HK1165999B - Pharmaceutical composition for a hepatitis c viral protease inhibitor - Google Patents

Description

Pharmaceutical compositions as hepatitis c virus protease inhibitors

Technical Field

The present invention relates generally to pharmaceutical compositions useful as hepatitis c virus protease inhibitors, methods of using the compositions to inhibit Hepatitis C Virus (HCV) replication and to treat HCV infection.

Prior Art

The following compounds (1) are known to be selective and potent inhibitors of the HCV NS3 serine protease:

compound (1) falls within the scope of HCV inhibitors of the acyclic peptide series disclosed in U.S. Pat. nos. 6,323,180, 7,514,557 and 7,585,845. Compound (1) is specifically disclosed as compound 1055 in U.S. Pat. No. 7,585,845, and compound 1008 in U.S. Pat. No. 7,514,557. Compound (1) can be prepared according to the general procedures described in the references cited above, which are incorporated herein by reference in their entirety. Preferred forms of compound (1) comprise crystalline forms, in particular crystalline sodium salt forms, which can be prepared as described in the examples section herein.

Compound (1) is also known to have another chemical structural formula below, which is equivalent to the above structure:

wherein B isL⁰Is MeO-; l is¹Is Br; and R²Is composed of

A general problem with protease inhibitors is that these compounds are lipophilic and have low water solubility. Due to poor water solubility, conventional solid and liquid pharmaceutical formulations containing these inhibitors may not be absorbed by the patient in a satisfactory manner. When administered orally, water solubility is often found to be the most important factor among the many factors that may affect the bioavailability of a drug, including water solubility, absorption of the drug through the gastrointestinal tract, dose intensity, and first pass effect. Poorly water soluble compounds often show erratic or incomplete absorption in the digestive tract and thus produce a less than expected response.

The compound (1) is a zwitterion and is capable of forming a salt with a strong acid and a base. Attempts to identify solid salts of this compound that substantially improve water solubility and thus bioavailability have not been successful. Therefore, there remains a need in the art for pharmaceutical compositions of compound (1) having improved bioavailability.

Methods of formulating certain lipophilic macrocyclic compounds into pharmaceutical formulations have been previously reported. For example, U.S. Pat. No. 4,388,307 to Cavanak discloses the preparation of an emulsified formulation of a commercially available cyclosporin, and U.S. Pat. No. 5,342,625 to Hauer et al, and WO 93/20833 to Meikner et al, disclose the preparation of a cyclosporin microemulsion and microemulsion preconcentrate. Komiya et al, U.S. patent 5,504,068, further discloses the preparation of a potentiated topical formulation of cyclosporine.

Examples of "self-emulsifying" formulations of lipophilic compounds include WO 96/36316 to Lipari et al, which discloses a self-emulsifying preconcentrate comprising a lipophilic compound, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), and a lipophilic phase. U.S. patent 6,121,313 to Gao et al discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising a pyranone compound, a mixture of monoglycerides and diglycerides, one or more solvents, and one or more surfactants; and U.S. patent 6,231,887B1 to Gao et al discloses a self-emulsifying formulation of a pyrone protease inhibitor comprising a pyrone compound, an amine, one or more solvents, and one or more surfactants. U.S. patent 5,993,858 to Crison et al discloses an excipient formulation comprising a self-microemulsifying emulsion comprising an oil or other lipid material, a surfactant and a hydrophilic co-surfactant.

Patel et al, U.S. Pat. Nos. 6,294,192 and 6,451,339, disclose a composition for delivery of a hydrophobic therapeutic agent that includes a carrier formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. U.S. patent 6,652,880 to Aylwin et al discloses a liquid pharmaceutical composition in which the active substance is dissolved in a liquid carrier comprising a glyceride of a long chain fatty acid and a lipophilic surfactant.

Self-emulsifying drug delivery systems (SEDDS) have also been developed for some anti-HCV compounds, as disclosed in U.S. patents 6,828,301 and 7,157,424, and U.S. patent application publication 2004/0033959. However, there remains a need in the art for pharmaceutical formulations of compound (1) that are sufficiently optimized, stable and bioavailable.

Summary of The Invention

The present invention overcomes the aforementioned problems by providing a lipid-based pharmaceutical composition of compound (1) suitable for oral administration via a liquid-or semisolid-filled capsule. The lipid-based pharmaceutical compositions of the present invention constitute a class of self-emulsifying drug delivery systems (hereinafter "SEDDS") and exhibit acceptable stability and bioavailability and are therefore particularly useful for delivering compound (1) in therapy.

The pharmaceutical compositions of the present invention each comprise compound (1) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable lipids and a hydrophilic surfactant. As will be described in detail below, the compositions of the present invention may optionally include one or more other ingredients, such as pharmaceutically acceptable hydrophilic solvents, solidifying agents, antioxidants, and the like. The pharmaceutical composition is liquid or semi-solid and is preferably encapsulated in a capsule for oral administration.

Another important aspect of the present invention includes a method of treating a hepatitis c virus infection in a mammal by administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the present invention.

Drawings

Figure 1 shows the results of in vitro dissolution tests of three formulations according to the invention, which describe the percentage of compound (1) sodium salt released/dissolved as a function of time.

Figure 2 shows the mean plasma concentrations of compound (1) in six dogs following administration of five different sodium salt formulations of compound (1).

Figure 3 shows the mean plasma concentrations of compound (1) in three dogs following administration of five different sodium salt formulations of compound (1).

Detailed Description

Terms not explicitly defined herein are definitions that may be specified by one of ordinary skill in the art in light of this disclosure and the context. As used in this specification, however, unless otherwise indicated, the following terms have the meanings indicated and are to be accorded the following.

The term "about" means within 20%, preferably within 10%, and more preferably within 5% of the specified value or range. For example, "about 10%" means 8% to 12%, preferably 9% to 11%, and more preferably 9.5% to 10.5%. When the term "about" is used in connection with a numerical range, such as "about X to Y%", the term "about" is intended to modify both the lower (X) and upper (Y) limits of the range. For example, "about 0.1 to 10%" is equivalent to "about 0.1% to about 10%".

All percentages used to describe the content of ingredients in the composition are percentages by weight relative to the total composition.

As used herein, the term "pharmaceutically acceptable" with respect to a substance is intended to mean a substance that, when used in the form of a pharmaceutical composition, is compatible with use in contact with the tissues of human beings and lower animals within the scope of sound medical judgment, does not have excessive toxicity, irritation, allergic response, and the like, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use.

The term "semi-solid" refers to a substance that is neither solid (elastic properties) nor liquid (viscous properties), and that is viscous and elastic. Examples of semisolid substances include gels, ointments, creams, and high viscosity liquids.

The term "treating" refers to a method of treating a hepatitis c virus infection in a patient, and includes:

(i) preventing the occurrence of hepatitis c virus infection in a patient, in particular when the patient shows a predisposition to the disease state, but is still undiagnosed;

(ii) inhibiting or ameliorating hepatitis c virus infection, i.e., preventing or delaying its development; or

(iii) Alleviating hepatitis c virus infection, i.e., leading to recovery or cure from the disease state.

The term "therapeutically effective amount" is intended to refer to an amount of a compound according to the present invention which, when administered to a patient in need thereof, is sufficient to effectively treat hepatitis c virus infection. Such therapeutically effective amounts can generally be determined by those skilled in the art based on their own knowledge, the prior art, and the present disclosure.

Preferred embodiments of the invention

As a general embodiment of the present invention, a pharmaceutical composition comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable lipids, and one or more pharmaceutically acceptable hydrophilic surfactants. In a more specific embodiment, the pharmaceutical composition consists essentially of a compound of formula (1) or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable lipids, and one or more pharmaceutically acceptable hydrophilic surfactants.

Compound (1)

Compound (1) may be used in its free form or in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts of compound (1) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water-or oil-soluble or dispersible, and effective for their intended use.

The term includes pharmaceutically acceptable acid addition salts as well as pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, in s.m. berge et al, j.pharm.sci.,1977,66, pages 1-19 and U.S. patent 7,585,845. Various salts listed in U.S. Pat. No. 7,585,845 are incorporated herein by reference.

A particularly preferred form of compound (1) for use in the compositions of the present invention is the sodium salt form of compound (1). Methods for preparing the crystalline sodium salt form are provided in the examples section herein. The sodium salt of compound (1) may be in crystalline form, amorphous form or a mixture thereof. It may also be a polymorphic form different from existing crystalline drugs as described herein. The compound (1) medicament may be used as it is or may be appropriately processed for: (1) reduce the degree of agglomeration of the drug particles and/or (2) reduce the particle size distribution of the drug primary particles. The processing may be screening, de-agglomeration, impact milling, jet milling, or a combination thereof to shorten the time for bulk filling production during packaging.

The amount of active ingredient of compound (1) present in the lipid-based system composition may vary over a wide range or may be adjusted over a wide range depending on the following factors: the intended route of administration, the potency of the particular active ingredient used, the severity of the hepatitis c virus infection and the concentration required. In one embodiment, the compound of formula (1) is present in an amount of about 1 to 50 wt.%, preferably about 5 to 30 wt.%, more preferably about 10 to 20 wt.% of the lipid-based system.

Lipid material

As is known in the art, the empirical parameter commonly used to describe the relative hydrophilicity and hydrophobicity of a compound is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more hydrophobic and more soluble in oils, while surfactants with higher HLB values are more hydrophilic and more soluble in aqueous solutions. Using HLB values as a rough indicator, hydrophilic surfactants are generally considered to be those compounds having HLB values greater than about 10, and anionic, cationic, or zwitterionic compounds, which are not generally applicable on the HLB scale. Similarly, hydrophobic surfactants are compounds having an HLB value of less than about 10.

Pharmaceutically acceptable lipids suitable for use in the compositions of the present invention include any lipophilic material having a hydrophilic-lipophilic balance (HLB value) of less than or equal to 10(HLB ≦ 10) and limited solubility in water. Examples of suitable pharmaceutically acceptable lipids include a number of water immiscible substances, for example, fatty acids, mono-, di-or triglycerides of medium or long chain fatty acids, propylene glycol esters of fatty acids (propylene glycol fatty acid esters), sorbitol esters of fatty acids (water insoluble vitamins), and mixtures thereof. In a preferred embodiment, the pharmaceutically acceptable lipid is selected from the group consisting of: monoglycerides of caprylic and capric acid, diglycerides of caprylic and capric acid, and mixtures thereof (e.g., available from Abitech corporation)MCM)。

The amount of lipid in the composition may vary over a wide range and the preferred amount for a particular composition may be determined by the skilled formulator based on the type and amount of other ingredients in the composition. However, the pharmaceutically acceptable lipid is typically present in an amount of about 20 to 70 wt.%, more preferably about 30 to 60 wt.%, or about 40 to 50 wt.%.

Hydrophilic surfactant

To facilitate self-emulsification, the compositions of the present invention include a pharmaceutically acceptable hydrophilic surfactant having an HLB value greater than or equal to 10(HLB ≧ 10) and which is sufficiently miscible with water. Examples of suitable pharmaceutically acceptable hydrophilic surfactants include polyethoxylated vegetable oils, polyethoxylated tocopherols, polyethoxylated sorbitan fatty acid esters (e.g., Tween 80), bile salts (bile salts), lecithin, and mixtures thereof. Preferred surfactants include tocopheryl polyethylene glycol succinate (Vitamin E TPGS), polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), and polyethylene glycol 35 castor oil (Cremophor EL), and mixtures thereof.

The amount of hydrophilic surfactant in the composition may also vary widely, and the preferred amount for a particular composition may be determined by the skilled formulator based on the type and amount of other ingredients in the composition. The pharmaceutically acceptable hydrophilic surfactant is preferably present in an amount of up to about 70 wt%, preferably from about 20 to 50 wt%, more preferably from 25 to 35 wt%.

Hydrophilic solvent

The compositions of the present invention may also optionally comprise a pharmaceutically acceptable hydrophilic solvent for: (1) enhance the solubility of the active agent and prevent it from precipitating out of the formulation, (2) shorten the time for bulk fill production during packaging, and/or (3) improve the dispersibility of the formulation in aqueous solutions. Examples of hydrophilic solvents that may be used include, for example, propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, dimethyl isosorbide, glycofurol (glycofurol), propylene carbonate, dimethylacetamide, water, or mixtures thereof. Preferred hydrophilic solvents include propylene glycol, polyethylene glycol (e.g., PEG 400), ethanol, water, and mixtures thereof.

The amount of solvent in the composition may also vary widely, and the preferred amount for a particular compound will be readily determined by one skilled in the art based on the type and amount of other ingredients in the composition. However, the solvent content is generally at most about 30% by weight, preferably at most 15% by weight.

Curing agent

The compositions of the present invention may also optionally include a curing agent to convert the liquid formulation into a semi-solid after encapsulation into two-piece hard capsules (e.g., hard gelatin capsules and HPMC capsules). Examples of curing agents that can be used include polyethylene glycol, poloxamers (poloxamers), polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivatives, polyacrylates, polymethacrylates, sugars, polyols, and mixtures thereof. Specific preferred examples include high molecular weight PEGs (including PEG3350, PEG6000, PEG8000), poloxamers or mixtures thereof. The method of including a curing agent is particularly useful for propylene glycol-or ethanol-containing compositions to reduce the activity of gelatin plasticizers during migration from the liquid fill to the capsule shell, thereby improving physical stability (with respect to softening and deformation of the dosage form). In another aspect, the method is also applicable to compositions containing PEG400 to reduce the hygroscopicity of the fill and the friability of the capsules. When a curing agent is used in the composition, it is preferably present in an amount up to about 50% by weight, preferably from about 1 to 20% by weight.

Optionally other ingredients

If desired, the compositions according to the invention may also comprise conventional pharmaceutical additives required or necessary to obtain a suitable formulation, such as antioxidants, lubricants, disintegrants, preservatives, buffers, stabilizers, scavengers, thickeners, colorants, sweeteners, flavourings, fragrances and the like. Other additives that may be suitable for use in the compositions of the present invention are disclosed in U.S. Pat. No. 6,323,180B1 to Llinas-Brunet et al.

In a preferred embodiment, the composition according to the invention further comprises one or more antioxidants. Preferred antioxidants include, for example, ascorbic acid, sulfatide salts, citric acid, propyl gallate, dl-alpha-tocopherol, ascorbyl palmitate, BHT or BHA. Antioxidants, if present, are generally present in an amount of about 0.01 to 1 weight percent.

In another preferred embodiment, the compositions of the present invention may further comprise a reactive carbonyl (e.g., aldehyde, ketone) scavenger (e.g., amines, including TRIS and meglumine) to reduce cross-linking with gelatin capsules that would otherwise adversely affect release of the formulation from the dosage form.

Stabilizers that can be used include, for example, some basic agents, including amines, that increase the apparent pH of the filled formulation.

Other preferred embodiments

In other embodiments, the compositions of the present invention are characterized by the absence (or inclusion of only a limited number) of one or more classes of substance that may be normally included in a pharmaceutical formulation. In the following description, the phrase "substantially free of a substance generally means that the formulation contains no more than a trace amount of the substance, e.g., no more than 1% by weight, preferably no more than 0.5% by weight, more preferably no more than 0.1% by weight.

The compositions of the present invention are characterized by one or more of the following properties:

(1) substantially free of any amine compound, or free of any amine compound;

(2) substantially free of any alcohol compound, or free of any alcohol compound;

(3) substantially free of any triglyceride compound, or free of any triglyceride;

(4) a glyceride substantially free of any long chain fatty acid, or free of any such glyceride;

(5) substantially free of any other surfactant compound, or free of any other surfactant compound;

a particular embodiment of a composition according to the invention relates to a pharmaceutical composition comprising (or consisting essentially of):

(a) about 5 to 30 weight percent of a compound of formula (1) or a pharmaceutically acceptable salt thereof;

(b) about 30 to 60% by weight of a pharmaceutically acceptable lipid;

(c) about 20 to 50% by weight of a pharmaceutically acceptable hydrophilic surfactant;

(d) optionally up to about 30% by weight of a pharmaceutically acceptable hydrophilic solvent;

another embodiment of the composition according to the invention relates to a pharmaceutical composition comprising (or consisting essentially of):

(a) about 10 to 20 weight percent of a compound of formula (1) or a pharmaceutically acceptable salt thereof;

(b) about 40 to 50% by weight of a pharmaceutically acceptable lipid;

(c) about 25 to 35% by weight of a pharmaceutically acceptable hydrophilic surfactant;

(d) about 5 to 15 weight percent of a pharmaceutically acceptable hydrophilic solvent;

another embodiment of a composition according to the invention relates to a pharmaceutical composition comprising (or consisting essentially of):

(a) about 5 to 30 weight percent of a compound of formula (1) or a pharmaceutically acceptable salt thereof;

(b) about 30 to 60% by weight of a pharmaceutically acceptable lipid selected from the group consisting of mono-, di-, or triglycerides of medium or long chain fatty acids, propylene glycol esters of fatty acids, sorbitol esters of fatty acids, water insoluble vitamins, and mixtures thereof;

(c) about 20 to 50% by weight of a pharmaceutically acceptable hydrophilic surfactant selected from the group consisting of polyethoxylated vegetable oils, polyethoxylated tocopherols, polyethoxylated sorbitol fatty acid esters, bile salts, lecithin, and mixtures thereof;

(d) optionally up to about 30% by weight of a pharmaceutically acceptable hydrophilic solvent selected from propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, dimethyl isosorbide, glycofurol, propylene carbonate, dimethylacetamide, water, or mixtures thereof;

another embodiment of a composition according to the invention relates to a pharmaceutical composition comprising (or consisting essentially of):

(a) about 10 to 20 weight percent of a sodium salt of a compound of formula (1);

(b) about 40 to 50% by weight of a pharmaceutically acceptable lipid selected from the group consisting of monoglycerides of caprylic and capric acids, diglycerides of caprylic and capric acids, and mixtures thereof;

(c) about 25 to 35% by weight of a pharmaceutically acceptable hydrophilic surfactant selected from the group consisting of tocopherol polyethylene glycol succinate, polyethylene glycol 40 hydrogenated castor oil, and polyethylene glycol 35 castor oil and mixtures thereof;

(d) about 5 to 10% by weight of a pharmaceutically acceptable hydrophilic solvent selected from the group consisting of propylene glycol, polyethylene glycol, ethanol, water, and mixtures thereof.

Preparation method and packaging method

The compositions of the invention may be prepared according to conventional methods, for example by a process comprising the steps of: mixing liquid components (e.g., one or more pharmaceutically acceptable lipids, surfactants, and solvents); optionally heating the resulting mixture, if necessary, to sufficiently melt one or more components of the mixture; the compound of formula (1) is added to the resulting mixture and further mixed until all or substantially all of the compound of formula (I) is dissolved, e.g., until the solution appears transparent. This method of preparing the composition forms a further aspect of the invention.

The resulting fill solution is then formulated into the desired dosage form, such as capsules, including hard shell capsules or soft gel capsules (e.g., hard gelatin capsules or soft gelatin capsules), by known manufacturing techniques. Examples of soft gelatin capsules that may be used include those disclosed in EP 649651B1 and U.S. patent 5,985,321.

In a particularly preferred embodiment, the compositions of the present invention are encapsulated in soft elastic capsules (e.g., soft gelatin capsules) and other soft gelatin capsules based on non-animal materials. Since the composition may be substantially free of polar solvents, it may provide the advantage that either an off-the-shelf standard gel composition may be used for making the capsule shell, or a new gel for the capsule shell is developed directly, to minimize development challenges and costs. The compositions of the present invention have the advantage of providing higher drug loading, since soft gels can provide larger fill volumes.

It should be noted that the composition of the invention may also comprise water originally contained in the drug, excipients, in particular surfactants and solvents having hydrophilic properties, as well as water generated during the encapsulation process. In particular, during the encapsulation of fill formulations with soft gelatin capsules, there may be a significant amount of moisture transferred from the moist gelatin band into the fill formulation. With proper drying methods, it is critical to remove any excess water from the fill composition to avoid any precipitation and hydrolytic degradation of the drug, as well as excessive softening of the capsule. The water content of the resulting softgel capsules of the invention should generally not exceed 5% by weight and more preferably not exceed 3% by weight of the filled formulation.

An important finding relating to the composition of the present invention is: the solubility of the sodium salt of compound (1) increases with decreasing temperature. This surprising property makes it possible to provide a unique opportunity to improve the stability of pharmaceutical products by low temperature storage (e.g. refrigeration) without concern as to whether the drug may precipitate at low temperature. Thus, the compositions of the present invention have surprising advantages in encapsulation development, which allows for the use of a wide range of encapsulation materials.

Method of treatment

The compounds of formula (1) are effective as HCV protease inhibitors, and these compounds, and pharmaceutical compositions comprising these compounds, are therefore useful for inhibiting HCV replication, as well as for treating HCV infections in mammals. Accordingly, the present invention also relates to a method of treating hepatitis c virus infection in a mammal by administering to the mammal a therapeutically effective amount of the pharmaceutical composition of the present invention.

The dosage of the compound of formula (1) and various treatment regimens for the monotherapy prevention and treatment of HCV infection is given in U.S. patent No. 7,585,845. However, as will be appreciated by those skilled in the art, the dosage of the compositions of the present invention may be less, depending on the degree of improvement in bioavailability. Combination therapy may also be performed with one or more other therapeutic or prophylactic agents as described in detail in U.S. Pat. No. 7,585,845. The additional agent may be mixed with the compound of the present invention to produce a single dosage form, or the additional agent may be administered to the mammal separately from the compound of the present invention as part of a multiple dosage form. An appropriate therapeutically effective amount of a pharmaceutical composition intended for administration can generally be determined by one of skill in the art based on his own knowledge, the prior art, and this disclosure.

In order that the invention may be more fully understood, the following examples are set forth. These examples are intended to describe embodiments of the invention and should not be construed as limiting the scope of the invention in any way.

Characteristics of the drug

Due to the lipophilic nature of the sodium salt of compound (1), the lipid-based drug delivery system of the present invention was chosen. Lipid-based SEDDS (self emulsifying drug delivery System) formulations are able to overcome solubility-limited absorption. Because the drug in the dosage form is contained in solution and because of the self-emulsifying nature of the formulation, the drug remains in solution upon contact with aqueous media, and therefore the rate of absorption is not limited by the dissolution rate.

Liquid-filled soft gelatin capsule formulations according to the present invention have been developed for clinical trials. Important properties include:

● bioavailability (rapid release upon dissolution in vitro; absorption in dogs comparable to powders in previous oral solution formulations)

● stability (demonstrating that the dosage form exhibits chemical and physical stability under ICH long term storage conditions (25 ℃/60% RH))

● manufacturability (batch size can be up to 25kg to support test requirements)

Data are provided in the examples section herein which demonstrate the excellent stability and bioavailability properties of the capsule formulations of the present invention.

The light transmittance (optical clarity) of the formulations of the invention is determined visually and by microscopy. A fill formulation was prepared according to example 1 below (and the corresponding vehicle and placebo formulations) and diluted 100-fold in aqueous medium to form a solution. The absorbance of each solution was measured at 400nm and 450nm using purified water as a standard, and the detailed results are given in the examples section herein. These results confirmed that the absorbance of the dispersion at 400nm was 2.36 to 2.99, and the absorbance at 450nm was 0.35 to 2.96. Thus, another embodiment relates to a pharmaceutical composition according to the invention, wherein the composition forms an aqueous dispersion having an absorbance at a wavelength of about 400nm of greater than about 1.0 (and preferably greater than about 2.0) when diluted with water at a water to composition ratio of 100:1 (by weight).

Examples

Three different liquid fill formulations were prepared, two of which were encapsulated in Soft Gel Capsules (SGC) and the other in Hard Shell Capsules (HSC).

Example 1: no. 1 soft gelatin capsule preparation

The liquid filling preparation comprises the following components:

two specific soft gelatin capsule pharmaceutical formulations were prepared according to formulation No. 1 above, which were 40mg product and 120mg product:

¹42.30mg of Compound (1) sodium salt equivalent to40.0mg of active fraction.

²126.90mg of the sodium salt of compound (1) is equivalent to 120.0mg of the active moiety.

³Nitrogen was used as a processing aid and it did not appear in the final product.

⁴The capsule shell had an approximate weight of 280mg before drying and completion. After drying and completion, the capsule shell had an approximate weight of 198 mg.

⁵The capsule shell had an approximate weight of 590mg prior to drying and completion. After drying and completion, the capsule shell had an approximate weight of 404 mg.

Example 2: no. 2 soft gelatin capsule preparation

The liquid filling preparation comprises the following components:

a specific 150mg soft gelatin capsule pharmaceutical formulation was prepared according to the general formulation described above.

Example 3: no. 3 hard shell capsule preparation

The liquid filling preparation comprises the following components:

a specific 150mg hard shell capsule pharmaceutical formulation was prepared according to the general formulation described above.

Preparation of formulations No. 1 to No. 3

The medicament is jet-ground to remove large agglomerates, so that the time for filling the bulk material for production is consistent and reasonably shortened. The particle size distribution of the drug substance was targeted to reduce x90(v/v) to no greater than 10 microns and x98(v/v) to no greater than 20 microns as measured by Sympatec. All excipients in the fill formulation are mixed in a mixing vessel and mixed until homogeneous, followed by addition of the drug. After addition of the drug, mixing was continued until the fill solution was visibly clear. During preparation, nitrogen blanket was always used over the fill solution as a standard operation. The fill solution is passed through a filter to remove any foreign particles. The filtered bulk fill material is encapsulated in capsules using standard soft or hard gelatin capsule technology and process controls. The filled capsules are dried and then washed with a polishing/washing solution, followed by encapsulation, resulting in bright, aesthetically pleasing pharmaceutical capsules.

Example 4 chemical stability Studies

The stability of a higher specification prototype capsule formulation (150mg, sodium salt based) containing relatively equal amounts of filling excipient and gel formulation as formulation No. 1 (example 1) and the same properties as formulation No. 1 was analyzed. No significant changes were observed in the analysis or impurity profile after 12 months of storage at 25 ℃/60% RH or 30 ℃/70% RH.

Example 5 dissolution and bioavailability study

Formulations nos. 1 to 3 were evaluated using an in vitro dissolution method. The results demonstrate that upon contact with aqueous media, the fill formulation is released from the capsule and the drug is dispersed in a lipid-based self-emulsifying drug delivery system. See fig. 1. Dissolution testing was performed according to the following protocol: two 150mg capsules per formulation; the test was performed in 500ml of pH 4.5 acetate buffer in each vessel; 100rpm, basket method, at 37 ℃.

In addition, in dogs, the bioavailability of the SEDDS formulation capsules was demonstrated in vivo, showing that absorption is comparable to that of "powder-in-bottle" oral solution formulations that have been shown earlier in human clinical studies to result in adequate exposure. The protocol and results of these in vivo studies are provided below.

Five-way crossover formulation study on beagle dogs

Animal/design: 6 male beagle dogs were used in the crossover design. There is a one week washout period (washout) between the first and second clinics, and between the third and fourth clinics. There are two week washout periods between the second and third clinics, and between the fourth and fifth clinics.

Pretreatment: 6 μ g/kg Pentagastrin (Pentagastrin) was administered intramuscularly one hour prior to administration of the formulation

Feeding state: fasted overnight (four hours after the indicated time point)

Preparation: a: bottled Powder (PIB) oral solution for stage Ia, and the dosage is 150mg, 48mg/mL

B: Ib/II bottled Powder (PIB) oral solution with dosage of 150mg and 48mg/mL

C: preparation No. 1 SGC capsule No. 1, dosage is 150mg

D: preparation No. 2 SGC capsule No. 2, dosage is 150mg

E: preparation No. 3, HGC Capsule, dosage 150mg

Administration: 48mg/mL of compound (1) sodium salt was used to formulate Ia and Ib/II PIB oral solutions. Dogs were given a volume of about 3.13mL (dose 150mg) via gastric tube, followed by a 50mL bolus of water via gastric tube. C, D, and E formulations were formulated separately such that each capsule contained 150mg of compound (1) sodium salt. The dogs received one capsule and were gavaged with 50mL of water via a gastric tube.

Collecting blood: blood samples (. about.2 ml) were taken before dosing, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6,8, 12, 24, 30, and 48 hours after dosing.

Anticoagulant: heparin lithium

Table 1 summary of pharmacokinetic parameters of compound (1) following oral administration of compound sodium salts of five different formulations to beagle dogs (n ═ 6)^a

^aExcept for t_maxThe data are expressed as mean (% RSD) values, except for the median (range). The table contains data obtained from all dogs regardless of whether they vomit.

The mean plasma concentrations of the corresponding compound (1) after administration of five different sodium salt formulations of compound (1) to all dogs (n ═ 6) are given in figure 2.

Table 2 summary of pharmacokinetic parameters of compound (1) after oral administration of compound sodium salts of five different formulations to beagle dogs (n ═ 3)^a

^aExcept for t_maxThe data are expressed as mean (% RSD) values, except for the median (range). The table excludes all formulation data for dog vomiting; 1494. 1912, 1916.

The mean plasma concentrations of compound (1) are given in figure 3 after five different sodium salt formulations of compound (1) were administered to three dogs.

Example 6 transmittance study

The transmittance of the formulations of the invention was determined visually and by microscopy. Fill formulations were prepared according to formulation No. 1 (example 1), and the corresponding vehicle and placebo formulations, and diluted to 100-fold solutions in three different aqueous media at different pH, respectively. Immediately and after 30 minutes, absorbance at 400nm and 450nm of each solution was measured using purified water as a standard, and detailed results are given below. These results confirmed that the resulting dispersion had an absorbance at 400nm of 2.36 to 2.99 and an absorbance at 450nm of 0.35 to 2.96.

Preparation

General operation:

add 0.1g of formulation sample to a 20mL scintillation vial

Add 9.9mL of aqueous medium to the vial

Fully dispersing the mixture by manual mixing

Measured immediately or after 30 minutes of standing

Dispersing samples before uv reading

Transfer aliquots to 1cm pathlength uv cuvettes

Single measurement or measurement of absorbance over a range of wavelengths

Aqueous medium: simulated gastric juice (SGF)

Acetate buffer solution

Simulated intestinal juice (SIF)

Equipment: cary 50UV-Vis spectrophotometer

Software: cary software program "simple reads"

Transmittance results (zero time point):

transmittance results (at 30 minutes):

examples 7 to 12: preparation of sodium salt of Compound (1)

Processes that can be used to prepare amorphous compound (1) can be found in U.S. patent No. 6,323,180, U.S. patent No. 7,514,557 and U.S. patent No. 7,585,845, which are incorporated herein by reference. Methods that can be used to prepare the sodium salt of compound (1) can be found in U.S. patent application publication 2010/0093792, and the examples shown below.

Example 7: preparation of Compound (1) type A

Amorphous compound (1) (batch 7, 13.80g) was added to a 1000ml three-necked flask. Anhydrous ethanol (248.9g) was added to the flask. The contents of the flask were heated to about 74 ℃ at 60 ℃/hour with stirring. (the solid does not dissolve at 74 ℃). Water (257.4g) was then added in a linear fashion to the resulting slurry over a 4 hour period while stirring and maintaining the temperature at 74 ℃. After the water addition was complete, the temperature was linearly lowered to ambient temperature at 8 ℃/hour with stirring and then held at ambient temperature for 6 hours. The resulting solid was collected by filtration and washed with 50ml 1/1(w/w) EtOH/water. The wet solid was dried on the funnel by pumping through the filter cake for 30 minutes from N2. (XRPD analysis of this sample indicated a pattern similar to that of EtOH solvate). The solid was then dried under vacuum (P ═ 25 inches of mercury) under a stream of nitrogen at 65 to 70 ℃ for 1.5 hours. The resulting solid (12.6g, 95.5% yield after correction) was confirmed to be compound (1) form a by XRPD.

Example 8: preparation of sodium salt of Compound (1): method 1

To a glass vial were added 2.1g of amorphous compound (1) sodium salt and 8.90g of acetone, and stirred at ambient temperature for 3 hours. The mother liquor in the slurry was filtered off and the resulting solid was dried under a stream of nitrogen for 20 minutes. 1.51g of compound (1) sodium salt crystalline solid was collected.

Example 9: preparation of sodium salt of Compound (1): method 2

To a 250ml reactor were added 15.6g A type compound (1), 175ml acetone and 3.6ml water and heated to 53 ℃ to dissolve the solid. To the reactor was added 900. mu.l of 10.0N NaOH and the solution was seeded with type A seeds. The seeded solution was stirred at 53 ℃ for 10 minutes. A second 900. mu.l portion of 10.0N NaOH was added and the system was stirred at 53 ℃ for 30 minutes during which time a slurry was formed. The slurry was cooled to 19 ℃ at a cooling rate of 15 ℃ per hour and allowed to stand overnight at 19 ℃. The resulting slurry was filtered and the wet solid was washed with 15ml of acetone. The solid was dried under vacuum at 52 ℃ for 1 hour under a stream of nitrogen and then exposed to laboratory air for one hour. 12.1g of compound (1) sodium salt crystalline solid was collected.

Example 10: preparation of sodium salt of Compound (1): method 3

To the reaction vessel were added 25.4Kg of amorphous compound (1), 228L of THF, and 11.1Kg of 10 wt% NaOH (aqueous solution). The components were mixed at 25 ℃ to dissolve all solids. The resulting solution was filtered, and the reaction vessel and filter were washed with 23L of THF. 180L of solvent were removed by atmospheric distillation at 65 ℃. 195L of MIBK was added and 166L of solvent was removed by vacuum distillation at about 44 ℃. 161L of MIBK and 0.41Kg of water were again added to the reaction vessel and the contents were heated to 70 ℃. 255g of seed crystals of the sodium salt of compound (1) were added at 70 ℃ and 1.42L of water were added over a period of 1.5 hours. After the addition of water, the slurry was left to stand at 70 ℃ for 45 minutes, and then cooled to 45 ℃ over a period of 1 hour. The resulting slurry was filtered and washed with 64L of MIBK containing about 0.8 wt% water. The wet cake was dried at 55 ℃ to obtain 25Kg of sodium salt compound (1) crystals.

Example 11: preparation of sodium salt of Compound (1): method 4

2.00g of amorphous compound (1), 9.96g of THF and 0.11g of water were added to the reaction vessel, and stirred at ambient temperature to dissolve the solid. While stirring the solution, 0.820ml of an ethanol solution containing 21% by weight of NaOEt was added dropwise to obtain a solution A. To the second reaction vessel, 15.9g n-BuAc and 160. mu.l water were added and heated to 65 deg.C (solution B). 2.56g of solution A was added to solution B at 65 ℃ and the resulting mixture was seeded with 40mg of compound (1) sodium salt seed crystals. The seeded mixture was allowed to stand at 65 ℃ for 45 minutes. 2.56g of solution B were added to solution A in four portions, each time and subsequently left to stand for 45 minutes. After the last addition and standing, the slurry was cooled to 50 ℃ over a period of 1 hour and filtered. The wet cake was washed with 6ml of n-BuAc containing 0.5 wt% water. The resulting solid was dried in vacuo at 50 ℃ under nitrogen. The resulting crystalline solid of the sodium salt of compound (1) was collected.

Example 12: preparation of sodium salt of Compound (1): method 5

An ethanol solution (21% by weight, 306ml) containing sodium ethoxide was added to a solution of compound (1) (745g) in THF (2000ml) and water (76.5ml) at room temperature with stirring. After stirring for 30 minutes, the mixture was filtered and the filter was washed with THF (85 ml). The resulting solution was heated to 65 ℃ and treated with filtered butyl acetate (6640ml, optionally preheated to 65 ℃) over 30 minutes. Seeding crystals (0.50g) were added and the mixture was stirred at 65 ℃ for 2 hours and crystallization started after about 30 minutes. The suspension was cooled to 50 ℃ over 1 hour and stirred for a further hour at this temperature. The title compound was isolated by filtration, washed with filtered butyl acetate (765ml, optionally preheated to 50 ℃) and dried at 65 ℃ for about 16 hours to give compound (1) sodium salt crystals (about 725 g).

Claims (4)

1. A self-emulsifying liquid pharmaceutical composition comprising:

(a)1 to 50% by weight of a sodium salt of a compound of formula (1), said compound of formula (1) being:

(b)20 to 70 wt% of one or more pharmaceutically acceptable lipids selected from the group consisting of: fatty acids, mono-, di-or triglycerides of medium or long chain fatty acids, propylene glycol esters of fatty acids, sorbitol esters of fatty acids, water insoluble vitamins, and mixtures thereof; and

(c)20 to 70 wt% of one or more pharmaceutically acceptable hydrophilic surfactants selected from the group consisting of: polyethoxylated vegetable oils, polyethoxylated tocopherols, tocopheryl polyethylene glycol succinates, polyethoxylated sorbitol fatty acid esters, bile salts, lecithin, and mixtures thereof, wherein said composition does not contain any amine compounds.

2. The pharmaceutical composition of claim 1, further comprising up to 30% by weight of a pharmaceutically acceptable hydrophilic solvent selected from the group consisting of propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, dimethyl isosorbide, glycofurol, propylene carbonate, dimethylacetamide, water, or mixtures thereof.

3. The pharmaceutical composition of any one of claims 1 and 2, wherein the composition forms an aqueous dispersion having an absorbance at a wavelength of 400nm of greater than 1.0 when diluted with an aqueous solution at a weight ratio of aqueous solution to composition 100: 1.

4. The pharmaceutical composition of any one of claims 1 and 2, comprising:

(A)

(a)5 to 30% by weight of a sodium salt of a compound of formula (1);

(b)30 to 60% by weight of a pharmaceutically acceptable lipid;

(c)20 to 50 wt% of a pharmaceutically acceptable hydrophilic surfactant selected from the group consisting of: polyethoxylated vegetable oils, polyethoxylated tocopherols, tocopheryl polyethylene glycol succinates, polyethoxylated sorbitan fatty acid esters, bile salts, lecithin, and mixtures thereof;

(d) optionally up to 30% by weight of a pharmaceutically acceptable hydrophilic solvent selected from propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, dimethyl isosorbide, glycofurol, propylene carbonate, dimethylacetamide, water, or mixtures thereof;

or

(B)

(a)10 to 20% by weight of a sodium salt of a compound of formula (1);

(b)40 to 50% by weight of a pharmaceutically acceptable lipid;

(c)25 to 35% by weight of a pharmaceutically acceptable hydrophilic surfactant;

(d)5 to 15% by weight of a pharmaceutically acceptable hydrophilic solvent;

or

(C)

(a)10 to 20% by weight of a sodium salt of a compound of formula (1);

(b)40 to 50% by weight of a pharmaceutically acceptable lipid selected from the group consisting of monoglycerides of caprylic and capric acids, diglycerides of caprylic and capric acids, and mixtures thereof;

(c)25 to 35% by weight of a pharmaceutically acceptable hydrophilic surfactant selected from the group consisting of tocopherol polyethylene glycol succinate, polyethylene glycol 40 hydrogenated castor oil, polyethylene glycol 35 castor oil, and mixtures thereof;

(d)5 to 10% by weight of a pharmaceutically acceptable hydrophilic solvent selected from the group consisting of propylene glycol, polyethylene glycol, ethanol, water, and mixtures thereof.