WO2022075760A1 - Pharmaceutical composition including apremilast - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition including apremilast or a pharmaceutically acceptable salt thereof, and may provide an oral pharmaceutical composition with improved bioavailability by using a specific excipient to solve, unlike formulations on the market, delays in disintegration time and dissolution rate that occur due to curing and cross-linking occurring over time when exposed to temperature and humidity.

Description

Pharmaceutical composition containing apremilast

The present invention relates to a pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salt thereof. More specifically, by using a specific excipient, it is possible to provide a pharmaceutical composition with significantly improved disintegration and dissolution delay over time.

Unlike existing DMARD (Disease-Modifying Anti-Rheumatic Drug) and biologic drugs, Apremilast increases the intracellular level of cAMP by inhibiting the intracellular enzyme PDE4 (Phosphodiesterase-4), thereby increasing TNF-α, IL- 23 and modulates the inflammatory response by modulating other inflammatory mediators. According to Korean Patent Registration No. 997001, Apremilast is related to depression, asthma, allergic rhinitis, inflammation, inflammatory skin disease, psoriasis, atopic dermatitis, contact dermatitis, rheumatoid arthritis, and arthritis through this inflammatory response control. Disorders, osteoarthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, inflammatory bowel disease, Crohn's disease, Behcet's disease, ulcerative colitis or colitis are disclosed.

Apremilast, under the product name of Otezla ^® , was approved by the US FDA in 2014 and the Korea Food and Drug Administration in November 2017 as 'Active cases in adults who do not respond adequately to or intolerant to previous DMARD therapy. It has been approved in doses ranging from 10 mg, 20 mg, and 30 mg for the treatment of adenoarthritis and moderate to severe plaque psoriasis in adult patients subject to phototherapy and systemic treatment. It is marketed in the form of an immediate release tablet, administered in 30 mg doses every 12 hours.

However, when administered orally, apremilast has a bioavailability of about 73% and is a poorly soluble substance that is difficult to dissolve in water belonging to BCS class IV. Disintegration time and dissolution rate may be lowered due to cross-linking, etc., so the stability of the formulation should not change during distribution and storage so that it exerts a certain medicinal effect. For this purpose, it is necessary to select the crystalline form of apremilast, the main ingredient, or to reduce the particle size or to mix with appropriate additives.

The dosage form of Otezla tablet currently on sale is disclosed in Korean Patent Registration No. 2035362 and Korean Patent Application No. 10-2019-7030218, which is a divisional application thereof. Due to the various characteristics of the active drug substance to be formulated, the dosage form is typically Disclosed are formulations using 50-65% by weight of lactose hydrate of the total composition as filler, stating that pharmaceutical excipients uniquely adapted to the active drug substance are required to achieve advantageous physical and pharmaceutical properties.

However, in the case of the above formulations currently on the market, the disintegration time and dissolution rate were delayed due to the occurrence of curing and crosslinking when exposed to temperature and humidity over time.

[Prior art literature]

[Patent Literature]

(Patent Document 1) Registered Patent Publication No. 10-0997001

(Patent Document 2) Registered Patent Publication No. 10-2035362

(Patent Document 3) Patent Publication No. 10-2019-0120418

Accordingly, the present inventors studied a method for improving the disintegration and dissolution delay of current commercial products containing apremilast as a main component when exposed to temperature and humidity. However, when exposed to high temperature and humidity, the surface and internal matrix structure of the tablet cross-link or harden more densely. As a result, there is a problem that the ability to dissolve the main ingredient is reduced due to the decrease in the ability to penetrate into the tablet, the swelling of the tablet, the decrease in wetting power, and as a result, the disintegration time is delayed. When using , it was confirmed that such a problem can be solved, and the present invention was completed.

Accordingly, the present invention aims to provide an oral formulation containing apremilast as a main component, and contains apremilast, and among low-substituted hydroxypropyl cellulose and mannitol, sorbitol, and pregelatinized starch. It is a specific problem to provide an oral formulation using one or more selected excipients.

In order to solve the above problems, the present invention discloses the following means.

apremilast or a pharmaceutically acceptable salt thereof; low-substituted hydroxypropyl cellulose; And it provides an oral pharmaceutical composition comprising one or more excipients selected from mannitol, sorbitol, and pregelatinized starch.

The low-substituted hydroxypropyl cellulose may be 3% to 40% of the total weight of the total composition.

The mannitol may be 10% to 50% of the total weight of the total composition.

The sorbitol may be 10% to 50% of the total weight of the total composition.

The pregelatinized starch may be 5% to 50% of the total weight of the total composition.

The oral pharmaceutical composition may further include one or more additives selected from a filler, a disintegrant, a lubricant, an adsorbent, and a coating agent.

In one embodiment, the oral pharmaceutical composition of the present invention may be a tablet used for preventing and treating diseases that are improved by inhibiting TNF-α production or inhibiting PDE4.

The oral pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salt thereof of the present invention does not delay disintegration and dissolution even when exposed to high temperature and humidity as time elapses after tablet preparation by using a specific excipient. It has the characteristic of solving the problems of commercial products.

1 is a graph showing the results of the initial dissolution test of the stability test.

2 is a graph showing the results of the dissolution test after 8 weeks of storage in the stability test.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is those well known and commonly used in the art.

In one aspect, the present invention relates to an oral pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salt thereof as a main component.

The apremilast is (+)-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4-acetylaminoisoindoline-1 having the following structure ,3-dione is a known substance and can be prepared according to a known method.

The pharmaceutically acceptable salts include conventional acid addition salts, for example, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, acetic acid, formic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid. , cinnamic acid, oleic acid, tannic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, gluconic acid, glucaronic acid, saccharic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid , hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid. In addition, the salt may be in the form of a conventional metal salt, for example, an alkali metal salt such as lithium, sodium, or potassium; alkaline earth metal salts such as calcium or magnesium salts; or chromium salts.

In the pharmaceutical composition of the present invention, an excipient is further included in addition to the main ingredient, apremilast. Such an excipient may be a material selected from at least one selected from mannitol, sorbitol, and pregelatinized starch along with low-substituted hydroxypropyl cellulose.

The low-substituted hydroxypropyl cellulose is 3% to 40% of the total weight of the composition, the mannitol is 10% to 50% of the total weight of the composition, and the sorbitol is 10% to 50% of the total weight of the composition, The pregelatinized starch may be included in an amount of 5% to 50% of the total weight of the total composition.

The pharmaceutical composition of the present invention may be prepared according to a commonly used formulation method by adding a pharmaceutically acceptable additive. Such additives may include excipients, disintegrants, lubricants, glidants, coating agents, and the like.

The excipient may include microcrystalline cellulose and the like, and may be included in an amount of 10% to 50% of the total weight of the total composition.

The disintegrant may include corn starch, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium, and the like. Preferably, it is croscarmellose sodium, and may be included in 1% to 5% of the total weight of the total composition.

The lubricant may include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil, magnesium stearate, and the like. Preferably it is magnesium stearate, and may be included in 0.5% to 3% of the total weight of the total composition.

Colloidal silicon dioxide may be used as the fluidizing agent, and may be included in 1% to 5% of the total weight of the total composition.

The coating agent may include hypromellose, polyvinyl alcohol, polyethylene glycol, talc, and the like. Preferably, it is a combination of polyvinyl alcohol, polyethylene glycol, and talc, and may be included in an amount of 30-50 wt%, 10-30 wt%, and 10-20 wt%, respectively, of the total coating agent.

The coating agent may further include a colorant, and may include, but is not limited to, titanium dioxide and iron oxide. Suitable colorants may be mixed to obtain the desired color of the coating formulation.

A more preferred embodiment of the present invention provides an excipient other than apremilast, which is the main component, of a three-component system of low-substituted hydroxypropyl cellulose, mannitol, and pregelatinized starch, or low-substituted hydroxypropyl cellulose, sorbitol, and pregelatinized starch. It may be a three-component system. By substituting the above three-component system instead of using lactose, the effect on disintegration and dissolution rate over time is minimized.

The oral pharmaceutical composition of the present invention is a solid preparation for oral administration, tablets, granules, capsules, liquid preparations for oral administration, and may be in the form of suspensions, internal solutions, emulsions, syrups, and the like. Preferably, it may be in the form of a tablet.

The oral pharmaceutical composition of the present invention may be prepared by a method well known in the pharmaceutical field. Specifically, it may be prepared by a direct tableting method, a dry granulation method, or a wet granulation method.

The preferred dosage of the oral pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for desirable effects, the oral pharmaceutical composition of the present invention may be administered in an amount of 10 to 100 mg per day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.

The oral pharmaceutical composition of the present invention is useful for preventing and treating diseases that are improved by inhibiting TNF-α production or inhibiting PDE4. Such diseases include depression, asthma, allergic rhinitis, inflammation, chronic lung inflammatory disease, inflammatory skin disease, psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, rheumatoid arthritis, arthritis-related disorders, osteoarthritis, systemic lupus erythematosus , chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, inflammatory bowel disease, Crohn's disease, Behcet's disease, ulcerative colitis, colitis, chronic obstructive pulmonary disease, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), etc. However, the present invention is not limited thereto.

In another aspect, the present invention inhibits TNF-α production comprising administering the oral pharmaceutical composition according to the above in a therapeutically effective amount to mammals, including humans, or by inhibiting PDE4 to prevent disease or It relates to treatment methods.

In another aspect, the present invention relates to the use of an oral pharmaceutical composition for preventing or treating a disease that is improved by inhibiting TNF-α production or inhibiting PDE4.

Matters mentioned in the oral pharmaceutical composition, prevention or treatment method, and use of the present invention are equally applied as long as they do not contradict each other.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

Examples 1 to 5.

According to the components and contents of Table 1 below, tablets containing apremilast as a main component were prepared. Specifically, a tablet was prepared by mixing a component other than magnesium stearate among the following components, mixing magnesium stearate with the mixture, and then compressing it into a single-layer tablet using a tablet press.

division	Example 1		Example 2		Example 3		Example 4		Example 5
Raw material name	mg/tablet	%	mg/tablet	%	mg/tablet	%	mg/tablet	%	mg/tablet	%
apremilast	30	10.0%	30	10.0%	30	10.0%	30	10.0%	30	10.0%
mannitol	150	50.0%	30	10.0%	-	-	-	-	-	-
sorbitol	-	-	-	-	150	50.0%	30	10.0%	-	-
Low-substituted hydroxypropyl cellulose	39	13.0%	93.9	31.3%	39	13.0%	93.9	31.3%	33.9	11.3%
pregelatinized starch	-	-	-	-	-	-	-	-	150	50.0%
Microcrystalline Cellulose	58.5	19.5%	123.6	41.2%	58.5	19.5%	123.6	41.2%	63.6	21.2%
Croscarmellose Sodium	9	3.0%	9	3.0%	9	3.0%	9	3.0%	9	3.0%
colloidal silicon dioxide	9	3.0%	9	3.0%	9	3.0%	9	3.0%	9	3.0%
magnesium stearate	4.5	1.5%	4.5	1.5%	4.5	1.5%	4.5	1.5%	4.5	1.5%
Sum	300	100%	300	100%	300	100%	300	100%	300	100%

Examples 6 to 10.

According to the components and contents in Table 2 below, tablets containing apremilast as a main component were prepared. Specifically, a tablet was prepared by mixing a component other than magnesium stearate among the following components, mixing magnesium stearate with the mixture, and then compressing it into a single-layer tablet using a tablet press.

division	Example 6		Example 7		Example 8		Example 9		Example 10
Raw material name	mg/tablet	%	mg/tablet	%	mg/tablet	%	mg/tablet	%	mg/tablet	%
apremilast	30	10.0%	30	10.0%	30	10.0%	30	10.0%	30	10.0%
mannitol	-	-	90	30.0%	90	30.0%	-	-	-	-
sorbitol	-	-	-	-	-	-	90	30.0%	90	30.0%
Low-substituted hydroxypropyl cellulose	108.9	36.3%	33.9	11.3%	10	3.3%	33.9	11.3%	10	3.3%
pregelatinized starch	15	5.0%	35.1	11.7%	35.1	11.7%	35.1	11.7%	35.1	11.7%
Microcrystalline Cellulose	123.6	41.2%	88.5	29.5%	112.4	37.5%	88.5	29.5%	120.65	40.2%
Croscarmellose Sodium	9	3.0%	9	3.0%	9	3.0%	9	3.0%	9	3.0%
colloidal silicon dioxide	9	3.0%	9	3.0%	9	3.0%	9	3.0%	3	1.0%
magnesium stearate	4.5	1.5%	4.5	1.5%	4.5	1.5%	4.5	1.5%	2.25	0.8%
Sum	300	100%	300	100%	300	100%	300	100%	300	100%

Example 11.

According to the components and contents in Table 3 below, tablets containing apremilast as a main component were prepared. Specifically, among the following components, components except for a part of magnesium stearate are mixed, the mixture is dry granulated, the dry granulated material is sized, and the magnesium stearate remaining in the sized product is mixed and lubricated, followed by a single-layer tablet using a tableting machine Tablets were prepared by tableting with

division	Example 11
Raw material name	mg/tablet	%
apremilast	30	10.0%
mannitol	90	30.0%
sorbitol	-	-
Low-substituted hydroxypropyl cellulose	33.9	11.3%
pregelatinized starch	35.1	11.7%
Microcrystalline Cellulose	88.5	29.5%
Croscarmellose Sodium	9	3.0%
colloidal silicon dioxide	9	3.0%
magnesium stearate	4.5	1.5%
Sum	300	100%

Comparative Examples 1 to 6.

According to the components and contents of Tables 4 and 5 below, tablets containing apremilast as a main component were prepared. Specifically, a tablet was prepared by mixing a component other than magnesium stearate among the following components, mixing magnesium stearate with the mixture, and then compressing it into a single-layer tablet using a tableting machine.

division	Comparative Example 1		Comparative Example 2		Comparative Example 3
Raw material name	mg/tablet	%	mg/tablet	%	mg/tablet	%
apremilast	30	10.0%	30	10.0%	30	10.0%
lactose hydrate	180	60.0%	100	33.3%	180	60.0%
Microcrystalline Cellulose	78.75	26.3%	158.75	52.9%	44.85	15.0%
Croscarmellose Sodium	9	3.0%	9	3.0%	9	3.0%
magnesium stearate	2.25	0.8%	2.25	0.8%	2.25	0.8%
Low-substituted hydroxypropyl cellulose	-	-	-	-	33.9	11.3%
mannitol	-	-	-	-	-	-
colloidal silicon dioxide	-	-	-	-	-	-
Sum	300	100%	300	100%	300	100%

division	Comparative Example 4		Comparative Example 5		Comparative Example 6
Raw material name	mg/tablet	%	mg/tablet	%	mg/tablet	%
apremilast	30	10.0%	30	10.0%	30	10.0%
lactose hydrate	-	-	-	-	-	-
Microcrystalline Cellulose	224.85	75.0%	168.75	56.3%	215.85	72.0%
Croscarmellose Sodium	9	3.0%	9	3.0%	9	3.0%
magnesium stearate	2.25	0.8%	2.25	0.8%	2.25	0.8%
Low-substituted hydroxypropyl cellulose	33.9	11.3%	-	-	33.9	11.3%
mannitol	-	-	90	30.0%	-	-
colloidal silicon dioxide	-	-	-	-	9	3.0%
Sum	300	100%	300	100%	300	100%

Experimental Example 1. Disintegration test

The tablets prepared in Examples 1 to 10, the tablets prepared in Comparative Examples 1 to 6, and the commercially available Otezla tablets 30mg and 20mg were used as Comparative Examples 7 and 8, respectively, and packaged in PTP, and then stored at 60° C. and at the beginning of the stability test. The disintegration time after 8 weeks was compared. Specifically, the disintegration time evaluation using a disintegration tester was performed according to the disintegration test method of the Korean Pharmacopoeia general test method. The time at which more than 80% of the disintegration was measured as the disintegration time, and the results are shown in Tables 6 and 7.

division	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7	Example 8	Example 9	Example 10
Early	52''	59''	57''	53''	1'02''	57''	51''	56''	52''	56''
after 8 weeks	5'22''	5'39''	5'27''	4'58''	5'09''	4'57''	4'39''	4'46''	4'41''	4'48''
division	Comparative Example 1	Comparative Example 2	Comparative Example 3	Comparative Example 4	Comparative Example 5	Comparative Example 6	Comparative Example 7	Comparative Example 8
Early	1'12''	1'09''	1'02''	57''	59''	56''	1'19''	1'03''
after 8 weeks	12'28''	12'16''	11'12''	8'07''	10'29''	8'13''	13'15''	10'03''

<Disintegration test using a disintegrator>

division	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7	Example 8	Example 9	Example 10
Early	1'32''	1'37''	1'28''	1'30''	1'29''	1'34''	1'27''	1'30''	1'26''	1'29''
after 8 weeks	10'28''	10'13''	9'55''	9'57''	10'28''	9'56''	9'12''	9'31''	9'14''	9'33''
division	Comparative Example 1	Comparative Example 2	Comparative Example 3	Comparative Example 4	Comparative Example 5	Comparative Example 6	Comparative Example 7	Comparative Example 8
Early	1'36''	1'32''	1'34''	1'27''	1'35''	1'31''	1'41''	1'21''
after 8 weeks	22'45''	23'19''	21'31''	16'57''	19'56''	17'11''	25'30''	22'07''

<Disintegration test using dissolution device>

From the results in Tables 6 and 7, in the case of tablets using lactose hydrate, it was confirmed that the disintegration time was delayed as time elapsed, and in the case of the tablet of the present invention, it was confirmed that the disintegration time delay did not occur.

In addition, it was confirmed that, even when the tablets prepared according to Example 11 were tested in the same manner, there was no delay in disintegration time after 8 weeks.

Experimental Example 2. dissolution test

The tablets prepared in Examples 1 to 10, the tablets prepared in Comparative Examples 1 to 6, and the commercially available Otezla tablets 30mg and 20mg were used as Comparative Examples 7 and 8, respectively, and packaged in PTP, and then stored at 60° C. and at the beginning of the stability test. The dissolution test was compared after 8 weeks. Specifically, the test was performed at 50 rpm for 60 minutes using 900 mL of 37 °C water test solution containing 0.3% SLS, and samples were collected at 15 minutes, 30 minutes, and 60 minutes and analyzed by HPLC. The results are shown in Tables 8 and 9 and FIGS. 1 and 2 .

Early	Dissolution rate (%)
Dissolution time (min)	0 minutes	15 minutes	30 minutes	60 minutes
Example 1	0	42.5	55.9	64.7
Example 2	0	46.9	58.6	68.3
Example 3	0	44.2	56.8	64.7
Example 4	0	47.2	58.4	65.3
Example 5	0	46.9	60.1	66.9
Example 6	0	48.1	61.5	68.7
Example 7	0	51.2	63.5	71.8
Example 8	0	46.2	60.8	68.5
Example 9	0	52.8	64.3	70.3
Example 10	0	45.8	59.1	68.2
Comparative Example 1	0	43.7	56.2	65.8
Comparative Example 2	0	46.7	58.1	67.8
Comparative Example 3	0	44.9	58.6	67.1
Comparative Example 4	0	50.3	64.5	70.5
Comparative Example 5	0	44.7	58.9	68.7
Comparative Example 6	0	19.5	64.1	69.3
Comparative Example 7	0	44.9	56.8	66.8
Comparative Example 8	0	48.2	60.2	69.4

<Result of initial dissolution test of stability test>

60°C/85%RH after 8 weeks	Dissolution rate (%)
Dissolution time (min)	0 minutes	15 minutes	30 minutes	60 minutes
Example 1	0	39.6	51.8	62.5
Example 2	0	42.9	54.1	64.1
Example 3	0	40.9	52.7	62.9
Example 4	0	43.5	56.7	64.0
Example 5	0	43.9	57.5	64.0
Example 6	0	45.2	58.6	65.2
Example 7	0	48.9	62.1	70.9
Example 8	0	44.8	58.4	66.3
Example 9	0	48.5	62.4	69.1
Example 10	0	44.5	57.9	66.5
Comparative Example 1	0	16.8	34.7	48.3
Comparative Example 2	0	18.5	36.7	52.4
Comparative Example 3	0	17.5	36.9	53.8
Comparative Example 4	0	22.3	42.9	56.8
Comparative Example 5	0	18.9	39.8	55.2
Comparative Example 6	0	21.4	42.1	55.3
Comparative Example 7	0	17.4	35.4	50.3
Comparative Example 8	0	21.5	40.2	52.9

<Result of dissolution test after 8 weeks of storage at 60℃/85%RH stability test>

From the results of Tables 8 and 9 and FIGS. 1 and 2, in the case of tablets using lactose hydrate, the dissolution rate decreased as time passed after the preparation of the tablet, but in the case of the tablet of the present invention, it was confirmed that the dissolution rate did not decrease even with the passage of time. .

In addition, it was confirmed that the dissolution rate did not decrease after 8 weeks even when the tablets prepared according to Example 11 were tested in the same manner.

The oral pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salt thereof of the present invention is used for the treatment of diseases related to inflammatory reactions, in particular, the prevention of psoriasis, psoriatic arthritis, dermatitis, sarcoidosis, and Behcet's disease. Or, since it exhibits a therapeutic effect, it can be used as a drug in the pharmaceutical industry and medical field.

Claims (7)

1. apremilast or a pharmaceutically acceptable salt thereof;

   low-substituted hydroxypropyl cellulose; and

   An oral pharmaceutical composition comprising at least one filler selected from mannitol, sorbitol, and pregelatinized starch.
2. The oral pharmaceutical composition according to claim 1, wherein the low-substituted hydroxypropyl cellulose is 3% to 40% of the total weight of the total composition.
3. The oral pharmaceutical composition according to claim 1, wherein the mannitol is 10% to 50% of the total weight of the composition.
4. The oral pharmaceutical composition according to claim 1, wherein the sorbitol is 10% to 50% of the total weight of the total composition.
5. The oral pharmaceutical composition according to claim 1, wherein the pregelatinized starch is 5% to 50% of the total weight of the total composition.
6. The oral pharmaceutical composition according to any one of claims 1 to 5, further comprising at least one additive selected from a filler, a disintegrant, a lubricant, an adsorbent, and a coating agent.
7. According to claim 1, wherein the composition is

   apremilast or a pharmaceutically acceptable salt thereof;

   low-substituted hydroxypropyl cellulose;

   pregelatinized starch; and

   mannitol or sorbitol

   An oral pharmaceutical composition comprising a.

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