WO2019245309A1

WO2019245309A1 - A sustained release pharmaceutical preparation comprising tacrolimus

Info

Publication number: WO2019245309A1
Application number: PCT/KR2019/007460
Authority: WO
Inventors: Min Young Kim; Min Soo Kim; Shin Jung Park; Jong Lae Lim
Original assignee: Chong Kun Dang Pharmaceutical Corp.
Priority date: 2018-06-22
Filing date: 2019-06-20
Publication date: 2019-12-26
Also published as: TWI762789B; JP2021526559A; JP7470161B2; KR20200000038A; CN112351773A; JP2022162149A; KR102081176B1; TW202015663A

Abstract

The present invention relates to a sustained release pharmaceutical preparation comprising, as an active ingredient, tacrolimus, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Specifically, the present invention relates to a pharmaceutical preparation which comprises a disintegrating agent to improve the dissolution rate and bioavailability of tacrolimus.

Description

A SUSTAINED RELEASE PHARMACEUTICAL PREPARATION COMPRISING TACROLIMUS

The present invention relates to a sustained release pharmaceutical preparation comprising tacrolimus, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. Specifically, the present invention relates to a pharmaceutical preparation which comprises a disintegrating agent to improve the bioavailability of tacrolimus.

Tacrolimus is a macrolide-based immunosuppressive agent with a chemical structure of the Formula 1 as follows, which is produced by Streptomyces tsukubaensis.

[Formula 1]

While tacrolimus is structurally different from cyclosporin A that is now widely used as an immunosuppressive agent, it is known to have a similar mechanism of action to cyclosporin A. Tacrolimus is used for primary therapy or alleviation therapy for tissue transplant rejection which is shown after kidney or liver transplant operation. Further, when used for primary therapy to prevent acute tissue transplant rejection or reduce the dose of corticosteroid, it is evaluated to have higher efficacy compared to cyclosporine A. Tacrolimus is also known as a pharmaceutical compound that is useful for treatment or prevention of transplant rejection, graft versus host disease caused by bone marrow transplant, auto-immune disease, inflammatory disease, or the like.

However, tacrolimus is highly insoluble in water (i.e., about 1.58 μM dissolved in water at 25℃) and, due to very poor dissolution rate, has extremely low bioavailability upon oral administration. Further, it has a wide range of the bioavailability of from 5 to 65%.

As such, as a method for increasing the dissolution rate of a tacrolimus component, a method of preparing a solid dispersion by using a water-soluble polymer such as hydroxypropyl methyl cellulose is disclosed in Korean Patent Publication No. 1995-7210. Further, a method of preparing an immediate release solid dispersion by using a polymer such as hydroxypropyl methyl cellulose and a disintegrating agent is already widely used.

An immediate release preparation of tacrolimus generally comprises sodium croscarmellose as a disintegrating agent, while a sustained released preparation comprises ethyl cellulose as a base for sustained release, not a disintegrating agent that may adversely affect delayed release.

Similarly, a sustained release preparation in the form of a solid dispersion comprising hydroxypropyl methyl cellulose and ethyl cellulose but without any disintegrating agent is disclosed in Korean Patent No. 10-0440553.

However, in case of a preparation comprising no disintegrating agent, disintegration and dissolution rate are highly affected even by a slight difference in physical properties of an active ingredient and additives, a preparation process (blending time, hardness, etc.), or the like. As such, the possibility where deviations in disintegration and dissolution rate are found among preparations is relatively high. On the other hand, in case of using a disintegrating agent, the disintegration and dissolution rate of a preparation are most largely affected by a used amount of a disintegrating agent. As such, the deviations among preparations is lower than a case of not using any disintegrating agent, so that it is possible to reproduce consistent values of the disintegration and dissolution rate.

A sustained release preparation of tacrolimus has the lower maximum plasma concentration after drug administration by about 20 to 30% compared to the immediate release preparation, while exerting AUC as constantly maintained, which allows sustained absorption of the drug.

Further, in order to enhance drug compliance in an organ transplant patient, the administration method should be simplified. The enhanced drug compliance is also necessarily required to improve the treatment efficacy.

Thus, in order to enhance the drug compliance of an organ transplant patient who takes the preparation of tacrolimus, the present inventors aimed to develop a sustained release preparation of tacrolimus which has slight deviations in absorption into a human body.

Tacrolimus is highly insoluble in water (i.e., about 1.58 μM dissolved in water at 25℃) and has a very poor dissolution rate, low correlation between administered dose and actual plasma concentration, and a low therapeutic index. Thus, there are different problems in preparation design.

In order to solve those problems, the present inventors aimed to develop a sustained release preparation which not only has an improved dissolution rate, but also shows improved plasma concentration and low relative standard deviation in pharmacokinetics (PK) test. As such, the present inventors adjusted the type and amount of a disintegrating agent, finally arriving at the present invention.

The present invention relates to a sustained release pharmaceutical preparation comprising, as an active ingredient, tacrolimus, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a disintegrating agent.

According to the present invention, tacrolimus has a chemical structure of the Formula 1 as follows:

[Formula 1]

Further, tacrolimus of the present invention may be produced by a microorganism of Streptomyces sp., or it may be chemically synthesized. It may be also in the form of non-toxic and pharmaceutically acceptable salt including alkali metal salt or alkali earth metal salt such as sodium salt, potassium salt, calcium salt, and magnesium salt; or amine salt such as ammonium salt, triethylamine salt, and N-benzyl-N-methylamine salt.

Alternatively, tacrolimus of the present invention may be a conformer or one or more stereoisomer such as optical and geometric isomer resulting from an asymmetric carbon atom or a double bond. Further, tacrolimus may also exist in the form of a hydrate or an ethanol solvate. Preferably, it may be in the form of a hydrate.

A disintegrating agent used in the present invention may be low-substituted hydroxypropyl cellulose, sodium croscarmellose, crospovidone, or sodium starch glycolate. Preferably, it is sodium croscarmellose.

The disintegrating agent may be comprised at 0.005 to 1.000% by weight based on the total weight of the preparation.

According to the present invention, by limiting the range of the disintegrating agent, the deviations in bioavailability can be reduced without affecting the sustained release of tacrolimus as an active ingredient.

The present invention also relates to a method for preparing a sustained release pharmaceutical preparation comprising, as an active ingredient, tacrolimus, a pharmaceutically acceptable salt thereof, or a hydrate thereof, including the steps of (i) adding tacrolimus hydrate, hydroxypropyl methyl cellulose, ethyl cellulose, lactose, and sodium croscarmellose to an organic solvent to prepare a solid dispersion; and (ii) blending the prepared solid dispersion with lactose and magnesium stearate.

The sodium croscarmellose may be comprised, as a disintegrating agent, in the range of from 0.005 to 1.000% by weight based on the total weight of the preparation. The present invention also relates to a sustained release pharmaceutical preparation for immunosuppression comprising tacrolimus and a disintegrating agent. As such, the preparation comprising tacrolimus and a disintegrating agent of the present invention exerts an immunosuppressive effect and can advantageously be used for the treatment and prevention of transplant rejection, graft versus host disease caused by bone marrow transplant, auto-immune disease, inflammatory disease, or the like.

The preparation prepared according to the present invention can be used as a pharmaceutical preparation for oral administration. If necessary, a pharmaceutically acceptable additive, for example, a stabilizing agent, a surfactant, a lubricant, a solubilizing agent, a buffer, a sweetening agent, a binding agent, an anti-oxidant, a filler, or the like may be further comprised.

The dosage and administration number of the pharmaceutical preparation according to the present invention can be adjusted depending on various factors such as age, condition, body weight of a patient, and severeness of a disease to be treated. Preferably, the preparation comprising tacrolimus is administered once a day.

The present invention provides a sustained release preparation which not only has an improved dissolution rate and bioavailability, but also shows improved plasma concentration and low relative standard deviation in pharmacokinetics (PK) test.

Fig. 1 represents the result of the dissolution test of Comparative Example and Examples 1 to 5.

Hereinbelow, preferred examples are given for better understanding of the present invention. However, the following examples are given only for better and easier understanding of the present invention and it is evident that the context of the present invention is not limited by the examples.

[Examples 1 to 5]

Preparation of a sustained release preparation comprising tacrolimus

A sustained release preparation comprising tacrolimus was prepared according to the following preparation method. To an organic solvent, tacrolimus hydrate, hydroxypropyl methyl cellulose, ethyl cellulose, lactose, and sodium croscarmellose were added to prepare granules, which were then dried and passed through a sieve to prepare a solid dispersion. The prepared solid dispersion was homogeneously mixed with lactose and magnesium stearate, followed by filled in a gelatin capsule.

Capsules of Examples 1 to 5 were prepared by varying the amount of sodium croscarmellose, which is a disintegrating agent, as described in Table 1 below.

Example	1	2	3	4	5
Tacrolimus hydrate	5.10mg	5.10mg	5.10mg	5.10mg	5.10mg
Lactose hydrate	487.42mg	486.50mg	485.00mg	477.50mg	462.50mg
Hypromellose	1.20mg	1.20mg	1.20mg	1.20mg	1.20mg
Ethyl cellulose	1.20mg	1.20mg	1.20mg	1.20mg	1.20mg
Sodium croscarmellose	0.08mg	1.00mg	2.50mg	10.00mg	25.00mg
Magnesium stearate	5.00mg	5.00mg	5.00mg	5.00mg	5.00mg
Weight (%) of sodium croscarmellose based on the total weight	0.02%	0.20%	0.50%	2.00%	5.00%
Total weight	500.00mg	500.00mg	500.00mg	500.00mg	500.00mg

[Test example 1]

Dissolution test

By using the capsules of Examples 1 to 5, a dissolution test was carried out according to the following conditions for dissolution test. As a Comparative Example, ADVAGRAF 5 mg extended release capsule manufactured by Astellas Pharma Korea was used.

1) Dissolution method : Korean Pharmacopoeia General test, Dissolution tests, Method 2 (Paddle method)

2) Test solution : 900 mL of solution obtained by adding hydroxypropyl cellulose (molecular weight : about 100,000) in 0.07% SLS such that it is contained at 0.005%, wherein 0.07% SLS has been adjusted to pH 4.5 with diluted phosphoric acid (3 → 50), followed by sufficient mixing

3) Temperature for dissolution : 37.0±0.5℃

4) Rotation speed : 50 rpm

1) Detector : Ultraviolet spectrophotometer (wavelength for measurement : 205 nm)

2) Column : Merck-RP 18 (4.0 x 55 mm, 3 ㎛) or a column equivalent thereto

3) Injection volume : 100 ㎕

4) Flow rate : 1.2 mL/min

5) Column temperature : Constant temperature near 60℃

6) Sample temperature : Constant temperature near 10℃

7) Mobile phase: Acetonitrile, tert-butyl methyl ether, and 6 mM phosphoric acid (430 : 50 : 520)

Results of the dissolution test are shown in Table 2 below and Fig. 1.

Time (hr)	0.16	0.25	0.50	0.75	1	1.5	2	3
Comparative Example	9.9%	15.4%	28.4%	42.0%	51.0%	62.3%	68.4%	75.0%
Example 1	9.4%	15.9%	38.0%	51.4%	58.1%	66.0%	69.7%	73.1%
Example 2	9.2%	20.4%	46.2%	57.6%	62.7%	68.6%	71.6%	73.9%
Example 3	17.1%	30.9%	53.1%	61.7%	66.0%	70.7%	72.6%	74.9%
Example 4	40.7%	53.1%	67.9%	73.3%	76.2%	78.3%	78.9%	79.8%
Example 5	46.1%	58.4%	70.0%	73.9%	75.0%	76.4%	76.4%	76.3%

As it is shown in Table 2 above and Fig. 1, the conditions for dissolution test as used are the conditions allowing the confirmation of a dissolution pattern of a sustained release preparation (i.e., conditions set in accordance with the guidelines for setting the dissolution standard of an oral medicinal drug described in Korean Pharmacopoeia), where about 20 to 30%, 50%, and 80% of a dissolution rate should be confirmed. It was confirmed that Examples 1 to 3 have a sustained release dissolution pattern. However, Examples 4 and 5 exhibited initial immediate dissolution, which is not appropriate as a sustained release dissolution pattern.

[Test example 2]

Pharmacokinetics (PK) test

A pK test was carried out for Example 1 and Comparative Example.

1) Comparative Example : ADVAGRAF 5 mg extended release capsule manufactured by Astellas Pharma Korea

2) Subjects: 50 in total

3) Design : 2 x 2 crossover study

4) Method : All subjects have a high-fat breakfast with at least 900 Kcal and at least 35% fat, within 20 minutes from 8:30 AM, followed by taking a test drug with 150 mL of water 30 minutes after starting the meal

5) Blood sampling : 17 points in total - immediately before the drug administration, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours after the administration

6) Substance to be analyzed : Measurement of the concentration of tacrolimus in blood

Results of the test are shown in Table 3 below.

	AUC (ng·hr/mL)		Cmax (ng/mL)		Tmax (hr)
	Comparative Example	Example 1	Comparative Example	Example 1	Comparative Example	Example 1
Mean	118.76	125.95	6.02	5.83	4.16	5.39
Standard deviation (SD)	47.94	43.65	2.23	1.75	1.73	1.98
Relative standard deviation (RSD)	40.4%	34.7%	37.0%	30.0%	41.6%	36.7%

As it is shown in Table 3 above, it was confirmed that the deviation in AUC and Cmax is smaller in Example 1 compared to the deviation of Comparative example. Since dosage and administration of tacrolimus depend on body weight and condition of a patient, the consistent absorption in body is much more important in comparison to other pharmaceuticals.

Because the RSD of AUC and Cmax in Comparative example were about 16% and 23% higher than Example 1, respectively. As such, it was found that Example 1 exerts more consistent absorption in body than Comparative example.

Tacrolimus has a low correlation between dosage and actual plasma concentration, as well as a low therapeutic index. As such, it is very important to provide a preparation having a low RSD.

Claims

A sustained release pharmaceutical preparation comprising, as an active ingredient, tacrolimus, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a disintegrating agent.
The sustained release pharmaceutical preparation according to Claim 1, characterized in that the disintegrating agent is comprised in the range of from 0.005 to 1.000% by weight based on the total weight of the preparation.
The sustained release pharmaceutical preparation according to Claim 1, characterized in that the disintegrating agent is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium croscarmellose, crospovidone, and sodium starch glycolate.
The sustained release pharmaceutical preparation according to Claim 3, characterized in that the disintegrating agent is sodium croscarmellose.
A method for preparing a sustained release pharmaceutical preparation comprising, as an active ingredient, tacrolimus, a pharmaceutically acceptable salt thereof, or a hydrate thereof, including the steps of:

- adding tacrolimus hydrate, hydroxypropyl methyl cellulose, ethyl cellulose, lactose, and sodium croscarmellose to an organic solvent to prepare a solid dispersion; and

- blending the prepared solid dispersion with lactose and magnesium stearate.
The method for preparing a sustained release pharmaceutical preparation according to Claim 5, characterized in that the sodium croscarmellose is comprised in the range of from 0.005 to 1.000% by weight based on the total weight of the preparation.