the case with certain excipients such as lactose. Lactose is commonly selected as an excipient in tablets and capsules. It is commercially available in an assortment of grades including anhydrous a lactose, a lactose monohydrate, anhydrous β lactose and spray-dried lactose. Spray-dried lactose (e.g., FAST-FLO lactose available from Foremost Farms, Baraboo, Wis.) is commonly selected as an excipient in direct compression formulations due to its superior flow and compression characteristics. This grade of lactose predominately contains pure a lactose monohydrate in combination with non-crystalline lactose. The non-crystalline component enhances the compressibility of lactose. Morita et al., “Physiochemical Properties of Crystalline Lactose, II. Effect of Crystallinity on Mechanical and Structural Properties”, Chem. Pharm. Bull., Vol. 32, p. 4076 (1984). The non-crystalline state is metastable in nature and recrystallization to a more thermodynamically stable form is inevitable. The tendency for non-crystalline lactose to rapidly recrystallize upon exposure to relative humidity greater than approximately 60% is well documented. Sebhatu et al., “Assessment of the Degree of Disorder in Crystalline Solids by Isothermal Microcalorimetry”, International Journal of Pharmaceuticals, Vol. 104, p. 135 (1994). However for many drug substances, this process can be delayed by the addition of such materials as microcrystalline cellulose, polyvinylpyrrolidone or citric acid. Buckton et al., “The Influence of Additives on the Recrystallization of Amorphous Spray-Dried Lactose”, International Journal of Pharmaceuticals, Vol. 121, p. 81 (1995).

Various unit operations are routinely employed during the manufacture of conventional steroid hormone products, including milling, blending, wet granulation, drying and compression. Each process is associated with the incorporation of mechanical and/or thermal energy into the system. Consequently, the potential for modification of various solid state properties of steroid active ingredients and excipients exists. Hüttenraunch, et al., “Mechanical Activation of Pharmaceutical Systems”, Pharmaceutical Research, Vol. 2, p. 302 (1985). As noted above, such changes may significantly alter properties such as dissolution rate and dissolution extent, as well as physical/chemical stability (e.g., conversion to a different solid state form, hydrolysis, etc). Increases in dissolution rate and extent and a decrease in physical/chemical stability are two potential consequences of modifying the stable crystalline form of a material. However it would be highly desirable to increase the dissolution rate while either improving or at least not reducing the physical/chemical stability. The probability of encountering such crystalline form modifications during dosage form processing is directly related to the propensity of each ingredient to exist in a variety of polymorphic forms.

Norgestimate is a potent progestational agent. A thorough investigation of the polymorphic potential of this substance demonstrated the existence of at least two solid state forms, a stable crystalline form and a relatively higher energy non-crystalline form. It is also known that a relatively higher energy non-crystalline form of lactose exists in addition to the stable crystalline form routinely employed in tablet manufacture. Similar to lactose, the higher energy non-crystalline form of norgestimate can be generated via physical or mechanical processes. The present inventors have found that non-crystalline norgestimate can be physically generated from solution subsequent to the rapid evaporation of various organic solvents. Laboratory experiments clearly demonstrate that non-crystalline norgestimate can also be generated by ball milling. An obvious reduction in norgestimate crystallinity can be observed within 5 minutes of milling. Considering the relative ease of crystalline structure modification via mechanical energy, as well as the inherent non-crystalline lactose content in conventional lactose preparations, it was hypothesized that co-processing of lactose and norgestimate could result in the generation of a solid solution. In theory this solid solution would consist of non-crystalline norgestimate solubilized within the non-crystalline domains of lactose resulting in a composition exhibiting a more rapid dissolution rate and possibly enhanced physical/chemical stability.

Research efforts were thus made to generate the non-crystalline form of norgestimate in the presence and absence of lactose via physical and mechanical processes. Various mixtures of norgestimate and lactose were prepared. To permit qualitative or semi-quantitative analysis, the ingredients were thoroughly mixed in ratios of 1:1 and 1:9 by either dissolving them in a co-solvent mixture or by co-grinding. Qualitative assessment of the degree of crystallinity was performed employing Powder X-Ray Diffractometry (PXRD). The minimum detectable level of crystalline norgestimate in this solid mixture was demonstrated to be approximately 3%.

The physical stability of non-crystalline norgestimate and non-crystalline lactose were assessed prior to investigation of the drug/excipient interaction. Room temperature storage conditions employed at various relative humidities (% RH) of 0%, 31% and 76% RH were employed. Complete recrystallization of amorphous norgestimate was observed within 3 days at all conditions tested. Based on these data, the ability of lactose to inhibit recrystallization and enhance the physical stability of non-crystalline norgestimate was investigated.

Co-precipitation of norgestimate and FAST-FLO lactose from a solvent mixture of ethanol and water was achieved by solvent evaporation under reduced pressure. In the presence of lactose, norgestimate remained totally amorphous for at least 32 days at room temperature in a 0% RH chamber. Norgestimate recrystallized within 3 days in the absence of lactose under the same conditions. As anticipated, PXRD analysis of both the 1:1 and 1:9 norgestimate:FAST-FLO lactose mixtures made in this manner demonstrated recrystallization of lactose within 1 hour at 75% RH. This was anticipated since non-crystalline lactose undergoes rapid recrystallization at approximately 60% RH. Sebhatu et al., supra. However, the norgestimate remained partially non-crystalline for at least 6 days at this high relative humidity. The fact that norgestimate remains in a non-crystalline form subsequent to the recrystallization of lactose implies that the two compounds are miscible in the solid state. These findings further support the hypothesis that a metastable solid solution is formed between lactose and norgestimate when dissolved in a hydro-alcoholic system and co-precipitated.

In an attempt to more closely mimic the process employed in the manufacture of steroid hormone tablets by dry processing, 1:9 crystalline norgestimate/FAST-FLO lactose mixtures were ball milled together for 20 minutes. PXRD analysis indicated an absence of crystalline norgestimate. However no visually obvious reduction in the crystallinity of lactose was observed. The milled mixture was stored at room temperature at 0% RH and at 31% and 40° C. at 75% RH. Based on visual observation, norgestimate remained in a non-crystalline form at room temperature for at least 103 days in this mixture. Recrystallization of norgestimate at the accelerated temperature/humidity condition was initiated between 54 and 82 days. These data further support the hypothesis that a non-crystalline form of norgestimate is physically stabilized by lactose even in the absence of detectable modification in the crystallinity of lactose. One would also anticipate a more rapid dissolution of norgestimate from a solid solution than from the crystalline form.

Employing the current dissolution standard (USP Apparatus 2, 75 rpm, 600 ml of 0.05% Tween 20), the dissolution rates and extent of dissolution for individual samples of both crystalline and non-crystalline norgestimate were compared. Not surprisingly, this preliminary investigation demonstrated a difference in dissolution behavior of the two solid state forms of norgestimate. The results of the study are set forth below in Table 1.

TABLE 1 Dissolution Amorphous Crystalline Time (min.) Norgestimate Norgestimate 5 0.44 ug/mL 0.43 ug/mL 60 1.38 ug/mL 0.81 ug/mL 120 1.88 ug/mL Not Determined 140 Not Determined 1.36 ug/mL

The dissolution rate and extent of norgestimate dissolution subsequent to co-milling with lactose at a ratio of 1:9 was also evaluated. PXRD indicated that norgestimate was rendered non-crystalline while lactose was rendered partially crystalline following milling. Employing a 100 ml volume of 0.05% Tween 20 as a medium, dissolution characteristics of norgestimate were determined as a function of storage time at approximately 40° C. at 75% RH. PXRD was employed to follow the recrystallization kinetics of the solid solution formed. As anticipated, lactose recrystallized between 0 and 2 days. Initiation of norgestimate recrystallization was noted between 17 and 22 days. Norgestimate remained partially crystalline for at least 44 days under the accelerated storage conditions. The results of the evaluation are set forth in Table 2.

TABLE 2 Dissolution Norgestimate Concentration Norgestimate Concentration Time (min.) Time = 0 Days Time = 44 Days 10 5.3 ug/mL 2.4 ug/mL 20 5.1 ug/mL 5.2 ug/mL 30 6.2 ug/mL 6.5 ug/mL 60 8.7 ug/mL 5.9 ug/mL 240 10 ug/mL 6.7 ug/mL 720 10.3 ug/Ml 7.3 ug/mL

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