AMORPHOUS SOLID DISPERSION COMPRISING PACLITAXEL, TABLET COMPRISING THE SAME, AND METHOD FOR

PREPARING THE SAME

FIELD OF THE INVENTION

The present invention relates to an amorphous solid dispersion comprising paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant; a tablet comprising the same; and the method for preparing the same.

BACKGROUND OF THE INVENTION

Paclitaxel, a diterpenoid natural product, is one of the most effective antineoplastic agents that has been widely prescribed to treat a wide variety of tumors, including ovarian carcinoma, breast cancer, head and neck cancers, non-small lung cancer, prostatic cancer, and advanced forms of Kaposi's sarcoma. One of the major limitations associated with this potent drug is its low aqueous solubility due to its extremely hydrophobic nature.

The water solubility of paclitaxel was -10 μg/mL and lack of functional groups in its chemical structure precluded any possible salt formation to improve its solubility. Therefore, various approaches to solubilize paclitaxel were carried out for more than a decade and the most successful one was Taxol ^® (Bristol-Myers Squibb), the commercially available formulation for intravenous administration, which is 6 mg/mL of paclitaxel in a 50:50% v/v mixture of Cremophor EL ^® and dehydrated ethanol.

However, the clinical application of Taxol ^® encountered many problems, including serious or even fatal hypersensitivity episodes due to histamine induction by Cremophor EL ^® and possible precipitation after dilution and leaching of the diethylhexyl phthalate (DEHP) from polyvinylchloride (PVC) infusion sets, necessitating the use of plasticizer-free containers or bags and causing inconvenience to medical staff and pain to patients. Besides, to alleviate the severe side-effects of Taxol formulation, patients are often required to receive premedication and/or prolonged infusion regimen (up to 24 hours) leading to either inconvenient long infusion time for patients or increased hospitalization cost of the patients for the entire 6 to 24-hour infusion duration. Moreover, such measures normally would not completely eliminate the side effects.

Accordingly, many formulation approaches such as to reduce the infusion time, to increase the stability of formulation, to prepare non-toxic formulations without cremophor or reduced cremophor amount, etc. have been made and disclosed in U. S. Pat. Nos. 6,569,459 (Method of administration of paclitaxel-plasma protein formulation), 5,681,846 (Extended stability formulations for paclitaxel), 6,919,370 B2 (Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof), 6,107,333 A (Parenteral paclitaxel in a stable non-toxic formulation), etc.

However, in general, an oral formulation is preferred because of the several advantages over other methods of administration, especially intravenous administration. In addition to the flexibility of treatment, oral formulations are inexpensive, convenient and have higher rate of compliance.

Accordingly, there exists a clear need for oral compositions of paclitaxel that are easy to prepare and have enhanced solubility and bioavailability.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an amorphous solid dispersion with enhanced solubility, which comprises paclitaxel as an active ingredient.

It is other object of the present invention to provide a tablet having good solubility, bioavailability and stability, which comprises the amorphous solid dispersion.

It is another object of the present invention to provide a method for preparing the amorphous solid dispersion.

In accordance with one aspect of the present invention, there is provided an amorphous solid dispersion comprising paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant.

In accordance with other aspect of the present invention, there is provided a tablet comprising the amorphous solid dispersion, an intragranular excipient, and an extragranular excipient.

In accordance with another aspect of the present invention, there is provided a method for preparing the amorphous solid dispersion, comprising the steps:

(a) dissolving paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant in a solvent; and

(b) drying the solution obtained in step (a) by using a fluid bed spray dryer.

Other features and embodiments of the present invention will be apparent from the following description and the appended claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the solubilities of the solid dispersions of Examples 1 and 2.

FIG. 2 is a graph showing the solubilities of the solid dispersions of Examples 3 to 6.

FIG. 3 is a graph showing the solubilities of the solid dispersions of Examples 7 to 10.

FIG. 4 is a graph showing the solubilities of the solid dispersions of Examples 11 and 12, and the liquid formulation of Comparative Example 1.

FIG. 5 is a graph showing the disintegration of the tablets of Examples 13 and 14 and Comparative Examples 2 and 3.

FIG. 6 shows the X-ray diffraction pattern of (A) paclitaxel API; (B) the tablet of Example 13; and (C) the tablet of Example 14.

FIG. 7 shows the pharmacokinetic profiles of the tablets of Examples 13 and 14, and Comparative Example 3 in beagle dogs.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an amorphous solid dispersion comprising paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant, and a method for preparing the amorphous solid dispersion. Also, the present invention provides a tablet comprising the amorphous solid dispersion, an intragranular excipient, and an extragranular excipient. The amorphous solid dispersion, the method thereof, and the tablet comprising the same are described in more detail below.

1. SOLID DISPERSION ACCORDING TO THE PRESENT INVENTION

In the present invention, a solid dispersion is provided which is used for delivering paclitaxel in vivo. In one embodiment, the solid dispersion comprises paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant.

The pharmaceutically acceptable salts of paclitaxel suitable for use in the solid dispersion of the present invention are conventional non-toxic salts and can include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Ν,Ν'- dibenzylethylenediamine salt, etc.), etc.; an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.) and the like.

The pharmaceutically acceptable polymers employable as an additive in the present invention may be a hydrophilic carrier polymer, which includes, but not limited to, hydroxypropylmethyl cellulose (HPMC, hypromellose), hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, cellulose acetate, cellulose acetate phthalate, methylcellulose, ethylcellulose, cellulose, carboxymethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl starch, polyethylene glycols, polyvinylpyrrolidone, polyglycolized glycerides, polymethacrylates, carrageenan, chitosans and starches (including corn, potato, rice, wheat, fully pregelatinized and partially gelatinized), and polyvinylprrolidone, e.g., PVP K-30 is preferred.

The weight ratio of the polymer and paclitaxel may be in the range of 3: 1 to 9:1. The polymer may be used in an amount of 10 to 80% by weight based on the total amount of the solid dispersion.

Further, the pharmaceutically acceptable surfactant employable as an additive in the solid dispersion of the present invention includes, but is not limited to, polysorbate (e.g., polysorbate 20, polysorbate 40, polyoxyl 60 stearate, polysorbate 80, polysorbate 85, polysorbate 60, etc.), polyoxyl 20 stearate, polyoxyl 35 castor oil, poloxamer, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, polyoxyl 40 hydrogenated castor oil, poloxamer 331, polyoxyethylene fatty acid esters, polyoxyl 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, sodium desoxycholate, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, N-carbamoyl methoxypolyethylene glycol 2000- 1,2-distearol, myristic acid, steareth, stearic acid, polyoxyl 40 stearate, sucrose stearate, tocopherol, polyoxyl castor oil, triglyceride synthetic, trimyristin, tristearin, magnesium stearate, lecithin, lauryl sulfate, vitamin E, egg yolk phosphatides, docusate sodium, dimyristoyl phosphatidylglycerol, dimyristoyl lecithin, Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate), deoxycholate, cholesterol, Cremophor EL, Propylene glycol alginate, Croval A- 10 (PEG 60 almond glycerides), Labrafil 1944 (oleoyl macrogol-6 glycerides), Labrafil 2125 (linoleoyl macrogol- 6 glycerides), Labrasol (caprylocaproyl macrogol-8 glycerides), Lauroglycol 90 (propylene glycol monolaurate), Lauroglycol FCC (propylene glycol laurate), calcium stearate, Lecithin Centromix E, Lecithin Centrophase 152, Lecithin Centrol 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3 -diisostearate), Plurol Oleique CC, POE 20 Sorbitan trioleate, Tagat TO (polyoxyethylene glycerol trioleate), or Solutol (Macrogol-15 hydroxystearate ) and mixtures thereof.

In a preferred embodiment, the pharmaceutically acceptable surfactant is Labrasol, polysorbate 20, polysorbate 80, PEG- Vitamin E, cremophor or mixtures thereof. More preferred pharmaceutically acceptable surfactant is a mixture of polysorbate 80 and sodium lauryl sulfate. The pharmaceutically acceptable surfactant may be used in in an amount ranging from 0.1 to 60, 0.5 to 5, 0.5 to 3, or 1 to 3 weight part, based on 1 weight part of paclitaxel. Also, the weight ratio of the surfactant to the polymer may be in the range of 1 : 1 to 1 :30, 1 : 1 to 1 :15, or 1 : 1 to 1 :5. Further, the pharmaceutically acceptable surfactant may be used in an amount of 10 to 50% by weight based on the total amount of the solid dispersion of the present invention.

In a preferred embodiment of the present invention, the amorphous solid dispersion comprises paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant, wherein the pharmaceutically acceptable polymer is polyvinylpyrrolidone and the pharmaceutically acceptable surfactant is a mixture of polysorbate and sodium lauryl sulfate.

The basic concept of the inventive method is to prepare an amorphous paclitaxel solid dispersion by dissolving paclitaxel in a sufficient amount of an organic solvent followed by mixing the solution obtained above with a hydroalcoholic solution containing a pharmaceutically acceptable polymer and a pharmaceutically acceptable surfactant, thereby preparing a spray solution. The solvent may then be evaporated away, leaving the drug dispersed/dissolved in the matrix. The solid matrix has paclitaxel finely dispersed (molecular dispersion) in such a way that the dissolution of paclitaxel is maximized, thus improving the bioavailability of paclitaxel.

Particularly, the method for the preparation of an amorphous paclitaxel solid dispersion by the spray drying technique of the present invention comprises the following steps:

1. Preparation of the spray solution containing paclitaxel and polymer/ surfactant.

2. Formation of solid dispersion by spraying the solution of Step 1) via a nozzle to obtain a solid dispersion.

3. Collection of the solid dispersion prepared thereby and drying if necessary.

The above steps of the inventive method are each described in detail as follows.

Step 1 : Preparation of the spray solution containing paclitaxel and polymer/surfactant In Step 1), the spray solution for producing a solid dispersion is prepared by mixing Solution A: an organic solvent solution containing paclitaxel, and Solution B: an aqueous- organic solvent solution containing a carrier polymer and a surfactant.

In accordance with the present invention, the organic solvent for dissolving paclitaxel in Solution A includes, but not limited to, ethanol, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, Ν,Ν-dimethylformamide, DMSO and tetrahydrofuran, preferably ethanol.

Further, the aqueous-organic solvent used for dissolving a carrier polymer and a surfactant in the Solution B include, but not limited to, ethanol/water, methanol/water and isopropanol/water, preferably ethanol/water (hydroalcoholic). Since the above two solvent systems can easily mix with each other, a mixture thereof forms a homogenous solution.

In a preferred embodiment, it is preferable to mix the Solution A and the Solution B in a weight ratio of 7:3 to 2:8, more preferably about 4:6, while the weight ratio of water to alcohol in the Solution B may range from 1 :20, more preferably 1 :10, and most preferably 1 :5.

Step 2: Formation of solid dispersion by spraying the solution obtained in Step 1

In this step, the solvent may be removed by evaporation by spray drying technique. The term "spray-drying" is used conventionally and broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray-drying apparatus where there is a strong driving force for evaporation of solvent from the droplets. In a typical spray drying process, the feed liquid may be a solution, slurry, emulsion, gel or paste, provided it is pumpable and capable of being atomized.

In one embodiment, the process according to the present invention is generally carried out by conventional spray drying technique. Spray-drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details on spray-drying processes and equipment are reviewed by Marshall, "Atomization and Spray- Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition 1985). The driving force for solvent elimination or evaporation is usually provided by keeping the partial pressure of solvent in the spray-drying equipment substantially below the vapor pressure of the solvent at the temperature of the drying droplets. In another embodiment according to the present invention, the process of producing a solid dispersion is a combination of fluid bed technology and spray-drying technology. In the fluid bed technology, powders are generally suspended in an upwardly moving column of air while at the same time a controlled and defined amount of liquid is injected into the powder stream to produce a moistened state or "agglomeration" of the powder; mild heat is then used to dry the agglomerated powder. Following this agglomeration, the powder has altered physical characteristics from the starting powder.

By combining the fluid bed and spray drying technology, solid dispersion particles of poorly water-soluble or substantially water-insoluble compound are produced by finely- spraying a non-aqueous solution of paclitaxel into a heated and fluidized bed of carrier excipients. The resulting product is a solid dispersion consisting of a free flowing mixture of relatively larger granular particles of carrier excipients and amorphous compound.

This process is generally carried out by a) introducing carrier excipients in the form of a dry powder, into a fluidized bed drier in which the bed is kept at from about 20°C to about 80°C, preferably about 25°C to about 50°C, in particular about 27°C to about 45°C; b) spraying of solution prepared in Step 1) onto the fluidized bed of excipients.

The fluid bed dryer may contain pharmaceutical excipients during the process of spray drying. This enables the drying and formation of solid dispersions on the pharmaceutical excipients inside the fluid bed dryer. The pharmaceutical excipients in accordance with the invention include, but not limited to, fillers, disintegrants, surfactants, adsorbents, and lubricants.

Fillers which are useable in accordance with the invention include, but are not limited to, lactose (anhydrous), lactose monohydrate, spray-dried lactose; compressible sugar, dextrose, dextrates; starches (including corn, potato, rice, wheat, fully pregelatinized and partially gelatinized); cellulose; inorganic salts such as calcium phosphate, tribasic calcium and calcium sulfate; and polyols such as mannitol, sorbitol and xylitol.

In a preferable embodiment of the present invention, microcrystalline cellulose is used in fluid bed of the fluid bed dryer when the solid dispersion solution is sprayed containing paclitaxel or its salt thereof.

In accordance with one preferred embodiment, the weight ratio of solid dispersion to filler in the fluid bed may be 0.1 : 1 to 1 :10.

In accordance with another preferred embodiment, the weight ratio of solid dispersion to filler in the fluid bed may be 0.5:1 to 1 :5.

Disintegrants which are useable in accordance with the invention include, but are not limited to, croscarmellose sodium, sodium starch glycolate, starches (including corn, potato, rice, wheat, fully pregelatinized and partially gelatinized), crospovidone, alginates such as calcium alginate and sodium alginate, alginic acid, and magnesium aluminum silicate.

In a preferable embodiment of the present invention, croscarmellose sodium may be used in fluid bed of the fluid bed dryer when the solid dispersion solution is sprayed containing paclitaxel or its salt thereof.

In another preferable embodiment of the present invention, the combination of microcrystalline cellulose and croscarmellose sodium is used in fluid bed of the fluid bed dryer when the solid dispersion solution is sprayed containing paclitaxel or its salt thereof.

In accordance with one preferred embodiment, the weight ratio of the solid dispersion to the disintegrant in the fluid bed may be 0.1 : 1 to 1 : 10.

In accordance with another preferred embodiment, the weight ratio of the solid dispersion to the disintegrant in the fluid bed may be 0.5:1 to 1 :5.

In accordance with one preferred embodiment, the weight ratio of filler to disintegrant in the fluid bed may be 1 : 1 to 1 : 10.

In accordance with another preferred embodiment, the weight ratio of filler to disintegrant in the fluid bed may be 1 :2 to 1 :5.

Surfactants which are employable in accordance with the present invention include, but not limited to, polysorbates, poloxamers, polyethylene glycols, bile salts, sodium desoxycholate, sodium lauryl sulfate, tocopherol, polyoxyl castor oil, lecithin, lauryl sulfate, Vitamin E, egg yolk phosphatides, docusate sodium, Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate), deoxycholate, and cholesterol. In a preferred embodiment, the surfactant is sodium lauryl sulfate, Labrasol, polysorbate 20, polysorbate 80, PEG- Vitamin E, or mixtures thereof. In a more preferred embodiment, the surfactant is sodium lauryl sulfate.

In accordance with one preferred embodiment, the amount of one or more surfactants may be in the range of 0.001% to 10% by weight based on the total weight of the solid dispersion.

Step 3: Collection of spray dried solid dispersion Once the spraying is over, the feed and atomization are stopped, and the resultant solid dispersion is collected and dried further if necessary in an oven at 40~60°C, more preferably at 40~50°C.

The result of analyzing the thermochemical properties of the inventive solid dispersion with a differential scanning calorimeter (DSC) shows that while a paclitaxel powder showed a strong endothermic peak at around 220°C, the paclitaxel solid dispersion of the present invention does not show any endothermic peak. Accordingly, it has been confirmed that the collected paclitaxel powder formulation of the present invention is a solid dispersion having an altered molecular arrangement (amorphous or non-crystalline). The resulting solid dispersion can be formulated into pharmaceutical compositions that exhibit high bioavailability.

2. PHARMACEUTICAL FORMULATION ACCORDING TO THE PRESENT INVENTION

Oral formulations of the present invention are preferably in the form of capsules, tablets, pills, dispersions, solutions, or suspensions. A therapeutically effective oral dosage for formulations of the invention is determined by standard clinical techniques according to the judgment of a medical practitioner. For example, in addition to information provided in medical reference books and pharmaceutical literature, well-known in vitro or in vivo assays can be used to help identify optimal dosages.

The tablet containing the solid dispersion of this invention can be prepared by mixing the amorphous solid dispersion with an intragranular excipient, and an extragranular excipient, and then by compressing the resulting mixture to form a tablet. In the tablet, the amorphous solid dispersion may be employed in an amount of 15 to 50% by weight, based on the total weight of the tablet.

In addition to the solid dispersion, the tablet of the present invention may further comprise fillers, disintegrants, lubricants, surfactants, or combinations thereof.

Fillers which are useable in accordance with the invention include, but are not limited to, lactose (anhydrous), lactose monohydrate, spray-dried lactose; compressible sugar, dextrose, dextrates; starches (including corn, potato, rice, wheat, fully pregelatinized and partially gelatinized); cellulose; inorganic salts such as calcium phosphate, tribasic calcium and calcium sulfate; and polyols such as mannitol, sorbitol and xylitol. The preferred filler is microcrystalline cellulose.

Disintegrants which are useable in accordance with the invention include, but are not limited to, croscarmellose sodium, sodium starch glycolate, starches (including corn, potato, rice, wheat, fully pregelatinized and partially gelatinized), crospovidone, alginates such as calcium alginate and sodium alginate, alginic acid, and magnesium aluminum silicate. The preferred disintegrant is croscarmellose sodium.

Lubricants which are useable according to the invention include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oils, mineral oil, polyethylene glycols, talc, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, leucine, and magnesium lauryl sulfate. The preferred lubricant is sodium stearyl fumarate. In accordance with one preferred embodiment, the lubricant may be used in an amount of 0.5 to 2%, more preferably 0.75% to 1% by weight based on the total weight of tablet.

The surfactant employable as an additive in the present invention includes, but not limited to, polysorbate, poloxamer, sodium lauryl sulfate, tocopherol, lecithin, lauryl sulfate, Vitamin E, egg yolk phosphatides, docusate sodium, Capryol, Labrafil, Labrasol, Lauroglycol, Solutol (Macrogol-15 hydroxystearate) and mixtures thereof. In a preferred embodiment, surfactants include polysorbates, sodium lauryl sulfate, labrasol, and lecithin.

In one embodiment, a tablet comprising the amorphous solid dispersion of paclitaxel of the present invention can be prepared by the method which comprises the steps of:

1. dissolving paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant in a solvent, and then removing the solvent from the solution, for example, by evaporation using the traditional spray drying technology, to produce a solid dispersion;

2. mixing together said solid dispersion, an intragranular excipient, and an extragranular excipient; and

3. compressing the resulting mixture to form a tablet.

In a more preferred embodiment, a tablet comprising the amorphous solid dispersion of paclitaxel of the present invention can be prepared by the method which comprises the steps of:

1. dissolving paclitaxel or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and a pharmaceutically acceptable surfactant in a solvent, and then removing the solvent from the solution, for example, by evaporation using the fluid bed spray drying technology, wherein the fluid bed comprises an intragranular excipient, to produce a solid dispersion;

2. mixing together said solid dispersion and an extragranular excipient; and

3. compressing the resulting mixture to form a tablet.

In accordance with one embodiment, the extragranular excipients could be one or more disintegrants and lubricants.

In the method of the present invention, the solvent may be a mixture of ethanol and water, and the weight ratio of ethanol and water may be in the range of 2: 1 to 25: 1.

In the method of the present invention, the intragranular excipient may be selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and a mixture thereof, and the extragranular excipient may be selected from the group consisting of croscarmellose sodium, sodium stearyl fumarate, and a mixture thereof.

Tablets, one example of solid oral dosage forms, particularly useful in the practice of the present invention include those selected from the group consisting of IR tablets, CR tablets, SR tablets, coated IR tablets, matrix tablets, coated matrix tablets, multilayer tablets, coated multilayer tablets, multilayer matrix tablets and coated multilayer matrix tablets.

A preferred solid oral dosage form is an immediate release dosage form, which disintegrates immediately in the stomach cavity, and releases the drug and excipients in the gastric region for enhanced absorption by the intestinal cells. A preferred tablet dosage form is a film coated tablet dosage form.

The tablet of the present invention may be film-coated with a coating agent. Examples of the coating agent are hydroxypropyl methyl cellulose, ethyl cellulose, etc. The coating agent may contain, for example, an opaquing agent such as titanium oxide or a plasticizer such as polyethylene glycol. 3. METHOD OF ADMINISTRATION ACCORDING TO THE PRESENT

INVENTION

A method for administering paclitaxel to a host in need thereof is provided, comprising: providing a pharmaceutical oral solid dosage formulation comprising: paclitaxel or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable surfactant prepared as a solid dispersion, and administering the pharmaceutical formulation in a therapeutically effective amount to a host in need thereof.

The method may be used for administering paclitaxel orally to patients with malignant diseases such as cancer including, but not limited to, human ovarian cancer, breast cancer, malignant lymphoma, lung cancer, melanoma, and Kaposi's sarcoma.

Paclitaxel is administered alone or in combination with other therapeutic agents which can act synergistically with paclitaxel.

In a more preferred embodiment, the invention encompasses methods of orally administering a tablet comprising the amorphous solid dispersion containing paclitaxel, and an additional therapeutic agent. In a further embodiment, the invention encompasses methods of orally administering a tablet comprising the amorphous solid dispersion containing paclitaxel to a patient in need thereof, an additional therapeutic agent, and a p-glycoprotein inhibitor.

Hereinafter, the present invention is described in more detail. The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention.

EXAMPLES

Examples 1 and 2: Preparation of solid dispersions with different types of polymer

The solid dispersions of Examples 1 and 2 presented in Table 1 were prepared by the traditional spray drying method using a traditional spray dryer. Two different polymers, HPMC and PVP, were used to prepare the paclitaxel solid dispersions.

Spray drying was performed on a Buchi Mini Spray Dryer. The feed material was atomized through nozzle with the following spray drying conditions: inlet temperature of 65°C, outlet temperature of 45°C, atomization pressure of 0.5 bar, and atomization flow rate of 10% with 80% aspiration. All solutions were prepared at 10% total solids in 3:2 (w:w) Ethanol: Water. Spray dried samples were then dried in a vacuum oven for at least 2 hrs at 50°C.

<Table 1>

Examples 3 to 6: Preparation of solid dispersions with different types of surfactants

The solid dispersions of Examples 3 to 6 as presented in Table 2 were prepared using the above-mentioned traditional spray drying method. Various types of surfactants were used to prepare the paclitaxel solid dispersions.

<Table 2>

Examples 7 to 10: Preparation of solid dispersions with different amounts of polymer

The solid dispersions of Examples 7 to 10 as presented in Table 3 were prepared using the above-mentioned traditional spray drying method. Various amounts of polymer were used to prepare the paclitaxel solid dispersions.

<Table 3>

Example 11: Preparation of solid dispersion by spray drying technology

The solid dispersion of Example 11 as presented in Table 4 was prepared using the traditional spray drying method as mentioned in Example 1. The final solid dispersion contained 30 mg equivalent paclitaxel per 210 mg of powder mixture.

<Table 4>

Example 12: Preparation of solid dispersion by fluid bed technology The solid dispersion of Example 12 as presented in Table 5 was prepared using the fluid bed spray drying technology. Spray solution was prepared by dissolving paclitaxel, surfactants, and polymer in ethanol/water solvent system. The solution was sprayed into 434 g mixture of excipients as shown in Table 5 in fluid bed system. The spray rate was 15-25 mL/min using one top gun. The static inlet pressure was 2.5-5 bar (250-500 kPa). The inlet temperature was 65~70°C and the product temperature was 30-40°C. The resulting paclitaxel powder mixture was free-flowing and contained 30 mg paclitaxel per 644 mg of final mixture.

<Table 5>

Comparative Example 1: Preparation of liquid formulation containing paclitaxel

The liquid formulation containing paclitaxel was prepared using the ingredients shown in Table 6. Specifically, paclitaxel as an active ingredient was completely dissolved in Tween 80 as a surfactant using a magnetic stirrer bar.

<Table 6>

Example 13: Preparation of tablet containing the solid dispersion of Example 11

The tablet was prepared using the solid dispersion of Example 11, as shown in Table 7.

Once the spray drying is over, the solid dispersion of Example 11 was mixed with the intragranular excipients and part of the lubricant was added to the granule mixture and tablets were produced for the slugging process with a hardness of less than 2 kp. The slug was then passed through sieve #20. Remaining amount of lubricant and extragranular excipients were then added to this slug and mixed well, and the final tablets were made by the tablet machine. The tablets prepared were oblong with a thickness of around 6.90 mm, diameter of around 15.83 mm, and a hardness of around 2-5 kp.

<Table 7>

Example 14: Preparation of tablet containing the solid dispersion of Example 12

The tablet was prepared using the solid dispersion of Example 12, as shown in Table 8.

Once the fluid bed process is over, part of the lubricant was added to the granule mixture and tablets were produced for the slugging process with a hardness of less than 2 kp. The slug was then passed through sieve #20. Remaining amount of lubricant was then added to this slug and mixed well, and the final tablets were made by the tablet machine. The tablets prepared were oblong with a thickness of around 6.90 mm, diameter of around 15.83 mm, and a hardness of around 2-5 kp.

<Table 8>

Ingredients (mg) Example 14 Solid dispersion of Example 12 210

Microcrystalline cellulose 210

Croscarmellose sodium 310

Sodium lauryl sulfate 14

Sodium stearyl fumarate 6

Total 750

Comparative Example 2: Preparation of tablet containing the solid dispersion of paclitaxel by fluid bed spray drying technology with paclitaxel : polymer ratio of 1:9 with SLS only

The tablet of Comparative Example 2 as presented in Table 9 was prepared using the fluid bed spray drying technology as mentioned in Example 12. Spray solution was prepared by dissolving paclitaxel, surfactant (sodium lauryl sulfate), and polymer (PVP K-30) in ethanol/water solvent system. The solution was sprayed into 300 g mixture of excipients (Microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate) as showed in Table 9, in the fluid bed system. The spray rate was 5~25 mL/min using one top gun. The static inlet pressure was 2.5-5 bar (250-500 kPa). The inlet temperature was 65~70°C and the product temperature was 30~40°C. The resulting granules were free-flowing containing amorphous paclitaxel coated on to the excipients' surface. The resulting paclitaxel granules were free-flowing and contained 30 mg equivalent paclitaxel.

Once the fluid bed process is over, part of the lubricant was added to the granule mixture and tablets were produced for the slugging process with a hardness of less than 2 kp. The slug was then passed through sieve sieve #20. Remaining amount of lubricant was then added to this slug and mixed well, and the final tablets were made by the tablet machine. The tablets prepared were oblong with a thickness of around 6.90 mm, diameter of around 15.83 mm, and a hardness of around 2-5 kp.

<Table 9> Sodium lauryl sulfate 30

Ethanol (2100)

Water (900)

Subtotal 330

Microcrystalline cellulose 210

Croscarmellose sodium 310

Sodium lauryl sulfate 14

Total 744

Sodium stearyl fumarate 6

Total 870

Comparative Example 3: Preparation of conventional tablet of paclitaxel

The conventional tablet containing paclitaxel was prepared using the ingredients shown in Table 10.

First, paclitaxel was mixed with PVP K-30, sodium lauryl sulfate, and Polysorbate 80 (Tween 80) as intragranular excipients and wet granulated to form granules. After drying the granules, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate and sodium stearyl fumarate as extragranular excipients were mixed, and the final tablets were made by the tablet machine. The tablets prepared were oblong with a thickness of around 6.90 mm, diameter of around 15.83 mm, and a hardness of around 2~5 kp.

<Table 10>

Test Example 1: Solubility study of solid dispersions of Examples 1 and 2

The solubilities of the solid dispersions of Examples 1 and 2 were investigated using USP XXIII, dissolution apparatus II with 300 mL of pH 1.2 buffer as dissolution medium at 37 ± 0.5°C with paddle speed of 50 rpm. The solid dispersions of paclitaxel (90 mg as of paclitaxel) were introduced into dissolution tester (Labfine, Korea). At predetermined time intervals, an aliquot of 5 mL was collected, filtered, and analyzed for the content of paclitaxel by the HPLC method. An equivalent volume (5 mL) of fresh dissolution medium was replaced to compensate the loss due to sampling, and the sink condition was maintained throughout the study. The theoretical concentration of paclitaxel in the medium is 300 PPM (90 mg paclitaxel in 300 mL medium). The results are shown in FIG. 1.

As shown in FIG. 1 , the solubility of the solid dispersion of Example 2 containing PVP polymer was better than that of the solid dispersion of Example 1. Also, the solubility of the solid dispersion of Example 2 containing PVP was higher and faster, which was chosen for further development.

Test Example 2: Solubility study of solid dispersions of Examples 3 to 6 The solubilities of the solid dispersions of Examples 3 to 6 were investigated using the same conditions discussed in Test Example 1. The effects of various types of surfactants on the solubility of paclitaxel in addition to SLS were shown in FIG. 2.

As can be seen in FIG. 2, it was clear that the solid dispersion of Example 4 containing Tween 80 and SLS as the surfactants showed highest solubility among the tested dispersions. The solid dispersion of Example 5 containing Labrasol and SLS only showed poor solubility of paclitaxel in the dissolution medium. The solid dispersion of Example 6 containing only SLS without additional surfactants exhibited the poorest solubility among the tested dispersions at paclitaxel dose of 30 mg. The solid dispersion of Example 3 containing Cremophor EL showed the second highest solubility. However, given that the Cremophor is toxic and one of the objectives of the invention is to prepare formulations without Cremophor, the use of surfactant Tween 80 in the preparation of solid dispersion was believed to be highly appropriate. Test Example 3: Solubility study of solid dispersions of Examples 7 to 10

The solubilities of the solid dispersions of Example 7 to 10 were investigated using the same conditions discussed in Test Example 1. The effect of the amount of polymer on the solubility of paclitaxel was investigated in this study. The amount of PVP K30 polymer ranging of 30-270 mg was used to prepare the solid dispersions. The results are shown in FIG. 3. The weight ratio of paclitaxel to PVP K-30 used were 1 :9 (30:270), 1 :6 (30: 180), 1 :3 (30:90), and 1 :1 (30:30).

There was no significant difference between Examples 7, 8 and 9, containing 270, 180 mg, and 90 mg of polymer, respectively, corresponding to a ratio of 1 :9, 1 :6, and 1 :3, respectively. However, the paclitaxel precipitated earlier at 90 min when the polymer amount was more than 90 mg, while the solubility was stable with 90 mg of polymer (ratio 1 :3). The solid dispersion of Example 10 containing a low amount of polymer (30 mg) showed poor solubility of paclitaxel suggesting poor carrier effect of polymer at this amount range.

Besides, it is known scientific fact that increasing polymer amount would increase the disintegration and dissolution of compressed tablets due to increased time for hydration leading to sustained effects. Considering this factor, use of minimal amount of polymer is advised and the ratio of 1 :3 is considered better in terms of prevention of precipitation, decreased disintegration time, and faster dissolution.

Test Example 4: Solubility test of solid dispersions of Example 11 and 12, and Comparative Example 1

The solubilities of the solid dispersions of Examples 11 and 12 were investigated using USP XXIII, dissolution apparatus II with 300 mL of pH 1.2 buffer as dissolution medium at 37 ± 0.5°C with paddle speed of 50 rpm. For comparison, the liquid formulation of Comparative Example 1 (equivalent to 90 mg of paclitaxel) was also added directly into the dissolution medium.

The solid dispersions of paclitaxel (90 mg as of paclitaxel) were introduced into dissolution tester (Labfine, Korea). At predetermined time intervals, an aliquot of 5 mL was collected, filtered, and analyzed for the content of paclitaxel by the HPLC method. An equivalent volume (5 mL) of fresh dissolution medium was replaced to compensate the loss due to sampling, and the sink condition was maintained throughout the study. The theoretical concentration of paclitaxel in the medium is 300 PPM (90 mg paclitaxel in 300 mL medium).

The solubility profiles of the solid dispersions of Examples 11 and 12, and the liquid formulation of Comparative Example 1 were shown in FIG. 4. The solubility of the solid dispersion of Example 12 prepared by fluid bed technology showed the fastest dissolution among the samples tested. The liquid formulation of Comparative Example 1 showed poor solubility and faster recrystallization compared to the solid dispersions. According to FIG. 4, it could be understood that amorphous solid dispersions prepared by either traditional or fluid bed technique was superior than even the liquid formulation, and this composition and process of preparation could be considered as excellent method for increasing solubility of paclitaxel.

Test Example 5: Solubility study of tablets of Examples 13 and 14, and Comparative Example 2

The solubilities of the tablets of Examples 13 and 14, and Comparative Examples 2 and 3 were investigated using the same conditions discussed in Test Example 1. Three tablets of each formulation containing paclitaxel of Examples 13 and 14, and Comparative Examples 2 and 3 (equivalent to 90 mg of paclitaxel) were introduced into dissolution tester (Labfine, Korea). The solubility profiles of all the formulations are shown in FIG. 5.

Among the samples tested, the tablet of Example 14, prepared by the fluid bed spray dry technology, showed the fastest and highest solubility. The dissolution rate was very fast and highest dissolution/solubility occurred within 20 min. This could be due to faster disintegration of tablet attributed to the process of preparation and faster dissolution of amorphous paclitaxel by the solid dispersion containing hydrophilic polymer and surfactants.

The tablet of Example 13, prepared by the traditional spray drying technology, showed comparatively slower and lower dissolution and solubility profile compared to that of Example 14, and complete dissolution occurred around 40 min. The tablet of Comparative Example 2, prepared by fluid bed spray drying technology and with highest amount of polymer content, showed the slowest disintegration and dissolution compared to other formulations tested. Despite being amorphous, the slow release and low solubility could be attributable to the highest polymer content that prevents fast hydration and release. The tablet of Comparative Example 3, prepared by conventional tab letting method, showed slow release and low solubility than the tablets of Examples 13 and 14, and the solubility was comparable to Comparative Example 2. From this test results, it is understandable that neither crystalline paclitaxel of Comparative Example 3 nor high polymer content of Comparative Example 2 produced expected solubility.

Test Example 6: Disintegration test of tablets of Examples 13 and 14 and Comparative Examples 2 and 3

The tablet of Example 13 prepared by the traditional spray drying technology, the tablet of Example 14 prepared by the fluid bed spray drying technology, the tablet of Comparative Example 2 with the highest polymer ratio and only SLS, and the conventional tablet of Comparative Example 3 were subjected to disintegration test as per United States Pharmacopoeia (USP). The disintegration time of the respective tablets are shown in Table 11.

The tablet of Example 14 showed shorter disintegration time compared to that of Example 13. The disintegration time for Comparative Example 2 with highest polymer ratio and only SLS was highest. The faster disintegration of Example 14 could be attributable to the fluid bed process technology which imparts lower density granules with highly porous surface which are easily wettable and so faster disintegration.

<Table 11>

Test Example 7: Solid state characterization of tablets of Example 13 and 14, and paclitaxel API

The solid-state characterization of the spray dried tablet of Example 13 prepared by the traditional spray drying process, the spray dried tablet of Example 14 prepared by the fluid bed spray drying process, and paclitaxel API was evaluated by XRD using M18XHF- SRA (Macsciences Co., Ltd., Japan) under the conditions of Cu X-ray, 40 kV and 100 mA, with a scan speed of 6 min.

The results of X-ray diffraction patterns of paclitaxel API, and the tablets of Examples 13 and 14 were shown in FIG. 6. As shown in FIG. 6 A, the active ingredient, paclitaxel, had peaks at two-theta (degree) 4.147, 5.224, 5.600, 6.138, 8.987, 9.711, 10.123, 11.195, 12.454, 13.690, 13.967, 15.682, 16.481, 17.144, 18.051, 18.791, 19.541, 20.191, 21.248, 22.022, 22.822, 23.558, 25.227, 26.339, 27.119, 28.689, 29.985, 31.963, 32.855, and 34.178. However, as shown in FIG 6B and 6C, the tablets of Examples 13 and 14 did not show any peaks because the spray drying process converted the crystalline active ingredient into amorphous form, resulting in amorphous solid dispersion composition.

Test Example 8: Comparison of in vivo PK parameters and bioavailability of tablets of Examples 13 and 14, and Comparative Example 3 in beagle dogs

In vivo dog bioavailability and pharmacokinetic studies were performed to investigate the increase in bioavailability of the tablets of Examples 13 and 14, and Comparative Example 3.

Dogs (beagle dogs weighing around 10-15 kg) were fasted overnight prior to dosing, but are permitted water ad libitum. The dogs were separated into three groups for Examples 13 and 14, and Comparative Example 3, and each dog received 30 mg of Pgp inhibitor orally approximately 30 minutes prior to dosing of paclitaxel formulations.

After 30 minutes, each dog was administered with the tablets equivalent to 60 mg of paclitaxel. The dose was followed by approximately 150 mL of water. Blood samples were obtained from each animal prior to dosing and at 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after drug administration. The plasma is separated by centrifugation and frozen (- 40°C) until analysis. The concentration of paclitaxel in the plasma was determined by reverse phase HPLC with low wavelength UV detection following liquid-liquid extraction of the plasma samples. Paclitaxel area under the curve is calculated by the trapezoidal method over the time course of the study. The values reported are averages for each group of dogs in Table 12.

<Table 12>

Parameters

AUCiast (ng.hr/mL) 781.15 ± 418.93 898.36 ± 318.51 223.38± 160.91

AUCinf (ng.hr/mL) 802.85 ± 404.99 990.01± 321.27 234.85 ± 185.42

Cmax (ng/mL) 136.35 ± 111.74 172.89 ± 71.26 38.85 ± 39.34

Tmax (hr) 1.45 ± 0.64 0.98 ± 0.37 2.08 ± 1.5

ti/2 (hr) 15.03 ± 3.73 13.83± 2.34 10.45 ± 4.64

FIG. 7 shows the pharmacokinetic profiles of the tablets of Examples 13 and 14, and Comparative Example 3 in beagle dogs. All data were listed as mean of six with standard deviation. The profiles were plotted with plasma concentration (ng/mL) against time. The FIG. 7 and Table 12 show that the tablet of Example 14 demonstrated highest bioavailability with highest C _max . While, the Comparative Example 3 prepared by conventional method showed lowest bioavailability.

The T _max was shorter and t was higher for the tablets of Examples 13 and 14. AUC of the tested tablets were higher for the tablets of Examples 13 and 14 as compared to Comparative Example 3 prepared by conventional method. Besides, the inter-individual variations for the solid dispersions of Examples 13 and 14 were comparatively lower compared to the Comparative Example 3.

The enhanced C _ma x and AUC coupled with reduced T _max could be due to the matrix of water soluble polymer and amorphous drug that enhances the solubility in vivo and preventing precipitation leading to enhanced absorption of paclitaxel.

It is clearly demonstrated that the administration of the tablet containing paclitaxel solid dispersion in dogs resulted in enhanced solubility and bioavailability.

Test Example 9: Stability of tablet of Example 14 at accelerated condition

The tablet of Example 14 was stored under accelerated conditions according to the following protocol. The amount of degradation products of each active ingredient was measured to compare the stability of the composite formulations. The results are shown in Table 14.

Accelerated Storage Conditions

-Storage conditions: contained in an HDPE bottle @ 40°C, 75% RH

-Test duration: initial, 1 and 3 months -Analysis target: paclitaxel and related compounds

Analysis Conditions of paclitaxel and its related compounds

Column: Stainless column (internal diameter of about 4.6 mm and length of 5 cm) packed with octadecylsilyl silica gel for liquid chromatography (e.g., Symmetry CI 8, μιη particle size)

Mobile phase: A: Acetonitrile: Water (7:3); B: Acetonitrile

Detector: UV-absorption detector (absorbance at 227 nm)

Flow rate : 1.2 mL/min

Injection volume: 10 μΐ,

Column temperature: 35°C

Gradient system:

<Table 13>

<Table 14>

According to the results, the stability of the tablet solid dosage formulation of Example 14 was excellent for up to 3 months in the accelerated condition. All known and unknown impurities were within the specified limits mentioned in USP.

Accordingly, this inventive method of preparing a tablet containing the paclitaxel solid dispersion prepared by traditional spray drying method or fluid bed spray drying method and pharmaceutical excipients would have advantage over other methods and could be utilized for oral administration of paclitaxel, especially as an oral solid dosage formulation. This inventive method of preparing a tablet containing paclitaxel solid dispersion proved to be highly stable, soluble, and highly bioavailable in vivo.

Although the present invention has been described by way of a detailed description in which various embodiments and aspects of the invention have been described, it will be seen by one skilled in the art that the full scope of this invention is not limited to the examples presented herein. Therefore, the substantial scope of the present invention will be defined by the accompanying claims and equivalents thereof.