Oral pharmaceutical composition containing taxane and preparation method thereof

Abstract

The invention relates to an oral pharmaceutical composition and a preparation method thereof. The oral pharmaceutical composition comprises: (a) taxane; (b) at least one medium chain triglyceride selected from the group consisting of glyceryl triacetate, glyceryl tributyrate, glyceryl trihexanoate, glyceryl tricaprylate, glyceryl tricaprylate, and glyceryl trioleate; (c) a glyceryl oleate complex comprising glyceryl monooleate, glyceryl dioleate, and glyceryl trioleate, the content of the glyceryl monooleate being 30 wt% to 99.9 wt%; (d) cholesterol, a cholesterol derivative, or a combination thereof; and (e) a surfactant.

Description

Technical Field

[0001] The present invention relates to an oral pharmaceutical composition containing taxane and a preparation method thereof. Background Art

[0002] Taxane is a diterpene (C20) compound produced by Taxus plants. It exerts anti-proliferative effects by affecting the reconstruction of the microtubule network in the cytoskeleton system. It has obvious cytotoxicity against various cancers such as ovarian cancer, breast cancer, esophageal cancer, melanoma, leukemia, etc., and is widely used as a chemotherapeutic drug. Non-limiting examples of taxanes include paclitaxel Docetaxel Cabazitaxel, larotaxel, ortataxel, and tesetaxel are mainly sold in parenteral dosage forms.

[0003] Taxanes generally have low water solubility. For example, formulations containing paclitaxel Currently, it is formulated in the form of an emulsion preconcentrate that is diluted before injection. However, injectable preparations have issues with patient compliance, formulation stability, and human safety, so oral preparations are being studied.

[0004] It has been reported that when taxanes such as paclitaxel are taken orally, their oral bioavailability is low due to the action of efflux pumps (Walle et al., Drug Metabo. Disp. 26(4): 343-346 (1998)), and there is also a problem of poor absorption (less than 1%) when paclitaxel is taken orally (Eiseman et al., Second NCI Workshop on Taxol and Taxus (Sept. 1992), Suffness (ed.) et al., TaxolTM Science and Applications, CRC Press (1995)).

[0005] In addition, existing paclitaxel oral dissolving compositions are all stored in a semi-solid form and then converted into a solution form for oral administration to patients. However, the semi-solid form of the composition stored in a refrigerated state will not be converted into a solution at room temperature and will remain in a semi-solid form even if left for a long time.

[0006] In this context, the inventors of the present invention developed an oral pharmaceutical composition comprising taxane, medium-chain triglycerides, oleylglycerol complexes, cholesterol or its derivatives, and a surfactant, and confirmed that the pharmaceutical composition is in liquid form at room temperature and can be conveniently administered to patients, and has a high oral absorption rate, which can reduce the dosage, thereby completing the present invention. Summary of the invention

[0007] Technical issues to be solved

[0008] The present invention aims to provide an oral pharmaceutical composition comprising taxane.

[0009] The present invention also aims to provide a method for preparing the oral pharmaceutical composition.

[0010] However, the technical problems to be solved by the present invention are not limited to the above-mentioned subjects, and other unmentioned subjects will be clearly understood by ordinary technicians in this field through the following description.

[0011] Technical methods to solve problems

[0012] In order to solve the above problems, the present invention provides an oral pharmaceutical composition which may include: (a) taxane; (b) at least one medium chain triglyceride selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein; (c) an olein complex comprising monoolein, diolein, and triolein, wherein the content of monoolein is 30 wt % to 99.9 wt %; (d) cholesterol, a cholesterol derivative or a combination thereof; and (e) a surfactant.

[0013] As an embodiment of the present invention, the cholesterol derivative may be cholesterol lacetate, β-sitosterol, β-sitosterol acetate or a combination thereof, but the embodiment is not limited thereto.

[0014] As another embodiment of the present invention, the surfactant can be Tween 80, D-α-tocopherol polyethylene glycol 1000succinate (TPGS), and combinations thereof, but the embodiment is not limited thereto.

[0015] As another embodiment of the present invention, the pharmaceutical composition comprises 0.9 wt % to 7.2 wt % of (d) cholesterol, cholesterol derivatives or combinations thereof, preferably 2 wt % to 3 wt %, based on the total weight of the pharmaceutical composition.

[0016] As another embodiment of the present invention, the weight ratio of (a) taxane to (d) cholesterol, cholesterol derivatives or a combination thereof in the pharmaceutical composition is 1:1.5 to 1:2, preferably 1:1.8.

[0017] As another embodiment of the present invention, the pharmaceutical composition comprises (a) 0.5 wt% to 4 wt% of taxane, (b) 15 wt% to 35 wt% of medium chain triglyceride, (c) 40 wt% to 60 wt% of olein complex, (d) 0.9 wt% to 7.2 wt% of cholesterol, cholesterol derivatives or combinations thereof, and (e) 10 wt% to 30 wt% of surfactant, based on the total weight of the pharmaceutical composition. Preferably, the pharmaceutical composition comprises (a) 0.5 wt% to 2 wt% of taxane, (b) 20 wt% to 30 wt% of medium chain triglyceride, (c) 45 wt% to 55 wt% of olein complex, (d) 2 wt% to 3 wt% of cholesterol, cholesterol derivatives or combinations thereof, and 15 wt% to 25 wt% of (e) surfactant.

[0018] As another embodiment of the present invention, the pharmaceutical composition is a physical mixture of (a) to (e). That is, no covalent bond or ionic bond may be formed between (a) to (e) in the pharmaceutical composition.

[0019] As another embodiment of the present invention, the pharmaceutical composition is in a liquid phase, preferably an oily liquid phase, at room temperature. Therefore, it can be prepared without a separate heating condition, and a heating step can be added to improve the preparation efficiency.

[0020] In addition, the present invention provides a method for preparing an oral pharmaceutical composition, comprising the steps of mixing (a) taxane; (b) at least one medium chain triglyceride selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein; (c) an olein complex comprising monoolein, diolein, and triolein, wherein the content of monoolein is 30 wt % to 99.9 wt %; (d) cholesterol, a cholesterol derivative or a combination thereof; and (e) a surfactant.

[0021] As one embodiment of the present invention, the preparation method is to physically mix (a) to (e) without using a solvent, or to physically mix (a) to (e) with the addition of a solvent and then remove the solvent.

[0022] As another embodiment of the present invention, the solvent may be a water-insoluble aprotic solvent such as dichloromethane (DCM, CH2Cl2), chloroform (CHCl3), etc.; a protic solvent such as ethanol, methanol, etc.; a water-soluble aprotic solvent such as acetone, ethyl acetate, dimethylformamide, acetonitrile (CH3CN), tetrahydrofuran (THF, oxolane), etc.; a non-polar solvent such as nucleic acid, benzene, toluene, carbon tetrachloride (CCl4), ether (diethyl ether, Et2O), etc., but the embodiment is not limited thereto. Preferably, it may be a water-soluble aprotic solvent or a protic solvent, and more preferably, a water-insoluble aprotic solvent.

[0023] As another embodiment of the present invention, the preparation method further comprises the steps of heating and drying, rotary concentration or freeze drying.

[0024] As another embodiment of the present invention, the temperature during heating and drying may be 40°C to 60°C, preferably 50°C.

[0025] In addition, the present invention provides a method for in vivo delivery of taxane, comprising the step of administering the oral pharmaceutical composition to a subject.

[0026] In addition, the present invention also provides a composition for preventing or treating cancer comprising the oral pharmaceutical composition.

[0027] In addition, the present invention also provides a method for preventing or treating cancer, comprising the step of administering the oral pharmaceutical composition to a subject.

[0028] The present invention also provides a use of the oral pharmaceutical composition for preparing a drug for preventing or treating cancer.

[0029] Effects of the Invention

[0030] The oral pharmaceutical composition according to one embodiment of the present invention includes cholesterol, cholesterol derivatives or a combination thereof, which can maintain high mucosal adhesion and control membrane fluidity. In addition, in addition to Tween 80, it also includes TPGS as a surfactant, which can improve oxidation and physical stability, thereby improving oral absorption rate.

[0031] The oral pharmaceutical composition according to an embodiment of the present invention has high solubility and bioavailability, and can be administered through capsules to improve the convenience of patients. In addition, even if the taxane content in the composition is relatively low, it can achieve the same or better efficacy as existing drugs, which can save the expensive drug cost.

[0032] The oral pharmaceutical composition according to an embodiment of the present invention can be simply prepared by physical mixing without forming a complex through covalent or ionic bonds, and precipitation can be minimized even when crystalline taxane is used instead of amorphous taxane.

[0033] The effects of the oral pharmaceutical composition according to an embodiment of the present invention are not limited to the above effects, and other effects not mentioned will be clearly understood by those skilled in the art through the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The results were obtained by using optical microscopy and polarized light microscopy in the presence of medium chain triglycerides ( 8000), oleylglycerol complex And the results of dissolving paclitaxel and cholesterol in a composition of Tween 80 (eLiporaxel) by weight ratio. Figure 1 (A) wherein paclitaxel is 4.0 wt%, cholesterol is 7.2 wt%, and the composition (eLiporaxel) is 88.8 wt%; Figure 1 In (B), paclitaxel is 5.0 wt%, cholesterol is 9.0 wt%, and the composition (eLiporaxel) is 86.0 wt%; Figure 1 In (C), paclitaxel is 10.0% by weight, cholesterol is 18.0% by weight, and the composition (eLiporaxel) is 72.0% by weight.

[0035] Figure 2 In the presence of medium chain triglycerides ( 8000), oleylglycerol complex And the results of dissolving cholesterol at 1 wt % to 10 wt % in a composition of Tween 80 (eLiporaxel).

[0036] Figure 3 In the presence of medium chain triglycerides ( 8000), oleylglycerol complex And the results of dissolving cholesterol acetate at 11 wt % to 20 wt % in a composition of Tween 80 (eLiporaxel).

[0037] Figure 4 In the presence of medium chain triglycerides ( 8000), oleylglycerol complex And the results of dissolving β-sitosterol at 1 wt % to 10 wt % in a composition of Tween 80 (eLiporaxel).

[0038] Figure 5 In the presence of medium chain triglycerides ( 8000), oleylglycerol complex And the results of dissolving β-sitosterol acetate at 1 wt % to 10 wt % in a composition of Tween 80 (eLiporaxel).

[0039] Figure 6 In the presence of medium chain triglycerides ( 8000), oleylglycerol complex And the results of dissolving TPGS in a composition of Tween 80 (eLiporaxel) at 1 wt % to 10 wt %.

[0040] Figure 7 The paclitaxel blood concentration (μg / ml) of Comparative Example 1 (liporaxel) and Examples 1-4, 1-5, and 1-6 changes with time.

[0041] Figure 8 These are the AUC% of Comparative Example 1 (liporaxel) and Examples 1-4, 1-5, and 1-6.

[0042] Fig. 9 The paclitaxel blood concentration (μg / ml) of Comparative Example 1 (liporaxel) and Examples 1-8 and 1-9 changes with time.

[0043] Fig.10 These are the AUC% of Comparative Example 1 (liporaxel) and Examples 1-8 and 1-9.

[0044] Fig.11 These are the AUC% of Comparative Example 1 (liporaxel) and Examples 1-1, 1-2, 1-3, and 1-7.

[0045] Fig.12 is the differential scanning calorimetry (DSC) result, where Fig.12 (A) is the DSC result of amorphous paclitaxel. Fig.12 (B) is the DSC result of crystalline paclitaxel.

[0046] Fig.13 is the result of differential scanning calorimetry (DSC), where Fig.13 (A) is the DSC result of cholesterol. Fig.13 (B) is the DSC result of the mixture of amorphous paclitaxel and cholesterol.

[0047] Fig.14 is the result of differential scanning calorimetry (DSC), Fig.14 (A) is the DSC result of a composition obtained by dissolving amorphous paclitaxel and cholesterol in dichloromethane and removing the solvent. Fig.14 (B) is the DSC result of a composition obtained by dissolving amorphous paclitaxel and cholesterol in acetone and then removing the solvent.

[0048] Fig.15 is the result of differential scanning calorimetry (DSC), Fig.15 (A) is the DSC result of amorphous paclitaxel. Fig.15 (B) is the DSC result of a composition obtained by dissolving amorphous paclitaxel in ethanol and removing the solvent. Fig.15 (C) is the DSC result of a composition obtained by dissolving amorphous paclitaxel and cholesterol in ethanol and then removing the solvent.

[0049] Figures 16a to 16d is the result of X-ray diffraction analysis (XRD), where Fig.16a is the XRD result of amorphous paclitaxel, Fig.16b is the XRD result of cholesterol, Fig.16c The XRD results of the mixture of amorphous paclitaxel and cholesterol are shown in Figure 2. Fig.16d The XRD result of a composition obtained by dissolving amorphous paclitaxel and cholesterol in dichloromethane and then removing the solvent.

[0050] Figures 17a to 17c is the result of X-ray diffraction analysis (XRD), Fig.17a is the XRD result of cholesterol, Fig.17b is the XRD result of crystalline paclitaxel, Fig.17c The XRD result of a composition obtained by dissolving amorphous paclitaxel and cholesterol in acetone and then removing the solvent.

[0051] Fig.18 is a scanning electron microscope (SEM) image, where Fig.18 (A) is a composition obtained by dissolving paclitaxel in dichloromethane and then removing the solvent, Fig.18 (B) is a composition obtained by dissolving paclitaxel in acetone and then removing the solvent, Fig.18 (C) is a composition obtained by dissolving paclitaxel and cholesterol in dichloromethane and then removing the solvent, Fig.18(D) is a composition obtained by dissolving paclitaxel and cholesterol in acetone and then removing the solvent, Fig.18 (E) is a composition obtained by dissolving paclitaxel and cholesterol acetate in dichloromethane and then removing the solvent, Fig.18 (F) is a SEM image of a composition obtained by dissolving paclitaxel and cholesterol acetate in acetone and then removing the solvent.

[0052] Best Mode for Carrying Out the Invention

[0053] The present invention provides an oral pharmaceutical composition, comprising: (a) taxane; (b) at least one medium chain triglyceride selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein; (c) an olein complex comprising monoolein, diolein, and triolein, wherein the content of monoolein is 30 wt % to 99.9 wt %; (d) cholesterol, a cholesterol derivative, or a combination thereof; and (e) a surfactant.

[0054] The present inventors have confirmed that, in a composition comprising taxane, medium-chain triglyceride, oleylglycerol complex and surfactant, the oral absorption rate can be improved if cholesterol or a derivative thereof is further included, and the bioavailability can be improved when the surfactant contains TPGS in addition to Tween 80. In addition, since the composition is in a liquid phase at room temperature, it can be directly administered to a patient without treatment such as heating, and precipitation can be minimized even if a crystalline taxane is used instead of an amorphous taxane.

[0055] In the present invention, taxane is a diterpene (C 20 ) compounds, non-limiting examples of the taxanes include paclitaxel, docetaxel, 7-epipaclitaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, and the like.

[0056] In the present invention, "medium chain triglycerides" refers to three molecules of saturated or unsaturated C2-C 20 A substance formed by connecting a fatty acid to a glycerol molecule through an ester bond. Non-limiting examples of medium-chain triglycerides include triacetin, tributyrin, tricaproin, tricaprylin, tricaprylin, tricaprin, triolein, and mixtures thereof.

[0057] In the present invention, "oleoyl glycerol complex" refers to a complex obtained by partial glycerolysis of a vegetable oil mainly containing oleic acid triglycerol, or a complex obtained by esterification of glycerol with oleic acid. The contents of monoolein, diolein, and triolein vary according to partial glycerol decomposition and / or esterification. The olein complex included in the present invention includes 30% to 99.9% by weight of monoolein, preferably, the olein complex used has a monooleyl glycerol content of 30% to 65% by weight; a diolein content of 15% to 50% by weight; and a triolein content of 2% to 20% by weight. As one embodiment of the present invention, the olein complex has a monoolein content of 32% to 52% by weight; a diolein content of 30% to 50% by weight; and a triolein content of 5% to 20% by weight. As another embodiment of the present invention, the monoolein content of the olein complex is 55 wt % to 65 wt %; the diolein content is 15 wt % to 35 wt %; and the triolein content is 2 wt % to 10 wt %. In addition, commercially available olein complexes having the above content ratios may also be used, for example (Gattefosse) or (Abitec Corporation) etc.

[0058] In the present invention, non-limiting examples of "surfactants" include Polyoxyethylene-polyoxypropylene copolymers, Sorbitol esters, Polyoxyethylene sorbitan, etc. Polyoxyethylene ether and TPGS, etc.

[0059] The pharmaceutical composition of the present invention may be in liquid phase at room temperature. In the present invention, "room temperature" may be 1°C to 35°C as specified in the Food Code, preferably 20°C to 35°C.

[0060] As one embodiment of the present invention, a method for preparing an oral pharmaceutical composition is provided, comprising the steps of mixing (a) 0.5 wt % to 4 wt % of taxane; (b) 15 wt % to 35 wt % of medium chain triglycerides; (c) 40 wt % to 60 wt % of olein complex; (d) 0.9 wt % to 7.2 wt % of cholesterol, cholesterol derivatives or combinations thereof; and (e) 10 wt % to 30 wt % of a surfactant.

[0061] As another embodiment of the present invention, the preparation method is to physically mix (a) to (e) without using a solvent, or to physically mix (a) to (e) with the addition of a solvent and then remove the solvent.

[0062] The amount of the solvent used is sufficient to dissolve (a) to (e), preferably 5% to 40% of the total volume of the composition, more preferably 10% to 25%, but the embodiment is not limited thereto. As an embodiment of the present invention, 200 g, about 150 mL, of dichloromethane can be used as a solvent when preparing 1 L of the composition. The solvent can be used in a range that can fully dissolve taxane compounds such as paclitaxel, while reducing waste caused by excessive use of solvents and efforts to remove organic solvents.

[0063] As another embodiment of the present invention, the preparation method can remove the solvent by conventional methods, preferably heating and drying, rotary concentration or freeze drying. Through the above-mentioned solvent dissolution and solvent removal process, the components in the obtained composition can be uniformly mixed in the solvent state (true solution).

[0064] In addition, the present invention may also provide a method for preventing or treating cancer, comprising the step of administering the above oral pharmaceutical composition to a subject.

[0065] In the present invention, the term "prevention" refers to all actions of inhibiting or delaying the occurrence, spread or recurrence of cancer by administering the composition of the present invention; "treatment" refers to all actions of improving or benefiting cancer symptoms by administering the composition of the present invention.

[0066] In the present invention, the term "pharmaceutical composition" is intended to prevent or treat diseases, and can be prepared into a variety of preparations according to conventional methods. For example, it can be prepared into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can also be prepared into dosage forms such as external preparations, suppositories, and sterile injections. The composition of the present invention is an oral dosage form, which is conducive to improving the convenience of patients taking it.

[0067] In addition, the oral pharmaceutical composition of the present invention may also contain one or more pharmaceutically acceptable carriers in addition to containing the above-mentioned (a) to (e) components. The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol and at least one mixture of these components, and may further include other common additives such as antioxidants, buffers, antibacterial agents as required. In addition, diluents, dispersants, surfactants, adhesives and lubricants may be further added to prepare injection preparations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets. In addition, it may be preferred to use appropriate methods in the art or use the methods disclosed in Lei's Pharmaceutical Science (Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA), and consider disease and ingredients to rationally prepare.

[0068] The oral pharmaceutical composition of the present invention can be orally administered in a pharmaceutically effective amount according to the desired method. The term "pharmaceutically effective amount" of the present invention refers to a reasonable benefit / risk ratio range applicable to drug treatment, and refers to a content that can fully treat the disease without causing side effects. The level of the effective amount can be determined based on many factors and other factors well known in the medical field. Factors to be considered may include the patient's health status, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment time, drugs prepared or taken at the same time, etc.

[0069] In the present invention, "cancer" includes skin cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, brain tumors, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymus cancer, urethral cancer, Kaposi's sarcoma or bronchial cancer, but the implementation methods are not limited to this.

[0070] In the present invention, the term "subject" may be any mammal such as livestock or humans for whom cancer prevention, treatment and / or diagnosis is required, and is not particularly limited, but is preferably a human.

[0071] The oral pharmaceutical composition of the present invention may further contain a known anticancer agent, and may be administered in combination with other known therapeutic methods for preventing or treating cancer.

[0072] The terms used in the embodiments are only used to illustrate specific example embodiments and are not used to limit the example embodiments. In the absence of special instructions in the content, the singular forms "one", "a", and "the" are intended to also include plural forms. In this specification, the terms "include / include" and / or "include / include" are used to express the existence of stated features, numbers, steps, operations, elements, and / or parts, but do not exclude the possibility of the existence or additional existence of one or more other features, numbers, steps, operations, elements, parts, and / or combinations thereof.

[0073] In the absence of other definitions, all terms, including technical or scientific terms used herein, have the common meanings understood by ordinary technicians in the field to which the examples belong. Commonly used terms as defined in dictionaries should be understood as the meanings in the relevant technical content, and should not be interpreted as idealized or overly formalized meanings if they are not clearly defined in this specification.

[0074] Also, when describing components of the exemplary embodiments, terms such as first, second, A, B, (a), (b), etc. may be used. These terms are only used to distinguish one component from other components and are not used to limit the nature, order, or sequence of the corresponding components. When it is described that a component is "connected," "coupled," or "attached" to another component, it should be understood that one component can be directly connected or attached to the other component, and intermediate components can also be "connected," "coupled," or "attached" to the component. DETAILED DESCRIPTION

[0075] Below, the exemplary embodiments will be described in detail with reference to the accompanying drawings. However, various changes can be made to the exemplary embodiments, and the present disclosure is not limited to the exemplary embodiments. All changes to the exemplary embodiments, their equivalents and even their substitutes are included in the scope of the rights of the present disclosure.

[0076] In the process of describing the examples with reference to the drawings, the same components are marked with the same reference numerals and repeated descriptions are omitted. In the process of describing the example embodiments, when it is determined that the detailed description of the relevant well-known structure or function will cause unnecessary confusion to the present disclosure, its detailed description is omitted.

[0077] The present invention may have a variety of variations and embodiments, and the following specific embodiments are used to illustrate and describe in detail in the accompanying drawings. However, the present invention is not limited to specific embodiments, but includes all changes, equivalents or substitutes within the spirit and technical scope of the present invention. In the process of describing the present invention, when it is judged that the specific description of the relevant known structure or function will cause unnecessary confusion to the present disclosure, its specific description is omitted.

[0078] Example 1. Preparation of the oral pharmaceutical composition of the present invention

[0079] All ingredients were mixed according to the ingredients and contents in Table 1 below, and then heated to about 37° C. to prepare an oral pharmaceutical composition containing taxane in an oily liquid state.

[0080] Specifically, Examples 1-1 to 1-6 are prepared by mixing amorphous paclitaxel with medium chain triglycerides, oleic acid glyceride complexes, cholesterol and its derivatives and surfactants without using a solvent. Examples 1-7 to 1-9 are prepared by dissolving amorphous, crystalline or mixed paclitaxel in 1 to 5 times the total weight of dichloromethane (DCM, CH2Cl2), and removing the solvent by heating and drying (50°C), rotary concentrating or freeze drying.

[0081]

Table 1

[0082]

[0083] Comparative Example 1. Preparation of existing oral pharmaceutical compositions

[0084] According to Korean Patent No. 10-1542364, paclitaxel and medium chain triglycerides are dissolved in dichloromethane and then dried under reduced pressure at 40°C to remove dichloromethane. After adding oleylglycerol complex and Tween 80 to the resulting mixture, the mixture is stirred at about 40°C to prepare a pharmaceutical composition in the form of a clear viscous solution as a comparative example. Here, the weight ratio of the composition of the comparative example is paclitaxel: medium chain triglyceride ( 8000):Olein Glyceride Complex Tween 80=1.0:27.5:55.0:16.5.

[0085] Experimental Example 1. Optimization of the composition of oral pharmaceutical compositions

[0086] In order to optimize the content of paclitaxel and cholesterol, a medium-chain triglyceride ( 8000), oleylglycerol complex and Tween 80 (eLiporaxel), and mixed with paclitaxel and cholesterol without using a solvent. After being placed at 37°C for 30 minutes, the mixture was stirred with a vortex mixer, and ultrasonicated with a bath sonicator, and the degree of dissolution was observed with an optical microscope and a polarizing microscope.

[0087] (1) 4.0 wt% (16.0 mg) of paclitaxel, 7.2 wt% (28.8 mg) of cholesterol, and 88.8 wt% (355.2 mg) of a composition (eLiporaxel) were mixed to prepare a composition, and then observed with an optical microscope and a polarizing microscope to find that no precipitate was formed ( Figure 1 (A)).

[0088] (2) 5.0 wt% (20.0 mg) of paclitaxel, 9.0 wt% (36.0 mg) of cholesterol, and 86.0 wt% (344.0 mg) of a composition (eLiporaxel) were mixed to prepare a composition, and then observed with an optical microscope and a polarizing microscope to find that a precipitate was formed ( Figure 1 (B)).

[0089] (3) 10.0 wt% (40.0 mg) of paclitaxel, 18.0 wt% (72.0 mg) of cholesterol, and 72.0 wt% (288.0 mg) of a composition (eLiporaxel) were mixed to prepare a composition, and then observed with an optical microscope and a polarizing microscope to find that a precipitate was formed ( Figure 1 (C)).

[0090] At the same time, it was confirmed that when the paclitaxel content was less than 0.5% by weight, the oral absorption rate was very low, and when the cholesterol content was less than 0.9% by weight, the oral absorption rate was low. Therefore, the paclitaxel content was determined to be 0.5% by weight to 4.0% by weight, and the cholesterol content was determined to be 0.9% by weight to 7.2% by weight.

[0091] In order to optimize the content of cholesterol, cholesterol derivatives and TPGS, cholesterol, cholesterol acetate, β-sitosterol, β-sitosterol acetate, and D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) were dissolved in the above composition (eLiporaxel) to measure the solubility. The results are shown in Table 2 below. Here, the weight ratio of the composition (eLiporaxel) is medium chain triglyceride ( 8000):Olein Glyceride Complex Tween 80=55.0:27.5:16.5.

[0092]

Table 2

[0093] Solubility (wt%) cholesterol 7% by weight Cholesterol acetate 15 wt% β-Sitosterol 6 wt% β-Sitosterol Acetate 5 wt% TPGS Miscible

[0094] When the weight ratio of cholesterol: eLiporaxel was above 8:92, cholesterol was not fully dissolved to form a slightly opaque mixture ( Figure 1 ), the cholesterol solubility is 7w / w%. When the weight ratio of cholesterol acetate: eLiporaxel is 16:84, cholesterol acetate is not fully dissolved to form an opaque mixture ( Figure 3 ), the solubility of cholesterol acetate is 15w / w%. When the weight ratio of β-sitosterol: eLiporaxel is 7:93, β-sitosterol is not fully dissolved to form a slightly opaque mixture ( Figure 4 ), the solubility of β-sitosterol is 6w / w%. When the weight ratio of β-sitosterol acetate: eLiporaxel is 6:94, β-sitosterol acetate is not fully dissolved to form a slightly opaque mixture ( Figure 5 ), the solubility of β-sitosterol acetate is 5w / w%. It is confirmed that TPGS is well miscible at all weight ratios ( Figure 6 ).

[0095] Experimental Example 2. Evaluation of oral absorption rate of oral pharmaceutical composition

[0096] The oral pharmaceutical compositions prepared in Example 1 and Comparative Example 1 were orally administered to ICR mice (6-week-old, female, Orient Bio, Korea) using a gastric sonde. Blood was collected from the mouse orbital vein at 0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after administration, and plasma samples were obtained by centrifugation at 8000×g for 20 minutes and stored at -70°C.

[0097] Thaw the plasma sample at room temperature and stir with a vortex mixer for 1 minute. Add 10.0 μL of internal standard solution (paclitaxel-d5 2.50 μg / mL, methanol solution) to 50.0 μL of plasma sample and stir for 3 minutes, then centrifuge at 4000 x g for about 1 minute. Take 100 μL of supernatant and add 100 μL of distilled water containing 0.1% (v / v) formic acid and stir for 3 minutes, then centrifuge at 4000 x g for about 1 minute at room temperature. Take 20.0 μL of supernatant and inject it into UPLC-MS / MS for analysis. At this time, the UPLC-MS / MS analysis conditions are as follows.

[0098] -UPLC: UPLC, Waters ACQUITY UPLCTM System, Waters Corporation

[0099] -Detector: Waters XevoTM TQMS, Waters Corporation

[0100] -Chromatographic column: Waters ACQUITY UPLCTM BEHC18, 1.7um (2.1mmID×50mmL)

[0101] -Data processing unit: MassLynx V4.1, Waters Corporation

[0102] -Mobile phase: 0.1% (v / v) formic acid in water: 0.1% (v / v) formic acid in acetonitrile (50:50, v / v)

[0103] - Flow rate: 0.4mL / min

[0104] -Detector conditions: ESI+, MRM mode

[0105]

Table 3

[0106]

[0107] The pharmacodynamic parameters calculated based on the measured paclitaxel blood concentration are shown in Table 4 below ( Figures 7 to 11 ).

[0108]

Table 4

[0109]

[0110] When the same dose is taken orally, the absorption rate of the oral pharmaceutical composition of the present invention is increased by up to 2.8 times compared with that of Comparative Example 1. When normalized based on the dose of paclitaxel, the absorption rate is increased by up to more than 2 times.

[0111] When cholesterol was included (Examples 1-6 and 1-9) a higher oral absorption rate was observed than when cholesterol was not included (Examples 1-5 and 1-8), and it was confirmed that when cholesterol acetate as a cholesterol derivative was included (Examples 1-2 and 1-7), the oral absorption rate was also improved. In addition, the higher the cholesterol content, the higher the oral absorption rate (Examples 1-1, 1-4). This is because cholesterol and its derivatives can maintain mucosal adhesion even when mixed with a large amount of water in the intestine, and control the release rate of the drug by regulating membrane fluidity.

[0112] At the same time, when TPGS was included (Examples 1-6 and 1-9) compared with when TPGS was not included (Examples 1-4 and 1-7), a higher oral absorption rate was observed. This is because TPGS, as an emulsifier with antioxidant function, helps to form a gel phase with high oxidizability and physical stability when it is mixed with gastric juice and intestinal juice in the body.

[0113] Experimental Example 3. Physicochemical properties and solvent optimization of oral pharmaceutical compositions

[0114] In order to confirm whether the oral pharmaceutical composition prepared in Experimental Example 1 is in an oily liquid state due to a simple mixture or a complex, differential scanning calorimetry (DSC) and X-ray diffraction analysis (XRD) were used for analysis, and scanning electron microscope (SEM) images were taken. Here, when paclitaxel and cholesterol were added simultaneously, the weight ratio was 1:1.8.

[0115] 3.1. Differential Scanning Calorimetry (DSC)

[0116] The temperature and heat flow associated with the thermal transition of the composition of the present invention were studied using differential scanning calorimetry (DSC). Specifically, each sample size was about 5.00 mg and was analyzed using DSC 650 for differential scanning calorimetry.

[0117] The glass transition temperature of amorphous paclitaxel was confirmed to be 156°C and the decomposition temperature was 234°C. Fig.12 (A)), the melting point of crystalline paclitaxel is 224°C, and the decomposition temperature is 233°C ( Fig.12 (B)), the melting point of cholesterol is 149℃ ( Fig.13 (A)).

[0118] When amorphous paclitaxel was mixed with cholesterol without solvent, a decrease in transition temperature and a broadening of the melting range of cholesterol were observed, and amorphous paclitaxel was decomposed ( Fig.13 When amorphous paclitaxel and cholesterol were dissolved in dichloromethane and the solvent was removed, the same state as the simple mixture of amorphous paclitaxel and cholesterol was observed ( Fig.14 This indicates that a physical mixture was formed between amorphous paclitaxel and cholesterol after the removal of dichloromethane.

[0119] At the same time, when amorphous paclitaxel and cholesterol were dissolved in acetone and the solvent was removed, there was no decrease in the melting point of cholesterol and no broadening of the melting range. Although the melting transition of paclitaxel was observed, considering the decrease in enthalpy change, it can be seen that paclitaxel did not become an impurity of cholesterol that underwent phase transition, and did not show the characteristics of crystalline paclitaxel ( Fig.14 (B)).

[0120] The heat flow of amorphous paclitaxel, amorphous paclitaxel dissolved in ethanol and the solvent removed, and amorphous paclitaxel and cholesterol dissolved in ethanol and the solvent removed were measured. As a result, the melting point of cholesterol decreased and the corresponding peak became broadened, just like dichloromethane. This indicates that after the removal of ethanol, a physical mixture ( Fig.15 ).

[0121] 3.2. X-ray diffraction analysis (XRD)

[0122] The chemical composition, crystal structure, crystal size, strain and other structural information of the composition of the present invention were studied by X-ray diffraction analysis (XRD).

[0123] It was observed that the XRD patterns of a simple mixture of amorphous paclitaxel and cholesterol and a composition obtained by dissolving amorphous paclitaxel and cholesterol in dichloromethane and removing the solvent were the same. This means that the composition solidified into amorphous paclitaxel, and thus still had the property of being easily soluble in oil even after removing dichloromethane, which can be understood as being easily soluble ( Figures 16a to 16d ).

[0124] Meanwhile, when amorphous paclitaxel and cholesterol were dissolved in acetone and the solvent was removed, it showed a different XRD pattern from a simple mixture of amorphous paclitaxel and cholesterol or crystalline paclitaxel. Combining the above DSC and XRD results, it can be seen that a new crystal form was formed during recrystallization from acetone. In addition, when medium-chain triglycerides, paclitaxel and cholesterol were dissolved in acetone and the solvent was removed, it was observed that a gel mixed with precipitates was formed at a concentration of 1% paclitaxel and 1% to 3% cholesterol instead of a clear oily solution ( Figures 17a to 17c ).

[0125] Scanning electron microscopy (SEM) images

[0126] In order to visually confirm the morphology of the composition of the present invention, a scanning electron microscope (SEM) image ( Fig.18 ).

[0127] When paclitaxel and cholesterol were dissolved in dichloromethane and then the solvent was removed, and when paclitaxel and cholesterol acetate were dissolved in dichloromethane and then the solvent was removed, an amorphous product was observed, whereas a crystalline product was observed when the solvent was removed after dissolving in acetone. The pharmaceutical composition of the present invention is an oral pharmaceutical composition, so it is very important to increase the solubility of powdered paclitaxel and cholesterol, and therefore it is preferred to use a solvent that can form amorphous paclitaxel to prepare the composition.

[0128] The above results show that the oral pharmaceutical composition of the present invention is not a complex formed by covalent bonds or ionic bonds but is physically mixed, and can be made into a simple mixture without a solvent. Various solvents can also be used, but it is preferred to use aprotic solvents such as dichloromethane, protic solvents such as ethanol, non-polar solvents, etc. In particular, ethanol is expected to play a greater role as a safe solvent.

[0129] Although the present disclosure includes specific examples, it will be apparent to those skilled in the art that various changes in form and detail may be made in these examples without departing from the spirit and scope of the claims and their equivalents. The examples described are to be understood to be merely descriptive and not restrictive. The descriptions of features or aspects in each example are to be understood to be applicable to similar features or aspects in other examples. Appropriate results may be obtained if the described techniques are performed in a different order, and / or if components in the described systems, architectures, devices, or circuits are combined in different ways, and / or replaced or substituted by other components or their equivalents.

[0130] Accordingly, other implementations are within the scope of the following claims.

Claims

1. An oral pharmaceutical composition, characterized in that: include: (a) Taxanes; (b) at least one medium chain triglyceride selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein; (c) an olein complex comprising monoolein, diolein, and triolein, wherein the content of monoolein is 30 wt % to 99.9 wt %; (d) cholesterol, cholesterol derivatives or combinations thereof; and (e) Surfactant.

2. The oral pharmaceutical composition according to claim 1, characterized in that The cholesterol derivative is at least any one selected from the group consisting of cholesterol acetate, β-sitosterol, β-sitosterol acetate and a combination thereof.

3. The oral pharmaceutical composition according to claim 1, characterized in that The surfactant is at least any one selected from the group consisting of Tween 80, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and a combination thereof.

4. The oral pharmaceutical composition according to claim 1, characterized in that The (d) cholesterol, cholesterol derivatives or combinations thereof included in the pharmaceutical composition is 0.9 wt % to 7.2 wt % of the total weight of the pharmaceutical composition.

5. The oral pharmaceutical composition according to claim 1, characterized in that The weight ratio of (a) taxane to (d) cholesterol, cholesterol derivatives or combinations thereof in the pharmaceutical composition is 1:1.5 to 1:

2.

6. The oral pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition, (a) 0.5 wt % to 4 wt % of taxane; (b) 15 wt % to 35 wt % of medium chain triglycerides; (c) 40 wt % to 60 wt % of olein complex; (d) 0.9 wt % to 7.2 wt % of cholesterol, cholesterol derivatives or combinations thereof; and (e) 10 wt % to 30 wt % of a surfactant.

7. The oral pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises (a) to (e) physically mixed.

8. The oral pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition is in liquid phase at room temperature.

9. A method for preparing an oral pharmaceutical composition, characterized in that: The method comprises the steps of mixing: (a) Taxanes; (b) at least one medium chain triglyceride selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein; (c) an olein complex comprising monoolein, diolein, and triolein, wherein the content of monoolein is 30 wt % to 99.9 wt %; (d) cholesterol, cholesterol derivatives or combinations thereof; and (e) Surfactant.

10. The method for preparing the oral pharmaceutical composition according to claim 9, characterized in that: The preparation method comprises physically mixing (a) to (e) without using a solvent, or physically mixing (a) to (e) with a solvent and then removing the solvent.

11. The method for preparing the oral pharmaceutical composition according to claim 10, characterized in that: The preparation method further comprises the steps of heating and drying, rotary concentration or freeze drying.

12. A method of delivering a taxane to a subject, characterized in that: The method comprises the step of orally administering the pharmaceutical composition according to any one of claims 1 to 8 to a subject.

Images