KR20210009153A - Composition for oral solid preparation of tadalafil using self-nanoemulsifying drug delivery system and methods for their preparation - Google Patents

Abstract

The present invention relates to an oral solid composition of tadalafil using a self-nanoemulsifying drug delivery system and a method for preparing the same and, more specifically, to an oral solid composition for self-nanoemulsifying drug delivery of tadalafil, which comprises tadalafil, a base composition for drug delivery and a solidifying agent, and a method for preparing the same. An object of the present invention is to provide an oral solid composition for drug delivery of tadalafil and a method for preparing the same, which can overcome the disadvantages of existing preparations showing low bioavailability by showing a rapid drug dissolution rate and being easily prepared without any inconvenience of intake and storage.

Description

Composition for oral solid preparation of tadalafil using self-nanoemulsifying drug delivery system and methods for their preparation}

The present invention relates to an oral solid composition of tadalafil using a self-nanoemulsifying drug delivery system and a method for preparing the same, and more specifically, tadalafil as an active ingredient, and peseol as oil, surfactant, and cosurfactant, respectively. (Glyceryl monooleate (Type 40)), Tween 80, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a self-nanoemulsifying drug of tadalafil containing calcium silicate or silicon dioxide as a solidifying agent It relates to a solid composition for delivery and a method for preparing the same.

Tadalafil (TDF) is a drug approved by the US FDA in 2003 as a treatment for erectile dysfunction (ED) and benign prostatic hyperplasia (BPH). Its IUPAC name is (6R,12aR)-6-(1,3-benzodioxol-5-yl)2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2 ':1,6]pyrido[3,4-b]indole-1,4-dione((6R,12aR) -6-(1,3-benzodioxol-5-yl)-2-methyl-2,3 ,6,7,12,12a-exahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione), and has a chemical structure of the following formula (1).

Formula 1

Tadalafil is a class II drug according to the biopharmaceutics classification systems (BCS), and has high membrane permeability but low solubility in water (Wlodarski et al., 2014). Due to such hydrophobic properties, tadalafil exhibits a very irregular and low dissolution profile in gastrointestinal fluid, which makes it difficult to predict bioavailability. Therefore, there is a need for a new formulation that improves the dissolution rate and dissolution profile of the drug than the tadalafil solid formulation currently on the market.

In order to improve the solubility and bioavailability of tadalafil, solid dispersion, nano-suspension, self-nanoemulsifying drug delivery system (SNEDDS) and nanostructured lipid carrier were used. Several technologies have been developed, including.

Among these methods, solid dispersion technology is the easiest approach to industrial constraints to date. As a related art, tadalafil solid dispersion formulation was prepared by lyophilizing in distilled water with solubilizers (HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus) (Wlodarski et al., 2015a). The solubility of the tadalafil/PVP-VA solid dispersion was increased 16 times over 10 minutes compared to the pure tadalafil powder. However, the solubility decreased from 50 ug/mL to 10 ug/mL over 24 hours. On the other hand, it was confirmed that the elution rate of the tadalafil/PVP-VA solid dispersion was 2.4ug/mL. In addition, tadalafil/PVP solid dispersion was prepared by a supercritical anti-solvent process (Park et al., 2014), and the elution rate of tadalafil/PVP solid dispersion was about 80% (4.4 ug/mL) in distilled water for 1 hour. Increased. In addition, a tadalafil/soluplus solid dispersion formulation (Krupa et al., 2016) was prepared using ball milling and supercritical carbon dioxide impregnation (ScCO 2), and the dissolution rate of this formulation was 0.1% sodium lauryl sulfate (SLS) ( w/v) increased up to 90% (9 ug/mL) than pure tadalafil in artificial gastric juice. These technologies require expensive equipment such as a freeze dryer, supercritical carbon dioxide impregnation, ball milling, etc., and have a disadvantage of increasing the dissolution rate in the presence of a surfactant such as sodium lauryl sulfate (SLS).

In addition, as a prior art patent, Korean Patent Publication No. 2016-0017798 discloses a technology in which a co-crystal with tadalafil is prepared by selecting caffeine, urea, saccharin, or malonic acid as a copolymer to improve the water solubility and dissolution profile of tadalafil. Is disclosed. However, in the case of tadalafil-caffeine, which showed the highest solubility in the comparative dissolution experiment performed with the final concentration of tadalafil at 100 ug/ml (50 mg/500 mL), the solubility of the raw material tadalafil was 0.6 ug/mL as the solubility of tadalafil at 60 minutes was 3.5 ug/mL It increased by 5.8 times compared to, but this is 3.5% of the amount of tadalafil added at the beginning, which is low solubility, so there is a problem in making it into a formulation. In addition, the prior art still has a problem that the solubility and dissolution rate of tadalafil are not satisfactory, and thus it is required to further improve the solubility and dissolution rate of tadalafil.

On the other hand, the recently used self nano-emulsifying drug delivery system is a liquid homogeneous mixture in which water is removed from the components of nano-sized emulsions. When it meets the water phase, it is self-emulsifying and dispersing faster than existing commercially available formulations, so rapid drug dissolution can be expected. In addition, it reduces the irritation caused by contact of the drug with the mucous membrane in the stomach after dispersion, which is a disadvantage of the nano-sized emulsion, and has the advantage of reducing the volume of the formulation since it is administered in a state in which the aqueous phase is removed from the composition. Individual microparticulates at the level of micrometers or nanometers formed by the self-nanoemulsifying drug delivery system can easily pass through the mucous membranes in the stomach and intestines, and the digested ultra-fine particles are then introduced into the blood, and the previous technologies, commercially available It can exhibit significantly increased physiological and chemical activity compared to the product. However, since this self-nanoemulsifying drug delivery system is liquid, it is mainly filled in soft capsules and used, which has a disadvantage of increasing the manufacturing cost and causing inconvenience in taking and storing.

In order to overcome these limitations, a solid self-nanoemulsifying drug delivery system was developed in which a liquid self-nanoemulsifying drug delivery system was converted into a powder form through spray drying. Such solid dosage forms can provide advantages such as high stability, ease of handling, improved water solubility and oral bioavailability. Nevertheless, the conventional solid self-nanoemulsifying drug delivery system has a problem that the water solubility is not improved by generating a relatively large and non-uniform emulsion upon contact with an aqueous medium.In the present invention, the SPG membrane emulsification method and the high pressure emulsification method To provide a solid composition using a solid self-nanoemulsifying drug delivery system that forms a smaller and more uniform emulsion when redispersed in an aqueous medium using the emulsification method of

Korean Patent Publication No. 2016-0058152 Korean Patent Publication No. 2017-0022565

Wlodarski, K., Sawicki, W., Paluch, K., Tajber, L., Grembecka, M., Hawelek, L., Wojnarowska, Z., Grzybowska, K., Talik, E., Paluch, M., 2014. The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil. European Journal of Pharmaceutical Sciences 62, 132-140. Wlodarski, K., Sawicki, W., Haber, K., Knapik, J., Wojnarowska, Z., Paluch, M., Lepek, P., Hawelek, L., Tajber, L., 2015a. Physicochemical properties of tadalafil solid dispersions-Impact of polymer on the apparent solubility and dissolution rate of tadalafil. European Journal of Pharmaceutics and Biopharmaceutics 94, 106-115.

An object of the present invention, tadalafil; A drug delivery base composition comprising an oil, a surfactant, and an auxiliary surfactant; A solid composition for self-nanoemulsion drug delivery of tadalafil containing a solidifying agent, wherein the base composition comprises 10 to 40% by weight of the oil, 10 to 70% by weight of the surfactant, and 10 to 50% by weight of the cosurfactant %, and 0.1 to 5 parts by weight of the tadalafil based on 100 parts by weight of the base composition; And it is to provide a solid composition for self-nanoemulsion drug delivery of tadalafil containing 25 to 50 parts by weight of the solidifying agent based on 100 parts by weight of the base composition.

Another object of the present invention is a method for preparing a solid composition for self-nanoemulsion drug delivery of tadalafil, peseol 10 to 40% by weight, Tween 80 10 to 70% by weight, d-α-tocopheryl polyethylene glycol 1000 succinate By mixing 10 to 50% by weight, preparing a base composition for drug delivery; Preparing a liquid self-nanoemulsifying drug delivery system by adding tadalafil to the base composition; Emulsifying the drug delivery system with an organic solvent; After the emulsification step, adding calcium silicate or silicon dioxide as a solidifying agent, drying and pulverizing to prepare a solid self-nanoemulsifying drug delivery system; It is to provide a method for preparing a solid composition for self-nanoemulsification drug delivery of tadalafil containing a.

However, the problem to be solved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

According to an embodiment of the present invention, tadalafil; A drug delivery base composition comprising an oil, a surfactant, and an auxiliary surfactant; A solid composition for self-nanoemulsion drug delivery of tadalafil containing a solidifying agent, wherein the base composition comprises 10 to 40% by weight of the oil, 10 to 70% by weight of the surfactant, and 10 to 50% by weight of the cosurfactant %, and 0.1 to 5 parts by weight of the tadalafil based on 100 parts by weight of the base composition; And there is provided a solid composition for self-nanoemulsion drug delivery of tadalafil containing 25 to 50 parts by weight of the solidifying agent based on 100 parts by weight of the base composition.

According to one side, the solid composition may be a solid composition for oral administration of tadalafil self-nanoemulsion drug delivery.

According to one side, the oil is cottonseed oil, corn oil, peanut oil, sesame oil, soybean oil, coconut oil, olive oil, linseed oil, mineral oil, peseol, Captax 300, Crodamol PC 1 selected from the group consisting of It may be a solid composition for self-nanoemulsion drug delivery of tadalafil containing more than one species.

According to one side, the surfactant is Tween 20, Tween 80, Span 20, Span 80, Labrasol, Cremophores, Transcutol P, Transcutol HP, Labrafil, Solutol HS 15, Plurol Dia. Isostearic, Capriol 90, Capriol PGMC, lauroglycol 90, lauroglycol FCC, poloxamer 188, poloxamer 407, aconon MC 8-2, polyethylene glycol 4000, polyethylene glycol 6000 selected from the group consisting of It may be a solid composition for self-nanoemulsion drug delivery of tadalafil, including one or more.

According to one side, the auxiliary surfactant may be a solid composition for self-nanoemulsion drug delivery of tadalafil, which is d-α-tocopheryl polyethylene glycol 1000 succinate.

According to one side, the solidifying agent may be a solid composition for self-nanoemulsion drug delivery of tadalafil, comprising at least one selected from calcium silicate and silicon dioxide.

According to one side, the particle size of the base composition may be a solid composition for self-nanoemulsion drug delivery of tadalafil having a particle size of 166.4 to 310.9 nm.

According to one side, the solid composition may be a solid composition for self-nanoemulsion drug delivery of tadalafil further comprising one or more additives selected from the group consisting of excipients, diluents, disintegrants, colorants, and lubricants.

According to another embodiment of the present invention, a method for preparing a solid composition for self-nanoemulsion drug delivery of tadalafil, peseol 10 to 40 wt%, Tween 80 10 to 70 wt%, d-α-tocopheryl polyethylene glycol Mixing 10 to 50% by weight of 1000 succinate to prepare a base composition for drug delivery; Preparing a liquid self-nanoemulsifying drug delivery system by adding tadalafil to the base composition; Emulsifying the drug delivery system with an organic solvent; After the emulsification step, adding calcium silicate or silicon dioxide as a solidifying agent, drying and grinding to prepare a solid self-nanoemulsifying drug delivery system; Preparation of a solid composition for self-nanoemulsion drug delivery of tadalafil containing A method is provided.

According to one side, the method of emulsifying the liquid self-nanoemulsifying drug delivery system may be a method of preparing a solid composition for self-nanoemulsification drug delivery of tadalafil, which is by an SPG membrane emulsification or high pressure emulsification method.

According to one side, in the step of emulsifying the drug delivery system with an organic solvent, the organic solvent comprises at least one selected from the group consisting of acetonitrile, ethanol, and dichloromethane, for self-nanoemulsion drug delivery of tadalafil. It may be a method of preparing a solid composition.

According to one side, in the step of drying after adding the solidifying agent, the drying method is by any one of spray drying, reduced pressure drying, and hot air drying method, of tadalafil's self-nanoemulsifying solid composition for drug delivery. It may be a manufacturing method.

The solid composition for self-nanoemulsion drug delivery of tadalafil according to the present invention spontaneously forms nano-sized emulsion particles when contacted with water in the stomach, which increases the solubility and dissolution rate of the tadalafil drug, thereby improving bioavailability. have. In addition, the solid composition for self-nanoemulsification drug delivery of tadalafil made by the production method of the present invention has excellent stability by maintaining the amorphous form by minimizing recrystallization of tadalafil in the solid composition even when stored for a long period of time.

The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be deduced from the configuration of the invention described in the detailed description or claims of the present invention.

1 is a virtual three-phase phase equilibrium diagram showing the self-emulsifying region of peseol, Tween 80, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS).
2 is a graph showing the effect of tadalafil drug on the particle size and polydispersity (PDI) of a composition by a liquid self-nanoemulsifying drug delivery system.
3A is a graph showing the effect of the stirring speed on the particle size and polydispersity (PDI) of the composition when the liquid self-nanoemulsifying drug delivery system is manufactured by the SPG membrane emulsification method.
3B is a graph showing the effect of operating time on the particle size and polydispersity (PDI) of the composition when manufacturing a liquid self-nanoemulsifying drug delivery system by the SPG membrane emulsification method.
4A is a graph showing the effect of pressure on the particle size and polydispersity (PDI) of a composition when manufacturing a liquid self-nanoemulsifying drug delivery system by a high pressure emulsification method.
4B is a graph showing the effect of the number of repetitions on the particle size and polydispersity (PDI) of the composition when manufacturing a liquid self-nanoemulsifying drug delivery system by a high pressure emulsification method. * Indicates that P <0.05 when compared to the drug powder.
5 is a graph showing the effect of the emulsification method on the particle size and polydispersity (PDI) of a composition by a solid self-nanoemulsifying drug delivery system.
6 is a scanning electron microscope photograph of tadalafil and calcium silicate, Examples 15, 16, and 17.
7 is a graph showing the measurement of the differential scanning calories of tadalafil, a physical mixture, and Examples 15, 16, and 17.
8 is a graph of tadalafil, a physical mixture, and powder X-ray diffraction measurement of Examples 15, 16 and 17.
9 is a Fourier transform infrared spectral graph of tadalafil, physical mixture, Examples 15, 16, and 17.
10 is a graph showing the drug concentration in the blood after administering tadalafil, an amount corresponding to 5 mg/kg as a drug, to SD rats of Example 17.

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

The terms used in the examples are used for illustrative purposes only and should not be interpreted as limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In the present specification, terms such as "comprise" or "have" are intended to designate the presence of features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, but one or more other features. It is to be understood that the presence or addition of elements or numbers, steps, actions, components, parts, or combinations thereof, does not preclude in advance.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiment belongs. Terms as defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and should not be interpreted as an ideal or excessively formal meaning unless explicitly defined in this application. Does not.

In addition, in the description with reference to the accompanying drawings, the same reference numerals are assigned to the same components regardless of the reference numerals, and redundant descriptions thereof will be omitted. In describing the embodiments, when it is determined that a detailed description of related known technologies may unnecessarily obscure the subject matter of the embodiments, the detailed description thereof will be omitted.

Hereinafter, terms used in the present invention will be described.

The term “drug delivery system (DDS)” as used in the present invention is designed to optimize drug treatment by designing a formulation to efficiently deliver the required amount of drugs to minimize side effects of existing drugs and maximize efficacy. It refers to technology.

The term “self-nanoemulsifying drug delivery system (SNEDDS)” used in the present invention is a semi-solid property and is nano-sized by relatively weak agitation such as gastrointestinal motion when exposed to water, such as body fluids. It is a drug delivery system capable of forming an emulsion. It provides an excellent vehicle that increases the bioavailability of hydrophobic drugs, and enables oral delivery thereof.

The term "base composition for drug delivery" used in the present invention refers to a composition comprising an oil, a surfactant, and an auxiliary surfactant having an effect of increasing the bioavailability of tadalafil, a poorly soluble drug.

The term “a composition using a liquid self-nanoemulsifying drug delivery system (L-SNEDDS)” used in the present invention refers to a tadalafil drug in the base composition for drug delivery: oil, surfactant, and cosurfactant. It means a composition made by adding.

The term "composition by solid self-nanoemulsifying drug delivery system (S-SNEDDS)" used in the present invention refers to a composition by a liquid self-nanoemulsifying drug delivery system after emulsifying with an organic solvent, It means a composition made by adding a solidifying agent.

Further, unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings commonly understood by one of ordinary skill in the art.

Hereinafter, the present invention will be described in detail.

The present invention, tadalafil; A drug delivery base composition comprising an oil, a surfactant, and an auxiliary surfactant; A solid composition for self-nanoemulsion drug delivery of tadalafil containing a solidifying agent, wherein the base composition comprises 10 to 40% by weight of the oil, 10 to 70% by weight of the surfactant, and 10 to 50% by weight of the cosurfactant %, and 0.1 to 5 parts by weight of the tadalafil based on 100 parts by weight of the base composition; And it provides a solid composition for self-nanoemulsion drug delivery of tadalafil containing 25 to 50 parts by weight of the solidifying agent based on 100 parts by weight of the base composition.

In a preferred embodiment, a drug of tadalafil comprising Peceol, Tween 80, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an oil, a surfactant and a cosurfactant, respectively A liquid self-nanoemulsifying drug delivery system is provided by adding tadalafil drug to the delivery base composition, and after emulsifying it with an organic solvent, it is mixed with calcium silicate or silicon dioxide as a solidifying agent to prepare a solid self-nanoemulsifying drug delivery system.

Finally, the present invention provides a solid composition for self-nanoemulsification drug delivery of tadalafil by a solid self-nanoemulsification drug delivery system to increase the solubility and dissolution rate of tadalafil drugs, and to improve bioavailability.

On the other hand, each component of the drug delivery base composition containing 10 to 40% by weight of the oil, 10 to 70% by weight of the surfactant, and 10 to 50% by weight of the co-surfactant consider the compatibility and solubility of tadalafil Therefore, it was selected in the optimal configuration, and it was formulated in the optimal ratio in consideration of the efficiency of self-nanoemulsification and the distribution of particle size.

In addition, the physicochemical properties of the solid composition of the present invention were evaluated by DSC (differential scanning calorimetry), SEM (scanning electron microscopy), FTIR (Fourier-transform infrared spectroscopy), and PXRD (powder x-ray diffraction), and tadalafil When compared with the powder formulation, improved solubility, dissolution pattern, and in vivo dynamic properties of the drug can be confirmed.

Each component included in the self-nanoemulsifying drug delivery solid composition of tadalafil according to the present invention will be described in more detail as follows.

In order to manufacture a solid self-nanoemulsifying drug delivery system that makes a solid composition for self-nanoemulsion drug delivery of tadalafil, the ultimate formulation of the present invention, first, a liquid self-nanoemulsification drug delivery system without adding a solidifying agent must be prepared.

The drug tadalafil, which is an active ingredient constituting the liquid self-nanoemulsifying drug delivery system of the present invention, and oil, surfactant, and cosurfactant, which are the base composition for drug delivery, will be described, and then the solid self-nanoemulsifying drug delivery system will be described. The solidifying agent required for production will be described in more detail.

Tadalafil is an active ingredient of the present invention, and is a drug having poorly soluble characteristics. The content of tadalafil is preferably 0.1 to 5% by weight based on 100 parts by weight of the base composition for drug delivery according to the present invention. If it is less than the above range, the drug content is lowered, the total weight of the formulation is increased, and there is a disadvantage of having to take a large amount of the composition.If it exceeds the above range, it is a range that exceeds the maximum solubility of the drug in the self-nanoemulsifying drug delivery system. The problem of drug dissolution may occur due to the emulsified drug delivery system.

The oil in the base composition for drug delivery of the present invention is from the group consisting of cottonseed oil, corn oil, peanut oil, sesame oil, soybean oil, coconut oil, olive oil, linseed oil, mineral oil, peseol, Captax 300, and Crodamol PC. It may include one or more selected, preferably glyceryl oleate-based peseol, but is not limited thereto.

The oil improves the bioabsorption rate of the tadalafil drug, which has a very strong hydrophobicity, used as an active ingredient in the present invention, and increases the solubility, thereby reducing the dosage of the drug. As peseol, a brand name Glyceryl monooleate (Type 40) is mentioned. The content of peseol may be included in 10 to 40% by weight of the base composition for drug delivery according to the present invention. If it is less than the above range, the solubility of tadalafil, which is a poorly soluble drug, cannot be improved, and emulsification is not formed and is formed into a head phase.Even if it exceeds the above range, the emulsification is incomplete and thus a single phase may not be formed. .

In addition, surfactants in the drug delivery base composition of the present invention not only enhance the absorption rate of drugs, but also are substances that stably disperse drugs regardless of the hydrogen ion concentration and temperature. As a surfactant capable of forming a nano-sized emulsion for oil containing an appropriate amount of tadalafil, it is preferable that the HLB (Hydrophilic Lipophlic Balance) value indicating the affinity between water and oil is 2 to 17, and the HLB value is Outside the range, problems may arise in terms of transparency, stability, and solubility of the nano-sized emulsion. Surfactants include Tween 20, Tween 80, Span 20, Span 80, Labrasol, Cremophores, Transcutol P, Transcutol HP, Labrafil, Solutol HS 15, Plurol Diisostearic, Capri All 90, Capriol PGMC, lauroglycol 90, lauroglycol FCC, poloxamer 188, poloxamer 407, aconon MC 8-2, polyethylene glycol 4000, polyethylene glycol 6000 contains at least one selected from the group consisting of It can be, and preferably Tween 80 is used, but is not limited thereto.

In the present invention, Tween 80 of the trade name Polyoxyethylene (20) sorbitan monooleate was used as a surfactant. The content of Tween 80 may be included in 10 to 70% by weight of the base composition for drug delivery according to the present invention. If it is less than the above range, the solubility of tadalafil, which is a poorly soluble drug, cannot be improved, and emulsification is not formed and is formed into a head phase.Even if it exceeds the above range, the emulsification is incomplete and thus a single phase may not be formed. .

In addition, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is preferably used as an auxiliary surfactant in the drug delivery base composition of the present invention, but is not limited thereto. TPGS acts as a co-surfactant that facilitates absorption in the gastrointestinal tract by controlling the HLB (Hydrophile-Lipophile Balance) value of the surfactant in tadalafil's liquid self-nanoemulsifying drug delivery system to act as a more stable emulsifier. The content of TPGS is preferably 10 to 50% by weight of the base composition for drug delivery according to the present invention. If it is less than the above range, the solubility of tadalafil, which is a poorly soluble drug, cannot be improved, and emulsification is not formed and is formed into a head phase.Even if it exceeds the above range, the emulsification is incomplete and thus a single phase may not be formed. .

In addition, a solidifying agent is added to prepare a solid composition for self-nanoemulsion drug delivery of tadalafil, the final formulation to be provided in the present invention. The solidifying agent is preferably selected from calcium silicate and silicon dioxide, but is not limited thereto. The content of the solidifying agent is preferably 25 to 50% by weight based on 100 parts by weight of the drug delivery base composition. If it is less than the above range, a complete solid cannot be formed and a problem of sticking to each other occurs, and if it exceeds the above range, the content of the drug in the solid composition for self-nanoemulsification drug delivery of tadalafil becomes too small, and the total formulation volume As a result, there may be a problem of reducing the convenience of taking drugs and improvement of patient compliance, which are the objects of the present invention.

The solid composition according to the present invention may be orally administered, a solid composition for self-nanoemulsion drug delivery of tadalafil.

As a method of administering the solid composition, oral administration, intravenous injection, intramuscular injection, intrathecal administration, transdermal administration, and the like can be used, but an oral administration method is preferably used.

The solid composition according to the present invention may be a solid composition for self-nanoemulsion drug delivery of tadalafil, having a particle size of the base composition for drug delivery of 166.4 to 310.9 nm. As a preferred embodiment, according to Example 4 of the present invention, after selecting 30% by weight of peseol and 70% by weight of Tween 80, after fixing the ratio of the selected peseol to 30% by weight, the weight% of Tween 80 and TPGS Experimented with changes. As a result, among Examples 1 to 9, for drug delivery comprising 30% by weight of peseol of Example 6, 20% by weight of Tween 80, and 50% by weight of TPGS having the smallest particle size (170.2 ± 3.8 nm) of the composition The base composition could be confirmed.

The solid composition for self-nanoemulsion drug delivery of tadalafil according to the present invention may further include at least one additive selected from the group consisting of excipients, diluents, disintegrants, colorants, and lubricants.

The solid composition comprising the additive may be prepared in various pharmaceutical forms, and may include coated tablets including tablets, capsules, granules, and the like.

Examples of the excipient include lactose, mannitol, sorbitol, microcrystalline cellulose, starch, gelatinized starch, calcium phosphate, silicon dioxide, cellulose, sodium hydrogen carbonate, and mixtures thereof, and examples of the disintegrant include croscarmellose sodium, Crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and the like, and examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, and the like.

For example, tablets may be prepared by mixing the solid composition with an excipient, a disintegrant, a lubricant, etc., or by putting an excipient into the solid composition and preparing it into granules, mixing an excipient, a disintegrant, a lubricant, etc. In addition, capsules can also be prepared by filling the above mixture into capsules. In addition, film-coating or enteric-coating may be applied for the purpose of improving stability, convenience of taking, and appearance.

The present invention is a method for preparing a solid composition for self-nanoemulsion drug delivery of tadalafil, peseol 10 to 40% by weight, Tween 80 10 to 70% by weight, d-α-tocopheryl polyethylene glycol 1000 succinate 10 to 50 By mixing the weight percent, preparing a base composition for drug delivery; Preparing a liquid self-nanoemulsifying drug delivery system by adding tadalafil to the base composition; Emulsifying the drug delivery system with an organic solvent; After the emulsification step, adding calcium silicate or silicon dioxide as a solidifying agent, drying and pulverizing to prepare a solid self-nanoemulsifying drug delivery system; It provides a method for preparing a solid composition for self-nanoemulsification drug delivery of tadalafil comprising a.

In the step of preparing the liquid self-nanoemulsifying drug delivery system, the mixing ratio of tadalafil, oil, surfactant, and co-surfactant components is the composition of the liquid self-nanoemulsifying drug delivery system made by mixing them in various ratios. It can be determined by finding the optimum ratio with a stable state and a small particle size.

In addition, when the composition by the liquid self-nanoemulsifying drug delivery system is put into water, an emulsion is formed even by small kinetic energy, so when administered in vivo, including oral administration, it is absorbed very quickly in the living body, thereby improving bioavailability compared to existing formulations. Can be expected to show.

The method of emulsifying the liquid self-nanoemulsifying drug delivery system is preferably by an SPG membrane emulsification or high pressure emulsification method, but is not limited thereto. As a method of emulsifying a liquid self-nanoemulsifying drug delivery system, a suspension polymerization method, dispersion polymerization method, emulsion polymerization method, or interfacial polymerization method in which nanocapsules are generated by addition of a polymer stabilizer or emulsifier can be used, but SPG It is preferable to use a membrane emulsification method or a high pressure emulsification method to prepare a composition having smaller and homogeneous particles.

In addition, in the step of emulsifying the liquid self-nanoemulsifying drug delivery system with an organic solvent, the organic solvent may be at least one selected from the group consisting of acetonitrile, ethanol, and dichloromethane. Preferably, an acetonitrile solution is used, but the present invention is not limited thereto.

In the step of preparing a solid self-nanoemulsifying drug delivery system including the step of drying after adding the solidifying agent, the method for preparing the solid agent composition follows a method commonly known to those skilled in the art. As a specific example, after completely dissolving the drug in the drug delivery base composition, it may be uniformly suspended in a suspension solvent such as water or an organic solvent with calcium silicate or silicon dioxide as a solidifying agent, and then solidified by a method such as spray drying. The drying method usable pharmaceutically is not particularly limited, and for example, spray drying using a spray dryer, a fluid bed granulator, a CF granulator, a reduced pressure dryer, etc., drying under reduced pressure, and hot air drying may be used.

As a preferred embodiment of the method for preparing a solid composition for self-nanoemulsification of tadalafil of the present invention, in the present invention, a drug containing 30% by weight of peseol, 20% by weight of Tween 80, and 50% by weight of TPGS of Example 6 The liquid self-nanoemulsifying drug delivery system of Examples 12 to 14 was prepared by adding 5 parts by weight of tadalafil based on 100 parts by weight of the base composition for delivery. Thereafter, among Examples 12 to 14, it was confirmed that the particle size and polydispersity measurements of the composition by the liquid self-nanoemulsifying drug delivery system using the high-pressure emulsification method of Example 14 were the lowest. Therefore, based on the liquid self-nanoemulsifying drug delivery system using the high pressure emulsification method of Example 14, by adding calcium silicate or silicon dioxide as a solidifying agent, the solid self-nanoemulsifying drugs of Examples 15 to 17 and Comparative Examples 4 to 6 The delivery system was prepared. Thereafter, the physical properties evaluation, water solubility test, dissolution test and in vivo dynamic test results of the tadalafil drug using the solid self-nanoemulsifying drug delivery system of Examples 15 to 17 and Comparative Examples 4 to 6, the solid self nanoparticles of Example 17 Tadalafil drug using the emulsified drug delivery system showed the highest effect in water solubility and dissolution rate, and it was confirmed that the oral bioavailability also had the highest effect.

Hereinafter, the present invention will be described in more detail by examples and experimental examples. However, the following examples and experimental examples are for illustrative purposes only, and the present invention is not limited by the following examples and experimental examples.

Experimental Example 1: Evaluation of water solubility of tadalafil and selection of base composition for drug delivery

Tadalafil water solubility evaluation experiment

The water solubility evaluation experiment of tadalafil, which is a poorly soluble drug, is a vehicle of various types.After adding an excess of tadalafil (about 10mg) to 1 ml of oil, surfactant, and cosurfactant each, agitate at 25℃ and 100rpm in a stirring bath for one week. Then, tadalafil was quantified using a high-performance liquid chromatography (HPLC (Agilent 1220 Infinity; Agilent Technologies, Santa Clara, CA, USA), Waters Sunfire ^® C18 column (5 μm, 150*4.6 mm)) system. At this time, the mobile phase was water-acetonitrile (50:50 v/v), the flow rate was 1 ml/min, and the UV absorbance value was 283 nm.

The results of the water solubility evaluation experiment of tadalafil are shown in Tables 1 and 2 below.

Looking at the vehicle types used in the experiment, the oils include cotton seed oil, corn oil, peanut oil, sesame oil, soybean oil, and coconut oil. oil), Olive oil, Linseed oil, Mineral oil, Peceol, Captex 300, and Crodamol PC were used.

Surfactants include Tween 20, Tween 80, Span 20, Span 80, Labrasol, Cremophor, and Transcutol P. ), Transcutol HP, Labrafil, Solutol HS15, Plurol diisostearique, Capryol 90, Capriol PGMC ( Capryol PGMC), lauroglycol 90 ( Lauroglycol 90), Lauroglycol FCC, Poloxamer 188, Poloxamer 407, Acconon MC8-2, Polyethylene glycol 4000 (PEG 4000), Polyethylene glycol 6000 (PEG 6000) was used.

Using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a co-surfactant, the results of the water solubility evaluation experiment of tadalafil were confirmed.

As a result of the experiment, among oils, Peceol increased the water solubility of the tadalafil drug most (Table 1). Almost all surfactants increase the water solubility of tadalafil drugs, but among them, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and Tween 80 are the most common and secondly, the water solubility of tadalafil drugs is increased. Increased (Table 2). Therefore, as a material that greatly increases the water solubility of tadalafil, Peceol as an oil, Tween 80 as a surfactant, and d-α-tocopheryl polyethylene glycol 1000 succinate as a co-surfactant (TPGS ) Was selected, and a composition containing these oils, surfactants, and co-surfactants was selected as the base composition for drug delivery of tadalafil of the present invention.

Water solubility evaluation experiment of tadalafil containing oil Ingredient name Water solubility (μg/ml) Castor oil 169.6 ± 17.8 Cotton seed oil 176.3 ± 3.2 Corn oil 200.8 ± 3.1 Peanut oil 113.9 ± 4.7 Sesame oil 133.5 ± 1.5 Soybean oil 178.9 ± 8.6 Coconut oil 184.1 ± 4.1 Olive oil 145.6 ± 4.9 Linseed oil 169.3 ± 5.1 Mineral oil 2.4 ± 0.2 Peceol 1811.1 ± 97.1 Captex 300 480.4 ± 5.3 Crodamol PC 423.0 ± 8.6

Water solubility evaluation experiment of tadalafil containing surfactant and co-surfactant Ingredient name Water solubility (μg/ml) Tween20 396.8 ± 4.8 Tween80 511.0 ± 3.7 Span20 90.1 ± 7.8 Span80 68.4 ± 16.2 Labrasol 388.2 ± 2.2 Cremophor EL 423.8 ± 3.6 Cremophor ELP 450.4 ± 3.1 Cremophor RH40 407.2 ± 1.9 Cremophor RH60 395.7 ± 3.3 Transcutol P 29.1 ± 2.1 Transcutol HP 35.1 ± 2.8 Labrafil M1944CS 16.7 ± 5.5 Labrafil M2125CS 28.4 ± 7.3 Solutol HS15 382.1 ± 2.7 Plurol diisostearique 122.9 ± 33.2 Capryol 90 16.1 ± 6.7 Capryol PGMC 12.2 ± 7.6 Lauroglycol 90 32.2 ± 5.4 Lauroglycol FCC 26.9 ± 0.9 Poloxamer 188 11.8 ± 0.8 Poloxamer 407 84.4 ± 1.1 Acconon MC8-2 301.6 ± 2.6 PEG 4000 13.6 ± 1.1 PEG 6000 14.0 ± 1.2 TPGS 732.7 ± 5.6

Selection of the ratio of each component of the drug delivery base composition

It was attempted to confirm the optimal component ratio of the base composition for drug delivery of tadalafil selected based on Experimental Example 1. By mixing the base composition for drug delivery including oil, surfactant, and co-surfactant showing high solubility through the water solubility evaluation experiment of the tadalafil at various weight ratios, the area where self-nanoemulsifying particles of 300 nm or less is formed is indicated. A three-phase phase equilibrium was prepared (see Fig. 1).

A series of self-nanoemulsification systems are spontaneous emulsification by adding 500 mL of water to various concentrations of peseol (oil), Tween 80 (surfactant), TPGS (co-surfactant) and tadalafil (10 mg) in a beaker and stirring at 37°C We looked at whether particles were observed. Particles easily spread in water, and if a milky emulsion was observed, it was well formed, and when agglomeration occurred immediately after stopping the stirring, and particle lumps were observed, it was judged that the emulsion was not well formed. The points where emulsification occurs well were indicated on the phase balance chart to determine the range. This process was repeated three times to observe whether similar results were obtained.

Among them, peseol (0 to 65% v/v), Tween 80 (15 to 90% v/v), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (15 to 90% v/v), etc. It was confirmed that it was a transparent liquid, and it was confirmed that this section (the black part in FIG. 1) can prepare a solid self-nanoemulsifying drug delivery system.

The efficiency of self-nanoemulsification was evaluated by the degree of emulsification and particle size distribution. In this self-nanoemulsification zone, as shown in Table 3, the experiment was conducted while controlling the weight ratio of peseol and Tween 80. After selecting 30% by weight of peseol and 70% by weight of Tween 80 in Example 4, after fixing the ratio of the selected peseol to 30% by weight, Tween 80 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) The experiment was performed by varying the weight% of.

As a result, it was confirmed that Example 6 having the smallest particle size (170.2 ± 3.8 nm) of Examples 1 to 9 (see Table 3), peseol 30% by weight, Tween 80 20% by weight, d-α -Tocopheryl polyethylene glycol 1000 succinate (TPGS) containing 50% by weight, it was possible to confirm the ratio of the components of the optimal drug delivery base composition.

Composition ratio and particle size of base composition for drug delivery Furtherance Ingredients (% by weight) Particle size (nm) Peseol Tween 80 TPGS Example 1 40 60 - 340.2 ± 20.4 Example 2 40 60 - 296.0 ± 14.9 Example 3 35 65 - 263.5 ± 12.2 Example 4 30 70 - 200.0 ± 16.1 Example 5 35 15 50 182.2 ± 6.3 Example 6 30 20 50 170.2 ± 3.8 Example 7 30 25 45 190.4 ± 8.5 Example 8 30 30 40 204.1 ± 3.1 Example 9 30 35 35 206.6 ± 7.7 Comparative Example 1 10 - 90 431.6 ± 21.9 Comparative Example 2 90 - 10 376.2 ± 30.2

Experimental Example 2: Preparation of a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) of tadalafil

100% by weight of a drug delivery base composition comprising 30% by weight of peseol, 20% by weight of Tween 80, and 50% by weight of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) of Example 6 selected based on Experimental Example 1 Liquid self-nanoemulsifying drug delivery system (L-SNEDDS) of Examples 10 to 14 and Comparative Example 3 while adding tadalafil, which is a drug active ingredient, in various ratios of 0.1 to 5 parts by weight with respect to parts Was prepared. As a result, it was confirmed that tadalafil, an active ingredient, was completely dissolved in the base composition for drug delivery, but the composition of Comparative Example 3 was not completely dissolved in the compositions of Examples 10 to 14 of the compositions in Table 4 below.

Therefore, in manufacturing a liquid self-nanoemulsifying drug delivery system of tadalafil, it was confirmed that the ratio of the tadalafil drug to 100 parts by weight of the drug delivery base composition is preferably 0.1 to 5 parts by weight.

Liquid self-nanoemulsifying drug delivery system (L-SNEDDS) manufacturing Furtherance Ingredients (% by weight) Tadalafil (% by weight)
(Base composition for drug delivery 100
Ratio to parts by weight) Peseol Tween 80 TPGS Example 10 30 20 50 0.1 Example 11 30 20 50 0.5 Example 12 30 20 50 One Example 13 30 20 50 2.5 Example 14 30 20 50 5 Comparative Example 3 30 20 50 5.5

Manufacturing of liquid self-nanoemulsifying drug delivery system (L-SNEDDS) using SPG membrane emulsification method

As a method to reduce the particle size and polydispersity (PDI) of the composition formed from the composition of the liquid self-nanoemulsifying drug delivery system (L-SNEDDS), the SPG membrane emulsification method was used, and stirring to optimize this method The conditions having the smallest particle size and polydispersity (PDI) of the composition were selected by varying two parameters: speed (100 to 300 rpm) and operating time (10 to 60 min).

The membrane pore size is preferably 1.1 μm, but is not limited thereto, and may include membrane pores of other sizes. The operating time was changed to 10 minutes or more, the stirring speed was changed to 100 to 300 rpm, and the particle size and polydispersity (PDI) of the composition were measured. As a result, there was no significant difference in the particle size and polydispersity (PDI) of the composition according to the stirring speed. Therefore, it was confirmed that the stirring speed had no effect on the particle size and polydispersity (PDI) of the composition, and the smallest stirring speed, 100 rpm, was selected as an appropriate stirring speed (see FIG. 3A).

For example, after the membrane pore size is fixed at 1.1 μm and the stirring speed is constant at 100 rpm, the operating time is changed to 10 to 60 minutes, and when measuring the particle size and polydispersity (PDI) of the composition, the particle size and All of the polydispersity (PDI) significantly decreased after 10 minutes, but 40 minutes in which the variation of the polydispersity (PDI) was small was selected as an appropriate operating time (see FIG. 3B).

Manufacturing of liquid self-nanoemulsifying drug delivery system (L-SNEDDS) using high pressure homogenizer (HPH) method

As another method to reduce the particle size and polydispersity (PDI) of the composition formed from the composition of the liquid self-nanoemulsifying drug delivery system (L-SNEDDS), a high pressure emulsification method was used, and to optimize this method, pressure The conditions having the smallest particle size and polydispersity (PDI) of the composition were selected by changing the two parameters of 900 mbar or more and the number of repetitions more than once.

First, after fixing the number of repetitions to one, the pressure is changed to 900 to 1500 mbar, and when measuring the particle size and polydispersity (PDI) of the composition, the particle size and polydispersity (PDI) of the composition according to the pressure are significantly different. There was no. However, since the average value of the particle size and polydispersity (PDI) of the composition tends to decrease as the pressure increases, the highest pressure, 1500 mbar, was selected as an appropriate pressure (see FIG. 4A).

Next, after fixing the pressure at 1500 mbar, the number of repetitions is changed to one or more times, and when measuring the particle size and polydispersity (PDI) of the composition, the particle size of the composition decreases significantly immediately after one time, Since the polydispersity (PDI) decreases after 3 times, 3 times in which both the particle size and the polydispersity (PDI) of the composition significantly decrease were selected as an appropriate number of repetitions (see FIG. 4B).

As a result of manufacturing a liquid self-nanoemulsifying drug delivery system with a pressure of 1500 mbar and 3 repetitions under optimized conditions, SPG compared to the untreated group (particle size: 176.9 ± 10.0, polydispersity (PDI): 0.42 ± 0.03) Group using the membrane emulsification method (particle size: 154.1 ± 5.2, polydispersity (PDI): 0.31 ± 0.01) and group using the high pressure emulsification method (particle size: 87.7 ± 8.4, polydispersity (PDI): 0.20 ± 0.01 ) Showed significantly reduced particle size and polydispersity (PDI) of the composition, and in particular, in the case of high pressure emulsification, both particle size and polydispersity (PDI) of the composition were significantly reduced to half the value of the untreated group. It was confirmed that it decreased (Table 5).

Size of composition (the mean ± S. D., n=3) and polydispersity (PDI) by liquid self-nanoemulsifying drug delivery system (L-SNEDDS) Liquid self-nanoemulsifying drug delivery system manufacturing method Composition size
(nm) Polydispersity Index (PDI)) Liquid self-nanoemulsifying drug delivery system
(No treatment) 176.9 ± 10.0 0.42 ± 0.03 Liquid self-nanoemulsifying drug delivery system using SPG membrane emulsification method 154.1 ± 5.2 0.31 ± 0.01 Liquid self-nanoemulsifying drug delivery system using high pressure emulsification method 87.7 ± 8.4 0.20 ± 0.01

As a result of the experiment, as shown in Table 5, the composition of the untreated group liquid self-nanoemulsifying drug delivery system formed large, non-homogeneous particles with a relatively high polydispersity value, whereas the SPG membrane emulsification method or high pressure It was confirmed that the composition by the liquid self-nanoemulsification system using the emulsification method formed small and homogeneous particles with a low polydispersity value.

Experimental Example 3: Preparation of tadalafil solid self-nanoemulsifying drug delivery system (S-SNEDDS)

The liquid self-nanoemulsifying drug delivery system (L-SNEDDS) of Example 14 prepared based on Experimental Example 2 was emulsified using 100 ml of a 50% acetonitrile solution as a solvent. As shown in Table 6, after emulsifying the liquid self-nanoemulsifying drug delivery system by dividing the emulsification method with no treatment, SPG membrane emulsification, and high pressure emulsification, calcium silicate or silicon dioxide was added as a solidifying agent, and spray dried to completely remove the solvent. By evaporation, tadalafil solid self-nanoemulsified drug delivery systems (S-SNEDDS) of Examples 15 to 17 and Comparative Examples 4 to 8 were prepared.

At this time, in the case of Comparative Examples 7 and 8, it was predicted that the amount of calcium silicate or silicon dioxide, which is a solidifying agent, was small, and thus did not solidify.

Manufacture of tadalafil solid self-nanoemulsifying drug delivery system (S-SNEDDS) Furtherance Ingredients (% by weight) Emulsification method For drug delivery
Pre-made composition
(Example 6) Tadalafil Calcium silicate Silicon dioxide Example 15 100 5 50 No treatment Example 16 100 5 50 SPG membrane emulsification Example 17 100 5 50 High pressure emulsification Comparative Example 4 100 5 50 No treatment Comparative Example 5 100 5 50 SPG membrane emulsification Comparative Example 6 100 5 50 High pressure emulsification Comparative Example 7 100 5 25 - Comparative Example 8 100 5 25 -

Experimental Example 4: Evaluation of physical properties of tadalafil drugs using solid self-nanoemulsifying drug delivery system

Experiments were conducted to evaluate morphology, crystal form, and particle size based on physical properties of tadalafil drugs using the solid self-nanoemulsifying drug delivery system of Examples 15, 16, and 17 prepared based on Experimental Example 3. The shape and surface of the drug tadalafil were examined using a scanning electron microscope (SEM, S-4800, Hitachi; Tokyo, Japan). In addition, the crystalline form was evaluated using a differential scanning calorimeter (DSC Q200; TA Instruments, New Castle, DE, USA) and X-ray powder diffraction (D/MAX-2500 PC, Rigaku Corporation; Tokyo, Japan). In addition, particle size and particle distribution were confirmed using a particle size analyzer (H1918; Sympatec GmbH, System-Partikle-Technik, Clausthal-Zellerfeld Saxony, Germany).

Tadalafil drugs using solid self-nanoemulsifying drug delivery system The particle size and polydispersity (PDI) decrease in the order of no treatment (Example 15)> SPG membrane emulsification (Example 16)> high pressure emulsification (Example 17), which increases the average value of the water solubility of the tadalafil drug and the dissolution rate. It was predicted to be related to an increase in (see Fig. 5).

As a result of confirming the shape and surface of the tadalafil drug using a solid self-nanoemulsifying drug delivery system, the untreated tadalafil powder showed an irregular shape, but in Examples 15, 16, and 17, tadalafil was added to the porous calcium silicate solidifying agent. It could be observed that the self-nanoemulsifying drug delivery system was enclosed (see FIG. 6).

In addition, an experiment was conducted to confirm the crystalline form of the tadalafil drug using a solid self-nanoemulsifying drug delivery system. Experimental conditions were specified from 50 to 350 ℃ under the condition of a temperature increase of 10 ℃ per minute. As a result, unlike the melting point peak of the drug appearing at 300° C. of tadalafil and the physical mixture, the melting point peaks of the drug disappeared in Examples 15, 16, and 17, so that the drug could be predicted to be converted to an amorphous form (see FIG. 7 ). ).

In addition, unlike tadalafil and the powder X-ray diffraction (PXRD) graph of the physical mixture, specific peaks appeared in Examples 15, 16, and 17, as these specific peaks disappeared, predicting that the drug was converted to amorphous form ( 8).

In addition, an experiment was conducted to confirm the chemical interaction between the drug and the carrier by confirming the tadalafil, the physical mixture, and Fourier transform infrared spectroscopy (FT-IR) of Examples 15, 16, and 17. In all of Examples 15, 16, and 17, it could be determined that there was no chemical interaction between the drug and the carrier as the drug's intrinsic peak appeared at wave numbers 3326, 2959, 1649, 1434, and 1240 cm ^-1 (see FIG. 9 ). ).

Experimental Example 5: Water solubility experiment and dissolution experiment of tadalafil drug using solid self-nanoemulsifying drug delivery system

Tadalafil drug solubility experiment

In order to measure the water solubility of tadalafil drugs using the solid self-nanoemulsifying drug delivery system, 10 ml of water was added to the solid self-nanoemulsifying drug delivery system (approximately 10 mg of tadalafil) and shaken for 3 days. The solution was centrifuged at 3000 g for 10 minutes, then filtered through a membrane filter paper, and the amount of tadalafil was measured using a high performance liquid chromatography (HPLC) system.

As a result, the solubility of the tadalafil drug was increased in the solid composition by the solid self-nanoemulsifying drug delivery system of Example 17 (145.7 ± 7.9 μg/ml), but when only tadalafil drug powder was applied, the water solubility of the drug was almost increased. It could be confirmed that it was not (0.3 ± 0.1 μg/ml) (see Table 7).

Tadalafil drug dissolution experiment

A solid self-nanoemulsifying drug delivery system (equivalent to 10 mg of tadalafil) was filled in a gelatin hard capsule, and an elution experiment was conducted with tadalafil powder under the following conditions. The eluate (1 ml) was collected at a given time, and the drug tadalafil was quantified under the conditions using the HPLC method of the aqueous solubility experiment. Using the second method of dissolution experiment (paddle method), a paddle rotation speed of 100 rpm, water as an eluent 900 ml, and an elution temperature of 37°C were used.

Water solubility and dissolution test of tadalafil drug using solid self-nanoemulsifying drug delivery system Water solubility (μg/ml) Dissolution rate at 30 minutes (%) Example 15 134.6 ± 6.6 50.6 ± 2.5 Example 16 136.1 ± 9.9 55.3 ± 2.3 Example 17 145.7 ± 7.9 57.2 ± 2.2 Comparative Example 4 109.8 ± 7.7 40.2 ± 1.0 Comparative Example 5 112.1 ± 5.6 43.1 ± 2.6 Comparative Example 6 115.4 ± 7.4 45.3 ± 1.2 Tadalafil powder 0.3 ± 0.1 2.9 ± 1.2

As shown in Table 7, the water solubility and dissolution test results of tadalafil drugs using a solid self-nanoemulsifying drug delivery system, when experiments were performed using only tadalafil powder in Examples 15, 16, 17 and Comparative Examples 4, 5, 6 Compared with, the water solubility and dissolution rate of the tadalafil drug were significantly increased, and in particular, in the case of Examples 15, 16, and 17 containing calcium silicate as the solidifying agent, Comparative Examples 4 and 5 including silicon dioxide as the corresponding solidifying agent. And 6, both the water solubility and dissolution rate of the tadalafil drug were significantly increased.

In addition, when looking at the difference according to the emulsification method in each of Examples 15, 16, 17 and Comparative Examples 4, 5 and 6, the average value of the water solubility of the tadalafil drug was high pressure emulsification (Example 17, Comparative Example 6)> SPG membrane Emulsification (Example 16, Comparative Example 5)> No treatment (Example 15, Comparative Example 4) increased in the order, but it was confirmed that there was no significant difference between them.

On the other hand, the dissolution rate of the drug tadalafil at 30 minutes was significant compared to the no treatment (Example 15, Comparative Example 4) during high pressure emulsification (Example 17, Comparative Example 6) and SPG membrane emulsion (Example 16, Comparative Example 5). However, it was found that there was no significant difference between the high-pressure emulsification method and the SPG membrane emulsification method (see Table 6 and Table 7).

Experimental Example 6: In vivo kinetics experiment of tadalafil drug using solid self-nanoemulsifying drug delivery system

To Sprague-Dawley (SD) rats, 5 mg/kg of tadalafil powder and a solid composition of tadalafil using the solid self-nanoemulsifying drug delivery system of Example 17 were respectively administered. Anesthetized rats were operated to intubate a polyethylene tube into the femoral artery, and tadalafil powder and solid self-nanoemulsion filled into very small capsules (#9, Suheung capsule Co.; Seoul, Korea) respectively. The solid composition was orally administered by the drug delivery system (equivalent to 10 mg of tadalafil), and 0.5 ml of blood was collected with a disposable syringe treated with heparin from the femoral artery at a certain time and centrifuged at 3,000 g for 10 minutes. 100 ug/ml of flubiprofen and 0.2 ml of acetonitrile, which are internal standard solutions, were added and centrifuged for 10 minutes at 8,000 g. With 10 μl of this solution, the concentration of the drug in plasma was measured by the above quantitative method.

Table 8 shows the pharmacokinetic parameters of the drug tadalafil, and FIG. 10 shows the drug concentration in the body in the blood over time. The total blood concentration of tadalafil drug using a solid self-nanoemulsifying drug delivery system was higher than that of tadalafil powder. Up to 1 hour and 30 minutes, compared to the powder (P<0.05), a significant increase in blood concentration was observed (see FIG. 10). This initial increase in blood concentration could be predicted to be due to an increase in the solubility and dissolution rate of tadalafil drugs by the solid self-nanoemulsifying drug delivery system.

In Table 8, 1) is the time to reach the maximum blood concentration, 2) is the maximum blood concentration, 3) is the area under the blood concentration-time curve, 4) is the drug disappearance rate constant, and 5) is the half-life of the drug. Is shown.

The solid composition of tadalafil by the solid self-nanoemulsifying drug delivery system of Example 17 according to the present invention was compared with when only tadalafil powder was applied, in the area under the blood concentration-time curve (AUC), which is an indicator of oral bioavailability. There was a significant increase. In addition, a significant increase was observed in the highest blood concentration (Cmax) (Table 8).

Therefore, it was confirmed that the solid composition of tadalafil by the solid self-nanoemulsifying drug delivery system exhibited superior oral bioavailability and increased absorption than tadalafil powder.

In vivo kinetics experiment of tadalafil drug using solid self-nanoemulsifying drug delivery system (parameter value (the mean ± S.D, n=6)) parameter Tadalafil powder Tadalafil's solid self-nano emulsion
Solid composition by drug delivery system (Example 17) 1) Tmax(hr) 2.33 ± 1.21 0.92 ± 0.58 2) Cmax(ng/ml) 92.5 ± 18.7 657.5 ± 80.2 3) AUC(hr×ng/ml) 707.7 ± 245.5 4486.3 ± 1714.5 4) Kel (hr-1) 0.10 ± 0.03 0.13 ± 0.10 5) t1/2 (hr) 7.02 ± 3.14 4.99 ± 2.44

* Compared to the drug powder, although the examples have been described by a limited drawing such as P <0.05 or more, a person of ordinary skill in the art can apply various technical modifications and modifications based on the above. For example, even if the described techniques are performed in a different order from the described method, and/or the described components are combined or combined in a form different from the described method, or are replaced or substituted by other components or equivalents. Appropriate results can be achieved.

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

Claims (12)

Tadalafil;
A drug delivery base composition comprising an oil, a surfactant, and an auxiliary surfactant;
As a solid composition for self-nanoemulsion drug delivery of tadalafil comprising a solidifying agent,
The base composition includes 10 to 40% by weight of the oil, 10 to 70% by weight of the surfactant, and 10 to 50% by weight of the co-surfactant,
0.1 to 5 parts by weight of the tadalafil based on 100 parts by weight of the base composition; And
A solid composition for self-nanoemulsion drug delivery of tadalafil comprising 25 to 50 parts by weight of the solidifying agent based on 100 parts by weight of the base composition.
The method of claim 1,
The solid composition is orally administered, a solid composition for self-nanoemulsion drug delivery of tadalafil.
The method of claim 1,
The oil comprises at least one selected from the group consisting of cottonseed oil, corn oil, peanut oil, sesame oil, soybean oil, coconut oil, olive oil, linseed oil, mineral oil, peseol, Captax 300, and Crodamol PC. , A solid composition for self-nanoemulsification drug delivery of tadalafil.
The method of claim 1,
The surfactants are Tween 20, Tween 80, Span 20, Span 80, Labrasol, Cremophores, Transcutol P, Transcutol HP, Labrafil, Solutol HS 15, Plurol Diisostearic, Capri All 90, Capriol PGMC, lauroglycol 90, lauroglycol FCC, poloxamer 188, poloxamer 407, aconon MC 8-2, polyethylene glycol 4000, polyethylene glycol 6000 contains at least one selected from the group consisting of To, a solid composition for self-nanoemulsification of tadalafil drug delivery.
The method of claim 1,
The auxiliary surfactant is d-α-tocopheryl polyethylene glycol 1000 succinate, a solid composition for self-nanoemulsion drug delivery of tadalafil.
The method of claim 1,
The solidifying agent is a solid composition for self-nanoemulsion drug delivery of tadalafil comprising at least one selected from calcium silicate and silicon dioxide.
The method of claim 1,
The particle size of the base composition is 166.4nm to 310.9nm, tadalafil self-nanoemulsion solid composition for drug delivery.
The method of claim 1,
The solid composition further comprises one or more additives selected from the group consisting of an excipient, a diluent, a disintegrant, a colorant, and a lubricant. A solid composition for self-nanoemulsion drug delivery of tadalafil.
A method for preparing a solid composition for self-nanoemulsification drug delivery of tadalafil,
10 to 40% by weight of peseol, 10 to 70% by weight of Tween 80, and 10 to 50% by weight of d-α-tocopheryl polyethylene glycol 1000 succinate to prepare a drug delivery base composition;
Preparing a liquid self-nanoemulsifying drug delivery system by adding tadalafil to the base composition;
Emulsifying the drug delivery system with an organic solvent;
After the emulsification step, adding calcium silicate or silicon dioxide as a solidifying agent, drying and pulverizing to prepare a solid self-nanoemulsifying drug delivery system; A method for producing a solid composition for self-nanoemulsion drug delivery of tadalafil comprising a.
The method of claim 9,
The method of emulsifying the liquid self-nanoemulsifying drug delivery system is by the SPG membrane emulsification or high-pressure emulsification method, a method for producing a solid composition for self-nanoemulsification of tadalafil drug delivery.
The method of claim 9,
In the step of emulsifying the drug delivery system with an organic solvent, the organic solvent comprises at least one selected from the group consisting of acetonitrile, ethanol, and dichloromethane. Preparation of a solid composition for self-nanoemulsion drug delivery of tadalafil Way.
The method of claim 9,
In the step of drying after adding the solidifying agent, the drying method is by any one of spray drying, reduced pressure drying, and hot air drying methods, a method for preparing a solid composition for self-nanoemulsification of tadalafil drug delivery

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