WO2024076056A1 - Oral pharmaceutical composition containing taxane and preparation method therefor - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition and a preparing method therefor, wherein the composition comprises: (a) taxane; (b) one or more medium-chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein; (c) an oleoyl glycerol complex including monooleoyl glycerol, dioleoyl glycerol, and trioleoyl glycerol, with the content of monooleoyl glycerol being between 30 to 99.9 weight%; (d) cholesterol, cholesterol derivatives, or a combination thereof; and (e) a surfactant.

Description

Pharmaceutical composition for oral administration containing taxane and method for producing the same

The present invention relates to a pharmaceutical composition for oral administration containing a taxane and a method for producing the same.

Taxane is a diterpene (C ₂₀ ) compound produced by plants of the genus Taxus. It exerts an anti-proliferative effect by acting on the organization of microtubules in the cellular cytoskeleton system, preventing ovarian cancer, breast cancer, It is widely used as a chemotherapy agent because it has significant cytotoxicity against various cancers such as esophageal cancer, melanoma, and leukemia. Non-limiting examples of taxanes include paclitaxel (Taxol ^® ), docetaxel (Taxotere ^® ), cabazitaxel, larotaxel, ortataxel, and tesetaxel, and are primarily marketed in parenteral dosage forms.

Taxanes are known to have very low solubility in water. For example, Taxol ^® , a paclitaxel-containing preparation, is currently formulated in the form of an emulsion preconcentrate and used by diluting it before injection. However, research on formulations for oral administration is in progress to overcome problems such as patient compliance, stability of the formulation, and safety to the human body due to the use of the injection form.

Meanwhile, it has been reported that when taxanes such as paclitaxel are administered orally, they exhibit low oral bioavailability due to an outward efflux pump action (Walle et al., Drug Metabo. Disp. 26(4): 343 - 346 (1998) ), it has also been reported that paclitaxel is very incompletely absorbed (less than 1%) when administered orally (Eiseman et al., Second NCI Workshop on Taxol and Taxus (sept. 1992), Suffness (ed.) et al., TaxolTM Science and Applications , CRC Press (1995)).

In addition, the conventional oral solubilized composition of paclitaxel is refrigerated in a semi-solid form, and when used, it is converted to a solution form and orally administered to the patient. However, the composition, which is refrigerated in a semi-solid form, does not convert into a solution at room temperature, and remains in a semi-solid form even if left for a long time.

Under this background, the present inventors developed a pharmaceutical composition for oral administration containing taxane, medium chain triglyceride, oleyl glycerol complex, cholesterol or a derivative thereof, and a surfactant, and the pharmaceutical composition exists in a liquid state at room temperature so that it can be administered to patients. The present invention was completed by confirming that not only can it be easily administered to humans, but also the amount of administered liquid is reduced due to the high oral absorption rate.

The object of the present invention is to provide a pharmaceutical composition for oral administration containing a taxane.

Another object of the present invention is to provide a method for producing the pharmaceutical composition for oral administration.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

In order to solve the above problems, the present invention provides (a) a taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) a surfactant; and provides a pharmaceutical composition for oral administration.

In one embodiment of the present invention, the cholesterol derivative may be cholesteryl acetate, beta-sitosterol, beta-sitosterol acetate, or a combination thereof. Not limited.

As another embodiment of the present invention, the surfactant may be Tween 80, TPGS (D-α-Tocopherol polyethylene glycol 1000 succinate), and a combination thereof, but is not limited thereto.

In another embodiment of the present invention, the pharmaceutical composition contains 0.9 to 7.2% by weight, preferably 2 to 3% by weight, of (d) cholesterol, cholesterol derivatives, or a combination thereof, based on the total weight of the pharmaceutical composition. You can.

As another embodiment of the present invention, the pharmaceutical composition may have a weight ratio of (a) taxane and (d) cholesterol, cholesterol derivative, or a combination thereof of 1:1.5 to 1:2, preferably 1:1.8. It can be.

In another embodiment of the present invention, the pharmaceutical composition contains (a) 0.5 to 4% by weight of taxane based on the total weight; (b) 15 to 35% by weight of medium chain triglycerides; (c) 40 to 60% by weight of oleyl glycerol complex; (d) 0.9 to 7.2% by weight of cholesterol, cholesterol derivatives, or a combination thereof; and (e) 10 to 30% by weight of a surfactant. Preferably, (a) 0.5 to 2% by weight of taxane; (b) 20 to 30% by weight of medium chain triglycerides; (c) 45 to 55% by weight of oleyl glycerol complex; (d) 2 to 3% by weight of cholesterol, cholesterol derivatives, or a combination thereof; and (e) 15 to 25% by weight of a surfactant.

As another embodiment of the present invention, the pharmaceutical composition may be a physical mixture of (a) to (e). That is, a covalent or ionic bond may not be formed between (a) to (e) in the pharmaceutical composition.

As another embodiment of the present invention, the pharmaceutical composition may be in a liquid phase, preferably an oily liquid, at room temperature conditions. Therefore, manufacturing is possible without separate heating conditions, but a heating step can be added to increase manufacturing efficiency.

Additionally, the present invention provides (a) taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) a surfactant; providing a method for producing a pharmaceutical composition for oral administration, comprising the step of mixing.

As an embodiment of the present invention, the production method may be physically mixing (a) to (e) without a solvent or physically mixing by adding a solvent and then removing the solvent.

In another embodiment of the present invention, the solvent is a water-insoluble aprotic solvent such as dichloromethane (DCM, CH ₂ Cl ₂ ), chloroform (CHCl ₃ ), ethanol, and methanol. Protic solvents such as acetone, ethyl acetate, dimethylformamide, acetonitrile (CH ₃ CN), tetrahydrofuran (THF, oxolane), etc. It may be a protic solvent (water-soluble aprotic solvent), nucleic acid, benzene, toluene, carbon tetrachloride (CCl ₄ ), non-polar solvent such as diethyl ether (Et ₂ O), etc., but is not limited thereto. Preferably, it may be a water-insoluble aprotic solvent or a protic solvent, and more preferably, it may be a water-insoluble aprotic solvent.

As another embodiment of the present invention, the production method may further include the steps of heat drying, rotational concentration, or freeze drying.

As another embodiment of the present invention, the temperature during heat drying may be 40 to 60°C, preferably 50°C.

Additionally, the present invention provides a method for delivering taxanes into the body, comprising administering the pharmaceutical composition for oral administration to a subject.

Additionally, the present invention provides a composition for preventing or treating cancer, including the pharmaceutical composition for oral administration.

Additionally, the present invention provides a method for preventing or treating cancer comprising administering the pharmaceutical composition for oral administration to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for oral administration for preparing a drug for preventing or treating cancer.

The pharmaceutical composition for oral administration according to an embodiment of the present invention maintains high mucosal adsorption by containing cholesterol, cholesterol derivatives, or a combination thereof, can control membrane fluidity, and contains TPGS in addition to Tween 80 as a surfactant. Oral absorption can be increased by increasing oxidation and physical stability.

Since the pharmaceutical composition for oral administration according to an embodiment of the present invention has high solubility and bioavailability, the patient's convenience in taking it can be improved by administering it using a capsule. In addition, even if a composition containing taxanes is administered at a relatively low concentration, the drug shows the same or better efficacy as before, thereby reducing the cost of expensive drugs.

The pharmaceutical composition for oral administration according to an embodiment of the present invention can be simply manufactured in a physically mixed form rather than forming a complex by covalent or ionic bonding, and is unlikely to precipitate even if crystalline taxane rather than amorphous taxane is used. It can be minimized.

The effects of the pharmaceutical composition for oral administration according to an embodiment of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

Figure 1 shows the results of dissolving paclitaxel and cholesterol in a composition (eLiporaxel) containing medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80 according to weight ratio, observed under optical and polarizing microscopes. It shows one result. (A) in Figure 1 contains 4.0% by weight of paclitaxel, 7.2% by weight of cholesterol, and 88.8% by weight of the composition (eLiporaxel); (B) in Figure 1 contains 5.0% by weight of paclitaxel, 9.0% by weight of cholesterol, and 86.0% by weight of the composition (eLiporaxel); Figure 1 (C) shows the case where paclitaxel is 10.0% by weight, cholesterol is 18.0% by weight, and the composition (eLiporaxel) is 72.0% by weight.

Figure 2 shows the results of dissolving 1-10% by weight of cholesterol in a composition (eLiporaxel) containing medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80, depending on the weight ratio.

Figure 3 shows the results of dissolving 11-20% by weight of cholesteryl acetate in a composition (eLiporaxel) containing medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80, depending on the weight ratio. It is shown.

Figure 4 shows the results of dissolving 1-10% by weight of beta-sitosterol in a composition (eLiporaxel) containing medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80, depending on the weight ratio. will be.

Figure 5 shows the results of dissolving 1-10% by weight of beta-sitosterol acetate in a composition (eLiporaxel) containing medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80, depending on the weight ratio. It is shown.

Figure 6 shows the results of dissolving 1-10% by weight of TPGS in a composition (eLiporaxel) containing medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80, depending on the weight ratio.

Figure 7 shows the concentration of paclitaxel in the blood (μg/ml) over time in Comparative Example 1 (liporaxel) and Examples 1-4, 1-5, and 1-6.

Figure 8 shows the AUC% of Comparative Example 1 (liporaxel) and Examples 1-4, 1-5, and 1-6.

Figure 9 shows the concentration of paclitaxel in blood (μg/ml) over time in Comparative Example 1 (liporaxel) and Examples 1-8 and 1-9.

Figure 10 shows the AUC% of Comparative Example 1 (liporaxel) and Examples 1-8 and 1-9.

Figure 11 shows the AUC% of Comparative Example 1 (liporaxel) and Examples 1-1, 1-2, 1-3, and 1-7.

Figure 12 shows the results of differential scanning calorimetry (DSC). Figure 12 (A) shows the DSC results of amorphous paclitaxel, and Figure 12 (B) shows the DSC results of crystalline paclitaxel.

Figure 13 shows the results of differential scanning calorimetry (DSC). Figure 13 (A) shows the DSC results of cholesterol, and Figure 13 (B) shows the DSC results of a mixture of amorphous paclitaxel and cholesterol.

Figure 14 shows the results of differential scanning calorimetry (DSC). Figure 14 (A) is a composition prepared by dissolving amorphous paclitaxel and cholesterol in dichloromethane and then removing the solvent, and Figure 14 (B) is a composition prepared by dissolving amorphous paclitaxel and cholesterol in dichloromethane and removing the solvent. This shows the DSC results of a composition prepared by dissolving and cholesterol in acetone and removing the solvent.

Figure 15 shows the results of differential scanning calorimetry (DSC), where (A) in Figure 15 is amorphous paclitaxel and (B) in Figure 15 is a composition prepared by dissolving amorphous paclitaxel in ethanol and then removing the solvent, Figure 15 (C) shows the DSC results of a composition prepared by dissolving amorphous paclitaxel and cholesterol in ethanol and removing the solvent.

Figures 16a to 16d show the results of This shows the XRD results of a composition prepared by dissolving in methane and removing the solvent.

Figures 17a to 17c show the results of This shows the XRD results.

Figure 18 shows a scanning electron microscope (SEM) image, where (A) in Figure 18 is a composition prepared by dissolving paclitaxel in dichloromethane and removing the solvent, and (B) in Figure 18 is a composition prepared by dissolving paclitaxel in acetone and removing the solvent. A composition prepared by removing, (C) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesterol in dichloromethane and then removing the solvent, and (D) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesterol in acetone and then removing the solvent. The prepared composition, (E) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesteryl acetate in dichloromethane and then removing the solvent, and (F) in Figure 18 is a composition prepared by dissolving paclitaxel and cholesteryl acetate in acetone and then removing the solvent. This shows an SEM image of the composition prepared by removing.

The present invention relates to (a) taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) a surfactant; and provides a pharmaceutical composition for oral administration.

The present inventors confirmed that the oral absorption rate increases when cholesterol or a derivative thereof is further included in a composition containing taxane, medium chain triglyceride, oleyl glycerol complex, and surfactant, and used TPGS as a surfactant in addition to Tween 80. It was confirmed that bioavailability improves when more is included. In addition, since the composition is liquid at room temperature, it can be administered directly to patients without additional treatment such as heating, and precipitation can be minimized even when crystalline taxanes are used rather than amorphous taxanes.

In the present invention, “taxane” refers to diterpenes (C ₂₀ ) compounds produced by plants of the genus Taxus. As a non-limiting example, the taxane includes paclitaxel, docetaxel ( docetaxel), 7-epipaclitaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel (10-desacetyl-7- epipaclitaxel), 7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel (7-N) ,N-dimethylglycylpaclitaxel), 7-L-alanylpaclitaxel, etc., but is not limited thereto.

In the present invention, “medium chain triglycerides” refers to a substance in which three molecules of saturated or unsaturated C ₂ -C ₂₀ fatty acid and one molecule of glycerol are linked by an ester bond. As a non-limiting example, the medium chain triglycerides include triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein. (triolein), mixtures thereof, etc., but is not limited thereto.

In the present invention, “oleoyl glycerol complex” is obtained by partial glycerolysis of vegetable oil containing mainly triglycerol of oleic acid or by esterification of glycerol and oleic acid. It refers to the obtained complex. The contents of monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol vary depending on partial glycerolysis and/or esterification. The present invention may include an oleyl glycerol complex comprising 30 to 99.9% by weight of monooleyl glycerol, preferably a monooleyl glycerol content of 30 to 65% by weight; It is possible to use oleyl glycerol complexes having a dioleyl glycerol content of 15 to 50% by weight: and trioleyl glycerol content of 2 to 20% by weight. In one embodiment of the present invention, the oleyl glycerol complex has a monooleyl glycerol content of 32 to 52% by weight; Dioleyl glycerol content of 30 to 50% by weight: and trioleyl glycerol content of 5 to 20% by weight. In another embodiment of the present invention, the oleyl glycerol complex has a monooleyl glycerol content of 55 to 65% by weight; Dioleyl glycerol content of 15 to 35% by weight: and trioleyl glycerol content of 2 to 10% by weight. Additionally, commercially available oleyl glycerol complexes having the above content ratio, such as PECEOL ^® , Gattefosse or CAPMUL ^® , Abitec, can be used.

In the present invention, “surfactant” is a polyoxyethylene-polyoxypropylene ^copolymer such as Poloxamer ^{® ,} a sorbitan ester such ^as Span ^® , a polyoxy surfactant such as Tween ^® It may be, but is not limited to, ethylene sorbitan, polyoxyethylene ether such as Brij ^{® ,} TPGS, etc.

The pharmaceutical composition of the present invention may be in a liquid state at room temperature conditions. In the present invention, “room temperature” may be 1 to 35°C, and preferably 20 to 35°C, as notified in the Food Code.

As an embodiment of the present invention, (a) 0.5 to 4% by weight of taxane; (b) 15 to 35% by weight of medium chain triglycerides; (c) 40 to 60% by weight of oleyl glycerol complex; (d) 0.9 to 7.2% by weight of cholesterol, cholesterol derivatives, or a combination thereof; and (e) mixing 10 to 30% by weight of a surfactant.

As another embodiment of the present invention, the production method may be physically mixing (a) to (e) without a solvent or physically mixing by adding a solvent and then removing the solvent.

The solvent may be used in an amount capable of dissolving (a) to (e), preferably 5 to 40% of the total composition volume, and more preferably 10 to 25% of the total composition volume. , but is not limited to this. As an example of the present invention, 200 g, or about 150 mL, of methylene chloride can be used as a solvent when preparing 1 L of the composition. The range of solvent usage can sufficiently dissolve taxanes such as paclitaxel while reducing waste due to excessive use of solvent and unnecessary effort in removing organic solvents.

As another embodiment of the present invention, the production method may be performed by a conventional method to remove the solvent, preferably by heat drying, rotary concentration, or freeze drying. By performing the dissolution and removal process using a solvent as described above, each component in the resulting composition can be uniformly mixed in a solvent state (true solution).

In addition, the present invention can provide a method for preventing or treating cancer, including the step of administering the pharmaceutical composition for oral administration to a subject.

In the present invention, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, or recurrence of cancer by administering the composition of the present invention, and "treatment" refers to the treatment of symptoms of the disease by administering the composition of the present invention. It means any action that improves or changes beneficially.

In the present invention, the term “pharmaceutical composition” refers to a product prepared for the purpose of preventing or treating disease, and can be formulated and used in various forms according to conventional methods. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can be formulated and used in the form of external preparations, suppositories, and sterile injection solutions. The composition of the present invention is an oral dosage form that can improve the patient's convenience in taking it.

Additionally, the pharmaceutical composition for oral administration of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the components (a) to (e) described above. The pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures of one or more of these ingredients, and may include antioxidants, buffers, and bacteriostatic agents as necessary. Other common additives may also be included. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets. Furthermore, it may be preferably formulated according to each disease or ingredient using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

The pharmaceutical composition for oral administration of the present invention can be administered orally in a pharmaceutically effective amount according to the desired method, and the term “pharmaceutically effective amount” in the present invention refers to a disease with a reasonable benefit/risk ratio applicable to medical treatment. It refers to an amount that is sufficient to treat and does not cause side effects. The effective dose level refers to the patient's health status, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, treatment. It may be determined based on factors including duration, combination or drugs used simultaneously, and other factors well known in the medical field.

In the present invention, “cancer” refers to skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, and blood. It may be cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, Kaposi's sarcoma, or bronchial cancer, but is not limited thereto.

In the present invention, the term “subject” is not limited to mammals such as livestock or humans that require cancer prevention or treatment, but is preferably a human.

The pharmaceutical composition for oral administration of the present invention may further include a known anticancer agent and may be used in combination with other known treatments for the prevention or treatment of cancer.

The terms used in the examples are for descriptive purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, but are not intended to indicate the presence of one or more other features. It should be understood that this does not exclude in advance the possibility of the existence or addition of elements, numbers, steps, operations, components, parts, or combinations thereof.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the technical field to which the embodiments belong. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and should not be interpreted in an ideal or excessively formal sense unless explicitly defined in the present application. No.

In describing the components of the embodiment, terms such as first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, sequence, or order of the component is not limited by the term. When a component is described as being "connected," "coupled," or "connected" to another component, that component may be directly connected or connected to that other component, but there is no need for another component between each component. It should be understood that may be “connected,” “combined,” or “connected.”

Hereinafter, embodiments will be described in detail with reference to the attached drawings. However, since various changes can be made to the embodiments, the scope of the patent application is not limited or limited by these embodiments. It should be understood that all changes, equivalents, or substitutes for the embodiments are included in the scope of rights.

In addition, when describing with reference to the accompanying drawings, identical components will be assigned the same reference numerals regardless of the reference numerals, and overlapping descriptions thereof will be omitted. In describing the embodiments, if it is determined that detailed descriptions of related known technologies may unnecessarily obscure the gist of the embodiments, the detailed descriptions are omitted.

Since the present invention can be modified in various ways and can have various embodiments, specific embodiments will be illustrated in the drawings and explained in detail in the detailed description below. However, this is not intended to limit the present invention to specific embodiments, and should be understood to include all transformations, equivalents, and substitutes included in the spirit and technical scope of the present invention. In describing the present invention, if it is determined that a detailed description of related known technologies may obscure the gist of the present invention, the detailed description will be omitted.

Example 1. Preparation of pharmaceutical composition for oral administration of the present invention

After mixing all the ingredients according to the ingredients and contents in Table 1 below, the mixture was heated to about 37° C. to prepare a pharmaceutical composition for oral administration containing an oily liquid taxane.

Specifically, Examples 1-1 to 1-6 were prepared by mixing amorphous paclitaxel with medium chain triglyceride, oleyl glycerol complex, cholesterol and its derivatives, and surfactant without solvent. In Examples 1-7 to 1-9, amorphous, crystalline, or mixed forms of paclitaxel were dissolved in 1 to 5 times the total weight of dichloromethane (DCM, CH ₂ Cl ₂ ), heated and dried (50° C.), It was prepared by removing the solvent through rotation concentration or freeze drying.

division ingredient 1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 taxane Paclitaxel 1.0 1.0 1.0 1.4 1.4 1.4 1.0 1.4 1.4 medium chain triglycerides Captex8000 27.0 27.0 26.1 26.7 26.0 25.3 27.0 26.0 25.3 Oleyl Glycerol Complex Peceol 54.0 54.0 52.2 53.4 52.0 50.6 54.0 52.0 50.6 Cholesterol and its derivatives cholesterol 1.8 0.0 0.0 2.5 0.0 2.5 0.0 0.0 2.5 cholesteryl acetate 0.0 1.8 0.0 0.0 0.0 0.0 1.8 0.0 0.0 Surfactants Tween80 16.2 16.2 15.7 16.0 15.6 15.2 16.2 15.6 15.2 TPGS 0.0 0.0 5.0 0.0 5.0 5.0 0.0 5.0 5.0 TOTAL(weight%) 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

Comparative Example 1. Conventional pharmaceutical composition for oral administration (Liporaxel ^® )Manufacture of

According to Korean Patent No. 10-1542364, paclitaxel and medium chain triglyceride were dissolved in methylene chloride, and then dried under reduced pressure at 40°C to remove methylene chloride. Oleyl glycerol complex and Tween 80 were added to the obtained mixture, and then stirred at about 40° C. to prepare a pharmaceutical composition in the form of a clear, viscous solution as a comparative example. At this time, the weight ratio of the comparative example composition was paclitaxel: medium chain triglyceride (Captex ^® 8000): oleyl glycerol complex (Peceol ^® ): Tween 80 = 1.0: 27.5: 55.0: 16.5.

Experimental Example 1. Optimization of composition of pharmaceutical composition for oral administration

To optimize the content of paclitaxel and cholesterol, a composition (eLiporaxel) was prepared containing a medium chain triglyceride (Captex ^® 8000), oleyl glycerol complex (Peceol ^® ), and Tween 80, and was prepared without paclitaxel, cholesterol, and solvent. Mixed. After leaving it at 37°C for 30 minutes, it was stirred with a vortex mixer, sonicated with a bath sonicator, and the degree of dissolution was observed using optical and polarizing microscopes.

(1) A composition prepared by mixing 4.0% by weight (16.0 mg) of paclitaxel, 7.2% by weight (28.8 mg) of cholesterol, and 88.8% by weight (355.2 mg) of the composition (eLiporaxel) was observed under an optical and polarizing microscope, and as a result, no precipitation was observed. did not form (Figure 1(a)).

(2) A composition prepared by mixing 5.0% by weight (20.0 mg) of paclitaxel, 9.0% by weight (36.0 mg) of cholesterol, and 86.0% by weight (344.0 mg) of the composition (eLiporaxel) was observed with an optical and polarizing microscope to form a precipitate. (Figure 1(b)).

(3) A composition prepared by mixing 10.0% by weight (40.0 mg) of paclitaxel, 18.0% by weight (72.0 mg) of cholesterol, and 72.0% by weight (288.0 mg) of the composition (eLiporaxel) was observed with an optical and polarizing microscope to form a precipitate. (Figure 1(c)).

On the other hand, when paclitaxel was administered orally at less than 0.5% by weight, the absorption rate was very low, and when cholesterol was administered at less than 0.9% by weight, the oral absorption rate was measured to be low. Therefore, the paclitaxel content was determined to be 0.5 to 4.0% by weight, and the cholesterol content was determined to be 0.9 to 7.2% by weight.

In order to optimize the content of cholesterol, cholesterol derivatives, and TPGS, cholesterol, cholesteryl acetate, beta-sitosterol, and beta-sitosterol acetate (β) were added to the composition (eLiporaxel) described above. -sitosterol acetate) and TPGS (D-α-Tocopherol polyethylene glycol 1000 succinate) were sequentially dissolved to measure solubility, and the results are shown in Table 2 below. At this time, the weight ratio of the composition (eLiporaxel) was medium chain triglyceride (Captex ^® 8000): oleyl glycerol complex (Peceol ^® ): Tween 80 = 55.0: 27.5: 16.5.

Solubility (% by weight) Cholesterol 7% by weight Cholesteryl acetate 15% by weight β-Sitosterol 6% by weight β-Sitosterol acetate 5% by weight TPGS Miscible

When the weight ratio of cholesterol:eLiporaxel was more than 8:92, cholesterol was not sufficiently dissolved and a slightly opaque mixture was formed (Figure 1), and the solubility of cholesterol was 7 w/w%. When the weight ratio of cholesteryl acetate:eLiporaxel was 16:84, cholesteryl acetate was not sufficiently dissolved and an opaque mixture was formed (Figure 3), and the solubility of cholesteryl acetate was 15 w/w%. When the weight ratio of beta-sitosterol:eLiporaxel was 7:93, beta-sitosterol was not sufficiently dissolved, forming a slightly opaque mixture (Figure 4), and the solubility of beta-sitosterol was 6 w/w%. When the weight ratio of beta-sitosterol acetate:eLiporaxel was 6:94, beta-sitosterol acetate was not sufficiently dissolved, forming a slightly opaque mixture (Figure 5), and the solubility of beta-sitosterol acetate was 5 w/w%. TPGS was confirmed to be very well mixed (miscible) at all weight ratios (FIG. 6).

Experimental Example 2. Evaluation of oral absorption rate of pharmaceutical composition for oral administration

The pharmaceutical composition for oral administration prepared in Example 1 and Comparative Example 1 was orally administered to ICR mice (6 weeks old, female, Orient Bio, Korea) using a gastric sonde. After drug administration, blood was collected from the infraorbital vein of the mouse at 0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours, and centrifuged at 8000 x g for 20 minutes to obtain plasma samples; It was stored at -70°C.

The plasma sample was left at room temperature to dissolve and then stirred for 1 minute with a vortex mixer. 10.0 μL of the internal standard solution (paclitaxel- _{d 5} 2.50 μg/mL, in methanol) was added to 50.0 μL of the plasma sample, stirred for 3 minutes, and then centrifuged at 4000 xg for about 1 minute. 100 μL of the supernatant was taken, 100 μL of distilled water containing 0.1% (v/v) formic acid was added thereto, stirred for 3 minutes, and then centrifuged at 4000 xg for about 1 minute at room temperature. 20.0 μL of the supernatant was taken and injected into UPLC-MS/MS for analysis. At this time, UPLC-MS/MS analysis conditions are as follows.

- UPLC: UPLC, Waters ACQUITY UPLC ^TM System, Waters

- Detector: Waters Xevo ^TM TQMS, Waters

- Column: Waters ACQUITY UPLC ^TM BEHC18,1.7um (2.1 mmID × 50 mmL)

- Data processing device: MassLynx V4.1, Waters

- Mobile phase: 0.1% (v/v) FA in DW: 0.1% (v/v) FA in ACN (50:50, v/v) (FA: formic acid, DW: distilled water, ACN: acetonitrile)

- Flow rate: 0.4 mL/min

- Detector conditions: ESI+, MRM mode

division compound Monitored transition (m/z) Cone voltage (V) Collision energy (eV) analyte Paclitaxel 854.67→286.21 20 20 Internal standard material paclitaxel- _{d 5} 859.63→291.26 20 20

Pharmacokinetic parameters calculated from the measured blood concentration of paclitaxel are shown in Table 4 below (FIGS. 7 to 11).

division 1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 Comparative Example 1 Paclitaxel administered dose (mg/kg) 50.0 50.0 50.0 70.0 70.0 70.0 50.0 70.0 70.0 50.0 Dosage amount (ml/kg) 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0

h/ml) AUC _{0_t} (ng

h/ml) 45.8 22.2 30.5 49.1 37.3 54.3 33.5 30.8 34.9 19.2 C _max (μg/ml) 8.8 4.9 6.0 9.5 8.2 15.5 8.4 7.2 11.9 4.1 T _max (h) 4.0 2.0 4.0 4.0 2.0 2.0 2.0 2.0 2.0 2.0 AUC% 140.3 115.5 158.5 255.8 194.4 282.5 174.3 160.5 181.5 100.0 AUC _norm 142.8 115.5 158.5 182.7 138.8 201.8 174.3 114.7 129.6 100.0

It was confirmed that the absorption of the pharmaceutical composition for oral administration of the present invention increased by up to 2.8 times compared to Comparative Example 1 when the same dosage amount was orally administered, and when normalized based on the paclitaxel dose, it increased by up to 2 times or more.

The case containing cholesterol (Examples 1-6, 1-9) showed a higher oral absorption rate compared to the case not containing cholesterol (Examples 1-5, 1-8), and cholesterol, a derivative of cholesterol, It was confirmed that oral absorption rate increased even when steryl acetate was included (Examples 1-2 and 1-7). In addition, as the cholesterol content increased, the oral absorption rate also increased (Examples 1-1 and 1-4). This is because cholesterol and its derivatives maintain mucosal adsorption even when mixed with a large amount of water in the intestines and control the drug release rate by regulating membrane fluidity.

On the other hand, the case containing TPGS (Examples 1-6, 1-9) showed a higher oral absorption rate compared to the case without TPGS (Examples 1-4, 1-7). This is because TPGS, an emulsifier with antioxidant properties, helps form a gel phase with high oxidation and physical stability when mixed with gastric and intestinal fluids in the body.

Experimental Example 3. Physicochemical properties and solvent optimization of pharmaceutical compositions for oral administration

Differential Scanning Calorimetry (DSC) and , XRD) was performed, and scanning electron microscope (SEM) images were taken. At this time, when paclitaxel and cholesterol were added together, the weight ratio was prepared at 1:1.8.

3.1. Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) was used to investigate the temperature and heat flow associated with the thermal transition of the compositions of the present invention. Specifically, approximately 5.00 mg of each sample was obtained and differential scanning calorimetry was performed using DSC 650.

Amorphous paclitaxel has a glass transition temperature of 156 °C and a decomposition temperature of 234 °C (Figure 12 (A)), and crystalline paclitaxel has a melting point of 224 °C and decomposition of 233 °C. The temperature is shown ((B) in Figure 12), and cholesterol has a melting point of 149°C ((A) in Figure 13).

When amorphous paclitaxel and cholesterol were mixed without a solvent, the transition temperature was lowered, a widened cholesterol melting transition appeared, and decomposition of amorphous paclitaxel was observed (Figure 13 (B)). When amorphous paclitaxel and cholesterol were dissolved in dichloromethane and the solvent was removed, the same behavior was observed as the simple mixture of amorphous paclitaxel and cholesterol described above (Figure 14 (A)). This means that a physical mixture is formed between amorphous paclitaxel and cholesterol after removal of dichloromethane.

On the other hand, when amorphous paclitaxel and cholesterol were dissolved in acetone and the solvent was removed, the melting point lowering and broadening of cholesterol did not appear, and although the melting transition of paclitaxel was seen, the enthalpy change was reduced, indicating that paclitaxel is the upper melting point of cholesterol. It can be seen that it does not act as an impurity and does not exhibit the characteristics of crystalline paclitaxel (Figure 14(B)).

The heat flow was measured when amorphous paclitaxel and amorphous paclitaxel were dissolved in ethanol and the solvent was removed, and when amorphous paclitaxel and cholesterol were dissolved in ethanol and the solvent was removed. As a result, it was confirmed that the melting point of cholesterol was lowered like that of dichloromethane, and the corresponding peak was also broadened. This means that a physical mixture is formed between amorphous paclitaxel and cholesterol after removal of ethanol (FIG. 15).

3.2. X-ray diffraction analysis (XRD)

Structural information such as chemical composition, crystal structure, crystalline size, and strain of the composition of the present invention was investigated using X-ray diffraction analysis (XRD).

The same XRD patterns were observed for a simple mixture of amorphous paclitaxel and cholesterol and a composition obtained by dissolving amorphous paclitaxel and cholesterol in dichloromethane and removing the solvent. This means that since the composition is solidified into amorphous paclitaxel, it has physical properties that are highly soluble in oils even after dichloromethane is removed, making the dissolution process easy (FIGS. 16A to 16D).

Meanwhile, when amorphous paclitaxel and cholesterol were dissolved in acetone and the solvent was removed, a different XRD pattern was shown than a simple mixture of amorphous paclitaxel and cholesterol or crystalline paclitaxel. Considering the above-mentioned DSC and XRD results, it can be seen that a new crystal form is formed during acetone recrystallization. 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 precipitation was formed rather than a clear oil solution at a concentration of 1% paclitaxel and 1 to 3% cholesterol (Figures 17a to 17a Figure 17c).

3.3. Scanning electron microscopy (SEM) image

A scanning electron microscope (SEM) image was taken to visually confirm the shape of the composition of the present invention (FIG. 18).

When paclitaxel and cholesterol were dissolved in dichloromethane and then the solvent was removed, and when paclitaxel and cholesteryl acetate were dissolved in dichloromethane and the solvent was removed, an amorphous form was observed, but when the solvent was removed after being dissolved in acetone, a crystalline form was observed. For the pharmaceutical composition of the present invention for oral administration, it is important to increase the solubility of paclitaxel and cholesterol in powder form, so it is preferable to prepare the composition using a solvent that forms an amorphous form.

From the above results, the pharmaceutical composition for oral administration of the present invention does not form a complex through covalent or ionic bonds, but is physically mixed, and can be manufactured as a simple mixture without a solvent, and various solvents can be used. , Preferably, it suggests that aprotic solvents including dichloromethane, protic solvents including ethanol, and non-polar solvents can be used. In particular, ethanol is expected to have higher usability as a safe solvent.

Although the embodiments have been described with limited drawings as described above, those skilled in the art can apply various technical modifications and variations based on the above. For example, the described techniques are performed in a different order than the described method, and/or components of the described system, structure, device, circuit, etc. are combined or combined in a different form than the described method, or other components are used. Alternatively, appropriate results may be achieved even if substituted or substituted by an equivalent.

Therefore, other implementations, other embodiments, and equivalents of the claims also fall within the scope of the following claims.

Claims (12)

(a) taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) surfactants; A pharmaceutical composition for oral administration containing. According to paragraph 1, The cholesterol derivative is characterized in that it is at least one selected from the group consisting of cholesteryl acetate, beta-sitosterol, beta-sitosterol acetate, and combinations thereof. , Pharmaceutical composition for oral administration. According to paragraph 1, A pharmaceutical composition for oral administration, wherein the surfactant is at least one selected from the group consisting of Tween 80, TPGS (D-α-Tocopherol polyethylene glycol 1000 succinate), and combinations thereof. According to paragraph 1, The pharmaceutical composition is characterized in that it contains 0.9 to 7.2% by weight of (d) cholesterol, cholesterol derivatives, or a combination thereof based on the total weight of the pharmaceutical composition. According to paragraph 1, The pharmaceutical composition is a pharmaceutical composition for oral administration, characterized in that the weight ratio of (a) taxane and (d) cholesterol, cholesterol derivatives, or a combination thereof is 1:1.5 to 1:2. According to paragraph 1, Based on the total weight, the pharmaceutical composition contains (a) 0.5 to 4% by weight of taxane; (b) 15 to 35% by weight of medium chain triglycerides; (c) 40 to 60% by weight of oleyl glycerol complex; (d) 0.9 to 7.2% by weight of cholesterol, cholesterol derivatives, or a combination thereof; and (e) 10 to 30% by weight of a surfactant. According to paragraph 1, The pharmaceutical composition is a pharmaceutical composition for oral administration, characterized in that (a) to (e) are physically mixed. According to paragraph 1, A pharmaceutical composition for oral administration, characterized in that the pharmaceutical composition is in a liquid phase at room temperature conditions. (a) taxane; (b) one or more medium chain triglycerides selected from the group consisting of triacetin, tributyrin, tricaproin, tricaprylin, tricaprine, and triolein; (c) an oleyl glycerol complex comprising monooleyl glycerol, dioleyl glycerol, and trioleyl glycerol, wherein the monooleyl glycerol content is 30 to 99.9% by weight; (d) cholesterol, cholesterol derivatives, or combinations thereof; and (e) surfactants; A method for producing a pharmaceutical composition for oral administration, comprising the step of mixing. According to clause 9, The manufacturing method is a method of producing a pharmaceutical composition for oral administration, characterized in that (a) to (e) are physically mixed without a solvent or physically mixed by adding a solvent and then removing the solvent. According to clause 10, The method of producing a pharmaceutical composition for oral administration further comprises the steps of heat drying, rotational concentration, or freeze-drying. A method of delivering a taxane to a subject, comprising the step of orally administering the pharmaceutical composition of any one of claims 1 to 8 to a subject.

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