JP2021088591A - Pharmaceutical formulation comprising one or more fumaric acid esters in erosion matrix - Google Patents

Abstract

To provide a pharmaceutical composition that is designed to deliver fumaric acid esters in a manner that is prolonged, sustained, retarded, slow and/or delayed.SOLUTION: Provided is a pharmaceutical formulation comprising an erosion matrix comprising one or more fumaric acid esters as well as one or more rate-controlling agents, where erosion of the erosion matrix permits controlled release of the fumaric acid ester(s).SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical preparation containing an erosion matrix. More specifically, the present invention relates to a pharmaceutical preparation containing a matrix that can be eroded, which comprises one or more fumaric acid esters and one or more rate-determining substances (where the erosion of the erosion matrix is Allows controlled or sustained release of the fumaric acid ester).

Psoriasis is a chronic skin disease with a high rate of genetic predisposition. The disease fluctuates between acute relapse and complete rest. Patients with psoriasis may have severe disability due to the appearance characteristics of the disease. This affects all parts of life, such as work history and personal life.

The therapeutic potential available up to the therapy of the present invention is limited, especially in patients with moderate to severe psoriasis, all of which provide only temporary and short-term improvement and / or severe adverse effects. / Has side effects. Due to the high recurrence rate of psoriasis, the majority of patients must receive long-term treatment.

Fumarate has been used to treat moderate to severe psoriasis for over 30 years. In 1994, Fumaderm® initial / Fumaderm®, a defined mixture of dimethyl fumarate and monoethyl fumarate (salt), was approved in Germany. Fumaderm® enteric coated tablets contain the following active ingredients: dimethyl fumarate 120 mg; ethyl fumarate, calcium salt 87 mg; ethyl hydrogen fumarate, magnesium salt 5 mg; hydrogen fumarate Ethyl, zinc salt 3 mg, and other ingredients: croscarmellose sodium, talc, magnesium stearate, colorants E 171 and E 132, methacrylic acid-methylmethacrylic acid-copolymer (1: 1), methacrylic acid- Ethyl Acrylate-Copolymer (1: 1), Macrogol 6000, Simeticon, Povidone, Triethyl Citrate, Microcrystalline Cellulose, Highly Dispersed Silicon Dioxide [Summary of Product Characteristics, Fumaderm®, January 2009]. To date, Fumaderm® represents approximately 66% of all prescriptions for systemic treatment of psoriasis in Germany. However, due to the high frequency of side effects, some patients discontinue early in treatment. It is believed that the side effects of the gastrointestinal tract and at least some of the flushing can be explained by the release properties of the prescription formulation that results in high local concentrations in the intestine.

We have improved treatment regimens with controlled, long-lasting, delayed, slow, and / or delayed active ingredients compared to commercial products ( Delayed) It is believed that it can be obtained by administering a pharmaceutical composition designed to be delivered.

Fumarate esters such as dimethyl fumarate can be decomposed and hydrolyzed. For example, dimethyl fumarate tends to be more easily hydrolyzed in alkaline / less acidic environments than in more acidic environments (Litjens et al, "In vitro pharmacokinetics of anti-psoriatic humaric acid ester", BMC Pharmacology 2004, 4). :twenty two). That is, dimethyl fumarate is considered to be more likely to be hydrolyzed in the small intestine than in the gastric ventricle. In addition to the above pH effect, esterase is thought to be involved in the hydrolysis of fumaric acid ester.

WO 2006/037342 discloses a controlled release pharmaceutical composition containing a fumaric acid ester as an active agent, the controlled release profile of which results in a reduction in GI (gastrointestinal) related side effects.
(Purpose of the present invention)

One embodiment of the present invention is a controlled or sustained release pharmaceutically containing fumaric acid ester as an active agent, which exhibits reduced GI (gastrointestinal tract) related side effects and / or reduced red tide as compared to a prior art Fumaderm® formulation. The purpose is to provide a formulation. Furthermore, it is an object of the present invention to provide a controlled or sustained release pharmaceutical preparation containing a fumaric acid ester as an active substance, which has an improved pharmacokinetic profile as compared with the conventional preparation. In particular, it is an object of the present invention to provide a controlled or sustained release pharmaceutical preparation containing a fumaric acid ester as an active substance, which shows a reduction in variability of _{AUC and / or C max} values as compared with a controlled release preparation of the prior art. And. In particular, it is an object of the present invention to provide a controlled or sustained release pharmaceutical preparation containing a fumaric acid ester as an active substance, which exhibits appropriate relative bioavailability as compared with, for example, a conventional Fumaderm® preparation. In particular, the present invention provides a controlled or sustained release pharmaceutical formulation containing a fumaric acid ester as an active agent, which exhibits reduced variability in _{AUC and / or C max} values as compared to, for example, the Fumaderm® formulation of the prior art. The purpose is to do.

(Summary of invention)
We have found that controlled or sustained release of one or more fumaric acid esters is obtained with erosion matrix tablets. The prolongation of API release can be regulated by the amount of rate-determining polymer relative to other components, and it is believed that high local concentrations of API can be avoided or reduced.

Controlled or sustained release of one or more fumaric acid esters at pharmaceutically relevant levels is obtained from smaller tablets compared to Fumaderm® to improve patient compliance and for a given time after reaching the absorption site. It has been found that high local concentrations of API can be avoided while ensuring that the active substance is delivered within as completely and reliably as possible, while at the same time resulting in reduced variability compared to Fumaderm®.

The pharmaceutical product of the present invention was found to have a good in vitro / in vivo correlation. In one aspect, the in vitro / in vivo correlation is determined by comparing the time at which 80% of the fumaric acid ester is released from the formulation with the C _{max measured in vivo after administration of the formulation.}

In addition, controlled release of API by erosion of the matrix is believed to reduce pre-absorption API degradation by reducing or minimizing exposure of API to hydrolysis in the gastrointestinal tract.

In the first aspect, this maintains the therapeutic effect while substantially reducing the unwanted side effects or adverse effects known for Fumaderm®, or tolerability compared to Fumaderm®. Is considered to improve.

In another aspect, it is believed that this can improve the therapeutic effect compared to Fumaderm® while reducing the unwanted side effects of psoriasis treatment with prior art Fumaderm®.

In another aspect, it is believed that this can maintain tolerance to Fumaderm® and at the same time improve the therapeutic effect.

In another aspect, it is believed that this can improve the tolerance to Fumaderm® and at the same time improve the therapeutic effect.

In a further aspect, in the first aspect, the present invention relates to pharmaceutical formulations in the form of an erosion matrix, including:
i) as active substance, 10% to 80% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or its pharmaceutically acceptable salt, and
ii) 1 to 50% by weight of 1 or more rate-determining substances,
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

In one aspect, the invention relates to pharmaceutical formulations in the form of an erosion matrix, including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof, and
ii) 1 or more rate-determining substances of 3-40% by weight;
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

In one aspect, the invention relates to a pharmaceutical formulation in the form of a monolithic erosion matrix, including:
i) as active substance, 10 to 80 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof, and
ii) 1 to 50% by weight of 1 or more rate-determining substances,
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

In one aspect, the invention relates to a pharmaceutical formulation in the form of a monolithic erosion matrix, including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof, and
ii) 1 or more rate-determining substances of 3-40% by weight;
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

In one aspect, the invention relates to pharmaceutical formulations in the form of an erosion matrix, including:
A) Tablet cores including:
i) as active substance, 40 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 4 to 6% by weight rate-determining substance,
iii) 35-55 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one aspect, the invention relates to pharmaceutical formulations in the form of an erosion matrix, including:
A) Tablet cores including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one aspect, the invention relates to a pharmaceutical formulation in the form of a monolithic erosion matrix, including:
A) Tablet cores including:
i) as active substance, 40 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 4 to 6% by weight rate-determining substance,
iii) 35-55 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one aspect, the invention relates to a pharmaceutical formulation in the form of a monolithic erosion matrix, including:
A) Tablet cores including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one aspect, the invention relates to pharmaceutical formulations in the form of an erosion matrix, including:
A) Tablet cores including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one aspect, the invention relates to a pharmaceutical formulation in the form of a monolithic erosion matrix, including:
A) Tablet cores including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one aspect, the invention relates to pharmaceutical formulations in the form of an erosion matrix, including:
A) Tablet cores including:
i) 30-60% by weight dimethyl fumarate,
ii) 3-6% by weight hydroxypropyl cellulose,
iii) 35-65% by weight lactose,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumal as follows. Causes the release of dimethyl acid:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of dimethyl fumarate contained in the formulation is released, and / or within the first 3 hours after the start of the test. About 20% w / w to about 75% w / w of dimethyl fumarate contained in the preparation is released, and / or within the first 4 hours after the start of the test, the fumarate ester contained in the preparation. About 50% w / w to about 98% w / w is released and / or about 70% w / w to about 100% of the total amount of dimethyl fumarate contained in the formulation within the first 5 hours after the start of the test. % W / w is released.

In one aspect, the invention relates to a pharmaceutical formulation in the form of a monolithic erosion matrix, including:
A) Tablet cores including:
i) 30-60% by weight dimethyl fumarate,
ii) 3-6% by weight hydroxypropyl cellulose,
iii) 35-65% by weight lactose,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumal as follows. Causes the release of dimethyl acid:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of dimethyl fumarate contained in the formulation is released, and / or within the first 3 hours after the start of the test. Approximately 20% w / w to approximately 75% w / w of dimethyl fumarate contained in the formulation is released, and / or the fumarate ester contained in the formulation within the first 4 hours after the start of the test. Approximately 50% w / w to approximately 98% w / w are released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the total amount of dimethyl fumarate contained in the preparation is released.

In the context of the present invention, the term "% by weight" refers to the weight percentage of each component in a core tablet excluding an outer coating or film.

In another aspect, the present invention relates to a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) Dissolve or suspend one or both of the rate-determining substances in the form of fumaric acid esters and polymerization matrix materials in water to obtain an aqueous suspension thereof.
b) Spray the granules of fumaric acid ester with the aqueous suspension and / or binder on it for a time sufficient to obtain a homogeneous coating.
c) The resulting granules are dried and
d) If desired, the granules are sieved or ground and
e) Mix all pharmaceutically acceptable excipients and additives according to known methods to obtain tablets.
f) Film or enteric coating the tablets according to known methods, if desired;
Here, all or all of the above steps are carried out at a temperature at which the temperature of the product is 45 ° C. or lower.

For example, it is known that dimethyl fumarate can sublimate and disappear, and the sublimation is more pronounced at higher temperatures.

In some aspects, the manufacture of the pharmaceutical product of the present invention is carried out at a relatively low temperature to reduce or minimize sublimation, with few intermediate steps and minimal intervention of machine-free operating steps. These factors contribute to the ability to extend and implement the manufacturing method on a commercial scale in commercial situations. In some aspects, it has been found that the formulations of the present invention can be produced on a larger scale, such as on a scale of at least 15 kg, such as on a scale of at least 20 kg, such as on a scale of at least 30 kg.

In another aspect, the present invention relates to a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) Dissolve or suspend a rate-determining substance in the form of a polymerized matrix substance in water to obtain its aqueous suspension.
b) Spray the aqueous suspension onto the granules for a time sufficient to obtain a uniform coating on the granules of fumaric acid ester.
c) The resulting granules are dried and
d) If desired, the granules are sieved or ground and
e) Mix all pharmaceutically acceptable excipients and additives according to known methods to obtain tablets.
f) Film or enteric coating the tablets according to known methods, if desired;
Here, all or all of the above steps are carried out at a temperature at which the temperature of the product is 45 ° C. or lower.

In another aspect, the present invention relates to a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) If desired, sieve or grind the crystals of fumaric acid ester and
b) Fumaric acid ester crystals, rate-determining material in the form of a polymerization matrix material, and pharmaceutically acceptable excipients and additives are directly mixed by compression to give tablets.
c) Film and / or enteric coating of the tablet by a known method, if desired;
Here, all or all of the above steps are carried out at a temperature at which the temperature of the product is 45 ° C. or lower.

In another aspect, the pharmaceutical formulations of the present invention include psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lupus erythematosus, multiple sclerosis (MS), juvenile onset. Diabetes, Hashimoto thyroiditis, Basedow's disease, SLE (systemic lupus erythematosus), Schegren's syndrome, malignant anemia, chronic active hepatitis (rheumatoid arthritis), rheumatoid arthritis (RA), lupus nephritis, severe myasthenia, vasculitis, refractory Lupus erythematosus, spring catarrh, lupus vulgaris, lupus erythematosus, optic neuritis, pain, such as lupus erythematosus, lupus erythematosus-related pain, neuropathic pain, or sciatica / sciatica pain, organ transplantation (prevention of rejection) ), Sciatica, lipoid necrosis, or ring granuloma.

Another aspect of the invention is psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes, Hashimoto thyroid. Flame, Basedow's disease, SLE (systemic lupus erythematosus), Schegren's syndrome, malignant anemia, chronic active hepatitis (rheumatoid arthritis), rheumatoid arthritis (RA), lupus nephritis, severe myasthenia, uveitis, refractory uveitis, Spring catarrh, lupus vulgaris, scleroderma, optic neuritis, pain, such as nerve root pain, root damage-related pain, neuropathic pain, or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, Use of the pharmaceutical formulation of the present invention to produce a medicament for treating lipoid necrosis, or rheumatoid arthritis.

Another aspect of the invention is plaque, lupus erythematosus, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple arthritis, multiple sclerosis (MS), juvenile diabetes, Hashimoto thyroid. Flame, Basedow's disease, SLE (systemic lupus erythematosus), Schegren's syndrome, malignant anemia, chronic active (wolves) hepatitis, rheumatoid arthritis (RA), lupus nephritis, severe myasthenia, plasteritis, refractory sciatica, Spring catarrh, lupus vulgaris, scleroderma, optic neuritis, pain, such as radiculopathy, radiculopathy-related pain, neuropathic pain, or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, A method for treating lipoid radiculopathy or rheumatoid arthritis, which comprises orally administering an effective amount of the controlled release pharmaceutical composition of the present invention to a patient in need thereof.

Examples 16, 18, 20 using 0.1N hydrochloric acid as the lysis medium for the first 2 hours of the test, then 0.05 M phosphate buffer pH 6.8 as the lysis medium and the paddle lysing device at 100 rpm for the rest of the test time. , And 22 show the in vitro dissolution profile of the films of the invention and enteric coated erosion matrix tablets at 37 ° C. The book according to Example 23, wherein 0.1 N hydrochloric acid is used as the dissolution medium for the first 2 hours of the test, then 0.05 M phosphate buffer pH 6.8 is used as the dissolution medium and the paddle solubilizer is used at 100 rpm for the remaining test time. The in vitro dissolution profile of the film-coated erosion matrix tablet of the present invention at 37 ° C. is shown.

(Detailed description of the invention)
In the context of the present invention, the terms "API" (abbreviation for "active pharmaceutical ingredient") and the term "active substance" are used for compatibility and represent fumaric acid esters released from the pharmaceutical formulations of the present invention.

In the context of the present invention, the term "controlled or sustained release" is used under equivalent conditions (eg, in vivo studies, dose equivalent (with or without standard diet), or in vitro studies, dose equivalent, dissolution. When tested with the test equipment and operating conditions (eg, composition, volume, temperature, rotation speed, etc. of the dissolution medium used), the fumaric acid ester persists compared to the release of the commercially available product Fumaderm®. Represents release from a formulation designed for delayed, slow, and / or delayed release.

In vivo release can be tested by measuring plasma concentration at a predetermined time to obtain a plasma concentration-to-time profile of the fumaric acid ester or its metabolites, if relevant. In addition, metabolism is believed to have already occurred in the gastrointestinal tract, upon passage through the gastrointestinal mucosa, or upon primary passage through the enterohepatic circulation. Therefore, the relevant component in plasma examined when administering the fumaric acid ester would be the monoethyl ester rather than the dimethyl ester of fumaric acid.

Other tests can be used to measure or obtain measurements of the release of active substances in vivo. That is, animals (eg, mini pigs, dogs, etc.) can be used as models. The composition is administered to the animal after a period of time under observation, a blood sample is collected to determine the content of the active ingredient (or its metabolites, if any) in plasma or specific organs, or the active ingredient. Is extracted from the intestinal contents.

Another study involves the use of certain fragments of the animal or human intestine. The fragment is placed in a suitable device containing two compartments (donor and receiver) separated by the fragment and the composition is placed in a suitable medium in one compartment (donor compartment) under observation. The composition releases the active agent, which is then carried across the intestinal fragment. Therefore, at appropriate time intervals, the concentration of active substance (or metabolites, if relevant) in the receiver compartment is measured.

One of ordinary skill in the art will be able to adapt the above method to a particular composition.

For in vitro methods, well-established methods are available, especially those described in the official monograph, United States Pharmacopeia (USP) or European Pharmacopoeia. One of ordinary skill in the art will understand which method to choose and how to choose the specific conditions for conducting an in vitro study. For example, the USP specifies that in vitro tests should be performed at 37 ± 1.0, eg 37 ± 0 ° C. In one aspect, a suitable dissolution test is to use the dissolution profile at 37 ° C. as described in the US Pharmacopeia, 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test, and then 0.05 M phosphate for the remaining test time. The measurement is performed using a buffer solution pH 6.8 as a dissolution medium and a paddle dissolution device at 100 rpm. Those skilled in the art will understand how to adjust applicable conditions such as temperature, pH, paddle speed, duration, etc. In a further aspect, the in vitro dissolution test is performed as follows: using a 1 liter container and USP device II (paddle). Set the bath temperature to 37 ° C ± 0.5 ° C and the paddle speed to 100 rpm. Place one tablet in one container containing 750 ml 0.1N HCl (pH 1.2) for 2 hours. Then add 220 ml of 0.2 M sodium phosphate buffer to change the pH to 6.8. Take 1.5 ml of sample at each sampling point and analyze DMF by HPLC. HPLC parameters are as follows: Column: Phenomenex Luna C18, 50 x 4.6 mm, 3 μm; Column Oven temperature 30 ° C: Mobile phase: Methanol: 20 mM Phosphate buffer pH 3.0 (35:65 V / V) , Injection volume: 5 μl, Flow velocity: 0.8 ml / min, Detector wavelength: 210 nm, Operating time 5 min, DMF retention time 3.5 min.

In the context of the present invention, the term "relative bioavailability" refers to a comparison of the amount of drug absorbed (expressed in area under the curve (AUC)) after administration of two different formulations or reference products. In the context of the present invention, the amount of drug absorbed (expressed in AUC) can be detected in the form of the actual drug administered, or as a metabolite thereof. Relative bioavailability can be expressed as a percentage of the reference AUC, i.e. AUC%.

In the context of the present invention, the term "variability" refers to the variability of PK parameters (eg, C _max and AUC) after administration of a pharmaceutical or reference formulation. Volatility can be expressed as the coefficient of variation (CV) of the PK parameter, i.e. the standard deviation / mean ratio.

In the context of the present invention, the term "tolerability" refers to the likelihood that a subject and / or patient will tolerate a drug. In some aspects, "tolerability" is defined as early in treatment, eg, within the first 3 months of starting treatment, eg, within the first month of starting treatment, eg, within the first 2 weeks of starting treatment, For example, within the first week of starting treatment, for example, within the first 3 days of starting treatment, for example, within the first day of starting treatment, for example, after the first administration of treatment, the subject and / or patient is drugged. Expressed as a possibility to withstand. Drugs with better tolerability have fewer side effects in the subject and / or patients than drugs with poor tolerability.

In the context of the present invention, the term "substantially absent" refers to a level of about 1% or less, such as about 0.5% or less, such as about 0.3% or less, such as about 0.0%.

In the context of the present invention, the terms "rate-determining substance" and "rate-determining substance in the form of a polymerization matrix substance" are used for compatibility to delay / sustain and / or prolong the release of an active substance in vivo and / or in vitro. Represents a drug that can be made to.

As mentioned above, the in vivo and / or in vitro release of the active substance is prolonged, slowed, and / or delayed compared to commercially available Fumaderm® compositions. In the context of the present invention, the term "prolonged" is longer than Fumaderm®, eg at least 1.2 times, eg at least 1.5 times, at least 2 times, at least 3 times, at least 3 times more than Fumaderm®. It is intended to indicate that it is released 4 times, or at least 5 times longer. That is, for example, if 100% dimethyl fumarate is released from the Fumaderm® tablet 3 hours after the start of the appropriate test, then 100% dimethyl fumarate in the composition of the invention will start the appropriate test. It will be released at least 3.6 hours later.

In the context of the present invention, the term "delayed" is used at a later point in time (eg, 30 minutes or later, eg 45 minutes or later, eg 1) when the release of the active substance is relative to Fumaderm®. It is intended to indicate that it will start after an hour, or 1.5 hours or later.

In the context of the present invention, the term "monolithic" refers to consisting of or constituting a single unit. The formulations of the present invention have improved tolerability, such as reduced and / or reduced severity of gastrointestinal (GI) side effects, such as reduced and / or reduced severity of redness, reduced severity of flushing. And / or considered to result in a decrease.

In the use of the present invention, the side effects of the gastrointestinal tract (GI) are, but are not limited to, diarrhea, abdominal pain (stomach ache, stomach pain, abdominal pain), abdominal cramps, nausea, flatulence, flatulence, bloating (stomach ache, stomach pain, abdominal pain). meteorism), increased bowel movements, bloating, and upper abdominal cramps.

In the context of the present invention, the reduction of GI-related side effects is the severity and / or in certain treated patient populations when comparing the GI side effects seen after administration of Fumaderm® with the GI side effects seen after administration of the formulations of the present invention. It is intended to show a reduction in incidence. That is, according to this definition, a reduction in GI-related side effects is a substantial reduction in the incidence of any of the above GI side effects, eg, a reduction of at least 10% in incidence, more preferably a reduction in incidence of at least 20%. Even more preferably interpreted as a reduction of at least 30% in incidence. Reduced GI-related side effects include diarrhea, abdominal pain (stomach ache, stomach pain, abdominal pain), abdominal cramps, nausea, flatulence, swelling, meteorism, increased bowel movements, bloating, or severe epigastric cramps. It can also be expressed as a substantial decrease in degree and / or frequency. The reduction of the above GI-related side effects can be monitored in clinical trials comparing the administration of Fumaderm® or placebo with the formulations of the present invention. For placebo-controlled clinical trials, the incidence of GI-related side effects in patients receiving the formulations of the invention compared to the placebo group can be compared to historical clinical trials comparing Fumaderm® with placebo ( For example, Altmeyer et al, J. Am. Acad. Dermatol. 1994; see all: Altmeyer PJ et al, Antipsoriatic effect of Fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J. Am. Acad. See Dermatol. 1994; 30: 977-81).

In a further aspect, oral administration of the pharmaceutical product of the present invention reduces GI side effects (frequency and / or severity) compared to oral administration of the same dose of Fumaderm® tablets.

In some embodiments, such clinical trials can be performed as shown in "Clinical Trials for Patients" below. In another embodiment, such a clinical trial can be performed as shown in "Clinical Trials for Healthy Volunteers" below.
Clinical trials for patients :

Patients with psoriasis are typically included in the study, and typically more than 10% of body surface area has psoriasis (severe psoriasis). However, patients with 2-10% of body surface area can also be included (moderate psoriasis). Patients can also be selected based on the Area Severity Index (PASI) score. It typically includes patients with PASI scores within a certain range, such as 10-40, such as 12-30, or 15-25, for example. In another embodiment, it comprises a patient having a constant minimum PASI score, eg, a PASI score of at least 8, eg, at least 10, eg, at least 12, eg, at least 15. It can include patients with all types of psoriasis (chronic plaque, rash-dropped, pustular, psoriatic erythematosus, or palm-sole), but in some cases only chronic plaque. In most cases, about 15 to 20 patients are sufficient for each treatment group (formation of the invention, Fumaderm®, or placebo), but each treatment group may include about 30 to 50 patients. More preferred. The total duration of the study can be only 1 day to 1 week, but more preferably the study lasts 8 to 12 weeks, or 16 weeks or more. Side effects are evaluated, for example, by the total number of times a side effect was reported for each group (regardless of how many patients experienced the side effect), or by a number of times during the duration of the study, eg. It can be evaluated by the number of patients who have experienced at least one, at least two, or at least three times. In addition, the severity of side effects can be monitored or may require a certain severity of side effects to be considered side effects in the study. A convenient method of assessing the severity of side effects is to use the visual analog (VAS) scale.
Clinical trials for healthy volunteers :

The study typically follows an open-label, randomized, cross-design, perhaps using the commercial formulation Fumaderm® as a standard for plasma concentrations, pharmacokinetics, safety, and the pharmaceutical formulation of the invention. This is a one-center clinical trial to examine tolerability. The clinical trial can be performed as described in detail in Example 25 below.

In a further aspect, the pharmaceuticals of the invention reduce flushing (frequency and / or severity) when administered orally compared to oral administration of the same dose of Fumaderm® tablets.

In the context of the present invention, the term "flushing" refers to sudden redness of the face and / or neck, and, less frequently, the upper trunk and upper abdomen or the skin with a feeling of warmth or warmth throughout the body. Flushing is distinguished from photosensitivity and persistent erythema of acute contact reactions in that it is transient in onset. Long-term recurrent flushing can result in telangiectasia and sometimes classical facial rosacea (Greaves MW. Flushing and flushing syndromes, rosacea and perioral dermatitis. In: Champion RH. Et al., Rook / Wilkinson / Ebling textbook of dermatology, 6th edition, vol.3. Oxford, UK: Blackwell Scientific, 1998: 2099-2104).

In the context of the present invention, a decrease in flushing is defined as the severity and / or incidence / frequency of flushing seen after administration of the formulations of the invention between predetermined treated patients after administration of Fumaderm®. It means a decrease compared to flushing, which can be measured, for example, as described in O'toole et al. Cancer 2000, 88 (4): p. 770-776. That is, according to this definition, a decrease in flushing can be interpreted as a decrease in the incidence and / or severity of flushing. In one aspect of the invention, the incidence of flushing is reduced by at least about 1/4, in another aspect of the invention, the incidence is reduced by at least about 1/3, and in another aspect of the invention, the The incidence is reduced by at least about 1/2, and in a further aspect of the invention, the flush incidence is reduced by about 2/3 or more. Similarly, in one aspect of the invention, the severity is reduced by at least about 1/4, at least about 1/3 in another aspect of the invention, at least 1/2 in another aspect of the invention, the invention. It will decrease by at least about 2/3 in the further phase of. A 100% reduction in flushing incidence and severity is most preferred, but not necessary. In clinical trials as described above, the decrease in flushing can be monitored, for example, by comparing the administration of the composition of the invention with the administration of, for example, Fumaderm®. For clinical trials using Fumaderm® as a control, the incidence and severity defined as mild, moderate, or severe flushing in patients receiving the compounds of the invention is defined as the Fumaderm® group. Can be compared.

In one aspect, the severity of flushing is determined by the affected body surface area.

In some embodiments, the clinical trial can be performed as described in the "Clinical Trials for Patients" section. In another embodiment, the clinical trial can be performed as described in the section "Clinical Trials for Healthy Volunteers".

In a further aspect, oral administration of the pharmaceutical product of the present invention reduces redness (frequency and / or severity) compared to oral administration of the same dose of Fumaderm® tablets.

In the context of the present invention, the term "redness" refers to sudden redness of the skin. In some aspects, redness occurs on the face, neck, and less often on the upper trunk and abdomen.

In the context of the present invention, reduction of redness is seen in the severity and / or incidence / frequency of redness seen after administration of the formulations of the present invention among predetermined treated patients after administration of Fumaderm®. It means that it is reduced compared to redness, and can be evaluated by, for example, a doctor or a nurse. That is, according to this definition, a decrease in redness can be interpreted as a decrease in the incidence and / or severity of redness. In one aspect of the invention, the incidence of redness is reduced by at least about 1/4, in another aspect of the invention, the incidence is reduced by at least about 1/3, and in another aspect of the invention, the The incidence is reduced by at least about 1/2, and in a further aspect of the invention, the incidence of redness is reduced by about 2/3 or more. Similarly, in one aspect of the invention, the severity is reduced by at least about 1/4, at least about 1/3 in another aspect of the invention, at least 1/2 in another aspect of the invention, the invention. It will decrease by at least about 2/3 in the further phase of. A 100% reduction in redness incidence and severity is most preferred, but not necessary. In clinical trials, the reduction in redness as described above can be monitored, for example, by comparing the administration of the compositions of the invention with the administration of, for example, Fumaderm®. For clinical trials using Fumaderm® as a control, the incidence and severity defined as mild, moderate, or severe redness in patients receiving the compounds of the invention are defined as the Fumaderm® group. Can be compared.

In one aspect, the severity of redness is determined by the affected body surface area.

In some embodiments, the clinical trial can be performed as described in the "Clinical Trials for Patients" section. In another embodiment, the clinical trial can be performed as described in the section "Clinical Trials for Healthy Volunteers".

In some embodiments, the relative bioavailability of the pharmaceutical product of the invention compared to Fumaderm® is at least about 75%, eg at least about 80%, eg at least about 85%, eg at least about 90%, eg at least about 95%. For example, about 100%.

In some embodiments, the relative bioavailability of the formulations of the invention compared to Fumaderm® is at least about 100%, eg at least about 110%, eg at least about 120%, eg at least about 125%, eg at least about 130%. Is.

In some embodiments, the relative bioavailability of the formulations of the invention compared to Fumaderm® is up to about 130%, such as up to about 125%, for example up to about 120%, for example up to about 110%, eg. The maximum is about 100%.

In the context of the present invention, the term "erosion matrix" refers to a matrix in which the release of the API is independent of the inherent diffusion process and is the result of the erosion rate of the matrix. A predetermined amount of API is obtained by removing the matrix layer that can be eroded in a well-controlled manner, and the release of the API is the swelling and dissolution or erosion rate of the matrix, as well as the dissolution rate, solubility, and diffusion of the API. Depends on speed.

In one aspect, the invention relates to an erosion matrix-containing pharmaceutical formulation comprising:
i) As the active ingredient, 10% to 80%, for example 20% to 70%, for example 20% to 60%, for example 30% to 60%, for example 35% to 60%, for example 35% to 55%, for example 40%. ~ 55%, for example 44% -55%, for example 40% -50%, for example 42% -48% by weight, di- (C ₁ -C ₅ ) alkyl ester of fumaric acid and mono- (C _{1) of fumaric acid.} -C ₅ ) One or more fumaric acid esters selected from alkyl esters, or pharmaceutically acceptable salts thereof, and
ii) 1% to 50% by weight of 1 or more rate-determining substances;
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

In one aspect, the invention relates to an erosion matrix-containing pharmaceutical formulation comprising:
i) As the active ingredient, 30% to 60%, for example 35% to 60%, for example 35% to 55%, for example 40% to 55%, for example 40% to 50%, for example 44% to 55%, for example 42%. ~ 48% by weight of fumaric acid _{ester selected from di- (C 1} -C ₅ ) alkyl ester of fumaric acid and mono- (C ₁ -C ₅ ) alkyl ester of fumaric acid, or pharmaceuticals thereof. Tolerable salts, and
ii) 1 or more rate-determining substances of 3% -40% by weight;
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

In certain embodiments of the invention, by obtaining sustained release with a relatively low amount of rate-determining substance while obtaining sufficient drug exposure with little absorption available in the small intestine, for example, the prior art Fumaderm®. ) It has been found that favorable pharmacokinetic properties, such as appropriate relative bioavailability, can be obtained compared to the formulation.

In a further embodiment, obtaining the enteric coated sustained release formulation of the present invention while obtaining sufficient drug exposure with slight absorption available in the small intestine is more convenient than, for example, the Fumaderm® formulation of the prior art. It has been found that various pharmacokinetic properties such as appropriate relative bioavailability can be obtained.

In some aspects of the invention, the rate-determining material is a water-soluble polymer.

As used herein, the term "water-soluble polymer" means a conventional polymer for use in pharmaceuticals having a solubility in water greater than 10 mg / mL. Suitable water-soluble polymers include, but are not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and carboxymethyl cellulose, for example. In one aspect, the water-soluble polymer is hydroxypropyl cellulose.

As used herein, the term "water-insoluble polymer" means a convenient polymer for use in pharmaceuticals having a solubility of 10 mg / mL or less in water.

In a further aspect of the invention, the erosion matrix is substantially free of water-insoluble polymers. In a further aspect, the erosion matrix is free of water-insoluble polymers.

In the context of the present invention, the term "substantially absent (not included)" refers to a level of about 1% or less, such as about 0.5% or less, such as about 0.3% or less, such as about 0.0%.

In certain aspects of the invention, the rate-determining material is a water-soluble polymer and the erosion matrix is substantially free of water-insoluble polymers.

In certain aspects of the invention, the rate-determining material is a water-soluble polymer and the erosion matrix does not contain a water-insoluble polymer.

In certain aspects of the invention, the rate-determining substance is a cellulose polymer or cellulose derivative or a mixture thereof. Non-limiting examples of cellulose polymers or cellulose derivatives or mixtures thereof include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose, and mixtures thereof.

In certain aspects of the invention, the rate-determining substance is hydroxypropyl cellulose. For example, there are various different grades of hydroxypropyl cellulose depending on its molecular weight, degree of etherification, viscosity and the like. Non-limiting typical embodiments of commercially available hydroxypropyl cellulose include, for example, registered trademarks Klucel® HPC-L, HPC-SL, HPC-SSL, HPC-M, HPC-H, etc. from Aqualon or Nippon Soda. Obtainable. In one aspect of the invention, the rate-determining material is hydroxypropyl cellulose having a viscosity (mPa.s) of 3.0-5.9 as measured in an aqueous solution containing 2% by weight dry HPC at 20 ° C. In aspects of the invention, the rate-determining substance is HPC-SL.

In certain embodiments of the invention, the rate-determining material is 1 to 40% by weight, such as about 3 to 35% by weight, such as about 4 to 15% by weight, such as about 4 to 10% by weight, such as about 3 to 15% by weight, such as about 3 to 15% by weight. It is present in an amount of about 3-10% by weight, such as about 3-6% by weight, such as about 3-5.5% by weight, such as about 4-6% by weight.

In certain embodiments of the invention, the rate-determining material is 1 to 40% by weight, such as 3 to 35% by weight, such as 4 to 15% by weight, such as 4 to 10% by weight, such as 3 to 15% by weight, such as 3 to 10% by weight. It is present in an amount of%, such as 3-6% by weight, such as 3-5.5% by weight, such as 4-6% by weight.

In another aspect of the invention, the rate-determining material is present in an amount of 15-40% by weight, for example about 15-25% by weight.

In another aspect of the invention, the rate-determining material is present in an amount of about 25-40% by weight, for example about 35-40% by weight.

In another aspect of the invention, the rate-determining material is present in an amount of about 0-5% by weight, eg, about 0-3% by weight, and does not contain, for example, substantially any rate-determining material.

In one aspect, the invention relates to a pharmaceutical formulation comprising an erosion matrix comprising:
i) As the active substance, 10% to 80%, for example 20% to 70%, for example 20% to 60%, for example 30% to 60%, for example 35% to 60%, for example 35% to 55%, for example 40%. ~ 55%, for example 40% -50%, for example 44% -55%, for example 42% -48% (weight) of di- (C _1- C ₅ ) alkyl ester of fumaric acid and mono-(C 1-C 5) of fumaric acid. C _1- C ₅ ) One or more fumaric acid esters selected from alkyl esters, or pharmaceutically acceptable salts thereof, and
ii) One or more rate-determining substances of 0% -40%, eg 0% -20%, eg 0% -10%, eg 0% -5%, eg 0% -1% (weight);
Here, erosion of the erosion matrix allows for controlled release of the active substance.

The amount of rate-determining substance, if any, will vary depending on the specific rate-determining substance used, the intended release profile, the concentration and nature of any excipients and additives present in the core tablets, and the like.

In certain aspects of the invention, the formulation further comprises a binder. Non-limiting examples thereof include water-soluble sugars and sugar alcohols such as lactose, saccharose, glucose, sorbitol, mannitol and the like. In that embodiment, the binder is lactose. Lactose is commercially available in many different grades, in particular depending on the manufacturing method used to provide different particle sizes, particle size distributions and the like. Examples of lactose include, but are not limited to, anhydrous lactose, lactose made from α-lactoose monohydrate, aggregated lactose, granular lactose, crystalline lactose, crystalline, sieved lactose (eg, Prisma Lac (eg, Prisma Lac). Registered Trademarks), eg PrismaLac® 40), Crystals, Polished Lactose (eg GranuLac®, eg GranuLac® 70, GranuLac® 140, GranuLac® 200, GranuLac (eg GranuLac®) 230 and GranuLac® 400), improved lactose, aggregated lactose (eg Tablettose®, eg Tablettose® 70, Tablettose® 80 and Tablettose® 100), Includes improved lactose, spray-dried lactose (FlowLac®, eg FlowLac® 90 and FlowLac® 100). Lactose is, for example, Trademark PrismaLac®, Capsulac®, eg Capsulac® 60, SacheLac®, SpheroLac®, Inhalac® GranuLac®, For example, GranuLac® 70, GranuLac® 140, GranuLac® 200, GranuLac® 230, and GranuLac® 400, SorboLac®, Tablettose®, for example. Can be obtained from Meggle Pharma with Tablettose® 70, Tablettose® 80 and Tablettose® 100, FlowLac®, such as FlowLac® 90 and FlowLac® 100.

In one aspect, the lactose is agglomerated lactose. In another aspect, the lactose is spray-dried lactose. In another aspect, the lactose is abrasive lactose.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 40 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 4 to 6% by weight rate-determining substance,
iii) 35-55% by weight binder.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 40 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 15-50% by weight rate-determining substance,
iii) 5-30% by weight binder.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, from 30% to 60% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65% by weight binder.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 35% to 55% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 6% by weight rate-determining substance,
iii) 40-60% by weight binder.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, from 40% to 50% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 6% by weight rate-determining substance,
iii) 45-55% by weight binder.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 42% to 48% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 5.5% by weight rate-determining substance,
iii) 45-52% by weight binder.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
iv) 0.15-0.7% by weight lubricant, and optionally 0.05-0.25% by weight flow regulator.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 35% to 55% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 6% by weight rate-determining substance,
iii) 40-60% by weight binder,
iv) 0.15-0.7% by weight lubricant, and optionally 0.05-0.25% by weight flow regulator.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, from 40% to 50% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 6% by weight rate-determining substance,
iii) 45-55 wt% binder,
iv) 0.15-0.7% by weight lubricant,
And optionally 0.05-0.25 wt% flow regulator.

In certain aspects of the invention, the formulations of the invention include:
i) as active substance, 42% to 48% by weight, of fumaric acid di - (C ₁ -C ₅₎ mono alkyl esters and fumaric acid - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumarate ester, or its pharmaceutically acceptable salt,
ii) 3 to 5.5% by weight rate-determining substance,
iii) 45-52% by weight binder,
iv) 0.2-0.5% by weight lubricant, and optionally 0.05-0.2% by weight flow regulator.

In certain aspects of the invention, the formulations of the invention include:
i) 30% -60% by weight dimethyl fumarate,
ii) 3-6% by weight HPC,
iii) 35-65% by weight lactose.

In certain aspects of the invention, the formulations of the invention include:
i) 35% -55% by weight dimethyl fumarate,
ii) 3-6% by weight HPC,
iii) 40-60% by weight lactose.

In certain aspects of the invention, the formulations of the invention include:
i) 40% to 50% by weight dimethyl fumarate,
ii) 3-6% by weight HPC,
iii) 45-55% by weight lactose.

In certain aspects of the invention, the formulations of the invention include:
i) 42% -48% by weight dimethyl fumarate,
ii) 3 to 5.5% by weight HPC,
iii) 45-52% by weight lactose.

In certain aspects of the invention, the formulations of the invention include:
i) 30% -60% by weight dimethyl fumarate,
ii) 3-6% by weight HPC,
iii) 35-65% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate, and optionally 0.05-0.25% by weight silicon dioxide.

In certain aspects of the invention, the formulations of the invention include:
i) 35% -55% by weight dimethyl fumarate,
ii) 3-6% by weight HPC,
iii) 40-60% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate, and optionally 0.05-0.25% by weight silicon dioxide.

In certain aspects of the invention, the formulations of the invention include:
i) 40% to 50% by weight dimethyl fumarate,
ii) 3-6% by weight HPC,
iii) 45-55% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate, and optionally 0.05-0.25% by weight silicon dioxide.

In certain aspects of the invention, the formulations of the invention include:
i) 42% -48% by weight dimethyl fumarate,
ii) 3 to 5.5% by weight HPC,
iii) 45-52% by weight lactose,
iv) 0.2-0.5% by weight magnesium stearate, and optionally 0.05-0.2% by weight silicon dioxide.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 30% -60% by weight, 0-5% particles have a particle size> 500 μm, 45-53% particles have a particle size> 250 μm, 7-15% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 35-65% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate, and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 35% -55% by weight, 0-5% particles have a particle size> 500 μm, 45-53% particles have a particle size> 250 μm, 7-15% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 40-60% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 40% -50% by weight, 0-5% particles have a particle size> 500 μm, 45-53% particles have a particle size> 250 μm, 7-15% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 45-55% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 42% -48% by weight, 0-5% particles have a particle size> 500 μm, 45-53% particles have a particle size> 250 μm, 7-15% particles. Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3 to 5.5% by weight HPC,
iii) 45-52% by weight lactose,
iv) 0.2-0.5% by weight magnesium stearate and 0.05-0.2% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 30% -60% by weight, 0-7% particles have a particle size> 500 μm, 42-59% particles have a particle size> 250 μm, 3-12% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 35-65% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 35% -55% by weight, 0-7% particles have a particle size> 500 μm, 42-59% particles have a particle size> 250 μm, 3-12% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 40-60% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 40% -50% by weight, 0-7% particles have a particle size> 500 μm, 42-59% particles have a particle size> 250 μm, 3-12% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 45-55% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 42% -48% by weight, 0-7% particles have a particle size> 500 μm, 42-59% particles have a particle size> 250 μm, 3-12% particles. Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3 to 5.5% by weight HPC,
iii) 45-52% by weight lactose,
iv) 0.2-0.5% by weight magnesium stearate and 0.05-0.2% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 30% -60% by weight, 0-10% particles have a particle size> 500 μm, 40-65% particles have a particle size> 250 μm, 2-10% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 35-65% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 35% -55% by weight, 0-10% particles have a particle size> 500 μm, 40-65% particles have a particle size> 250 μm, 2-10% particles Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 40-60% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 40% to 50% by weight, 0 to 10% particles have a particle size> 500 μm, 40 to 65% particles have a particle size> 250 μm, and 2 to 10% particles. Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3-6% by weight HPC,
iii) 45-55% by weight lactose,
iv) 0.15-0.7% by weight magnesium stearate and 0.05-0.25% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In certain aspects of the invention, the formulations of the invention include:
A) Tablet core consisting of:
i) As active ingredients, 42% to 48% by weight, 0 to 10% particles have a particle size> 500 μm, 40 to 65% particles have a particle size> 250 μm, and 2 to 10% particles. Dimethyl fumarate with a particle size distribution such that has a particle size <100 μm,
ii) 3 to 5.5% by weight HPC,
iii) 45-52% by weight lactose,
iv) 0.2-0.5% by weight magnesium stearate and 0.05-0.2% by weight silicon dioxide, and
B) An enteric coating in an amount of about 1.5-3.5% by weight of the core.

In some embodiments, the formulations of the present invention further comprise one or more lubricants.

In some embodiments, the formulations of the present invention further comprise one or more flow regulators.

In some embodiments, the formulations of the present invention further comprise one or more lubricants and one or more flow regulators.

In some embodiments, the formulations of the present invention are pharmaceutically acceptable selected from the group consisting of lubricants, flow promoters, disintegrants, flow regulators, solubilizers, pH regulators, surfactants, and emulsifiers. Contains excipients and additives.

In some embodiments, the pharmaceutical product of the present invention is produced without the use of a disintegrant.

Some of the formulations of the present invention show a biphasic in vitro disintegration profile, and the release of APIs, such as dimethyl fumarate, is a USP lysing device, even though the solubility of APIs may be the same in acid and alkaline environments. It is slow in the acid environment for the first 2 hours of the above, and it becomes faster when the dissolution medium is changed to pH 6.8. For drugs that require relatively low gastric exposure and at the same time require release / absorption in the small intestine, it is possible to limit API exposure to the stomach while optimizing API exposure in the small intestine. There will be. In some embodiments, the in vitro lysis profile of the formulation is biphasic, API release is slow in the acid environment for the first 2 hours of the USP lysis device and accelerated when the lysis medium is changed to pH 6.8.

The in vitro dissolution rate describes how the amount of API released in the formulation of the present invention changes over time when an in vitro dissolution test is performed. Higher / faster in vitro lysis rates release more APIs over a period of time, slower / slower in vitro lysis rates release less APIs over the same time under the same in vitro lysis test conditions Means that.

In one embodiment of the invention, in an in vitro dissolution test used to measure the in vitro dissolution rate, 0.1N hydrochloric acid was used as the dissolution medium for the first 2 hours of the test, then 0.05 M phosphate buffer pH 6.8 was dissolved. Used as a medium.

In certain aspects of the invention, the in vitro dissolution rate of the API contained in the non-enteric coated formulation of the invention was 0.1 N hydrochloric acid as the first 2 hour dissolution medium of the test, followed by 0.05 M phosphate buffer pH 6.8. When an in vitro dissolution test using the solution (pH 6.8) was performed, the buffer solution (pH 6.8) phase was higher than the acid phase (0.1N hydrochloric acid as a dissolution medium) in the in vitro dissolution test, and the buffer solution (pH 6.8) was used. The phase is, for example, at least 10% higher, for example at least 20% higher, for example at least 30% higher, for example at least 40% higher, for example at least 50% higher than the acid phase of the in vitro dissolution test (using 0.1N hydrochloric acid as the dissolution medium). For example, at least 60% higher, for example at least 70% higher, for example at least 80% higher, for example at least 90% higher, for example at least 100% higher, for example at least 125% higher, for example at least 150% higher, for example at least 200% higher, for example At least 250% higher, eg at least 300% higher, eg at least 350% higher, eg at least 400% higher. In some embodiments, the comparison comprises an in vitro lysis rate in the first hour of the test (time = 0 to time = 1 hour) and an in vitro lysis rate in the third hour of the test (time = 2 to time = 3 hours). Do between. In another embodiment, the comparison comprises an in vitro lysis rate in the first 2 hours of the test (time = 0 to time = 2 hours) and an in vitro lysis rate in the third hour of the test (time = 2 to time = 3 hours). ). In another embodiment, the comparison comprises an in vitro lysis rate in the first 2 hours of the test (time = 0 to time = 2 hours) and an in vitro lysis rate in the next 2 hours of the test (time = 2 hours to time =). 4 hours). In another embodiment, the comparison is between the in vitro lysis rate in the first hour of the test (time = 0 to time = 1 hour) and the time of the test = 2 hours to time = 2.5 hours. Do it with.

In some embodiments, the formulations of the present invention further comprise one or more coating agents. In certain aspects of the invention, the one or more coatings are added to improve the stability and swallowing properties of the tablet or to delay the release of the API. In that embodiment, the coating agent is a film coating agent and / or an enteric coating agent. The film coating can improve swallow properties and stability and reduce the risk of sublimation of the active pharmaceutical ingredient. In addition, film coatings can improve the safety aspects of tablet handling. A film coat that is layered with an enteric coat or is itself an enteric coat may have similar advantages as described above for film coatings. However, in addition, the active pharmaceutical ingredient is not released into the acidic environment of the stomach and may protect the gastric mucosa from irritation if the API is potentially irritating to the gastric mucosa.

In certain aspects of the invention, the coating is an enteric coating.

The enteric coating material can be selected from many any commercially available coating material. Non-limiting examples thereof include Eudragit® E, L, S, L30D55, Kollicoat® 3OD, Cellulose Acetate Phthalate, Polyvinyl Acetate Phthalate, and Hypromerose Phthalate.

In certain aspects of the invention, the enteric coating is applied in an amount of about 1.0-5.0% by weight of the core.

In certain aspects of the invention, the enteric coating is about 1.0-4.5% by weight of the core, such as 1.5-4.0% by weight of the core, such as about 1.5-3.5% by weight of the core, such as about 2.0-3.5% by weight of the core. Applies at a level of%, eg, about 2-3% by weight of the core.

In certain aspects of the invention, the enteric coating is applied at a level of about 1.5-3.5% by weight of the core.

Enteric coating is a well-established method for suppressing or minimizing the release of drugs in the stomach and allowing release in the small intestine. Such enteric polymer coatings act on the principle of pH-dependent solubility and are insoluble in low pH conditions of the stomach, but soluble in an environment of near neutral pH in the proximal small intestine, where the pH ranges from 5 to 6. is there.

For drugs that require absorption in the small intestine, this means that the release is slightly open and between the solubilization of the enteric coating and the release of the API from the formulation is eg about 5 hours, eg about 4 hours, eg about. Open for 3 hours, for example about 2 1/2 hours, for example about 2 hours. In one aspect of the invention, rapid solubilization of the enteric coating is possible by applying a relatively thin coat, which is subjected to an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for 2 hours. For example, it exhibits a release of 10% or less, for example, 5% or less, for example, 2% or less, for example, about 0% of the fumaric acid ester contained in the preparation, and surprisingly, the necessary protection for the acid environment of the stomach is obtained. I understood.

In some embodiments of the invention, the in vivo release of the fumaric acid ester exhibits an earlier onset of release than the prior art formulation Fumaderm® and, for example, at least 20 minutes, at least 30 minutes, than Fumaderm® under fasting conditions. , At least 40 minutes, at least 50 minutes, at least 60 minutes, at least 70 minutes, at least 80 minutes, at least 90 minutes, at least 100 minutes, at least 110 minutes, or at least 120 minutes earlier.

In certain aspects of the invention, the formulations of the invention comprise an enteric coating, and the in vivo release of fumaric acid ester indicates an earlier onset of release than the prior art formulation Fumaderm®, under fasting conditions Fumaderm ( For example, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 70 minutes, at least 80 minutes, at least 90 minutes, at least 100 minutes, at least 110 minutes, or at least 120 minutes earlier than the registered trademark). ..

In certain aspects of the invention, the in vivo release of fumaric acid ester has a lag time of 15 minutes to 2 hours under fasting conditions, eg, up to 120 minutes, up to 110 minutes, up to 100 minutes under fasting conditions. Ragtime up to 90 minutes, up to 80 minutes, up to 70 minutes, up to 60 minutes, up to 50 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes, or up to 15 minutes Shown.

In certain aspects of the invention, the pharmaceutical product of the invention comprises an enteric coating and the in vivo release of fumaric acid ester is up to a lag time of 15 minutes to 2 hours under fasting conditions, eg, under fasting conditions. 120 minutes, up to 110 minutes, up to 100 minutes, up to 90 minutes, up to 80 minutes, up to 70 minutes, up to 60 minutes, up to 50 minutes, up to 40 minutes, up to 30 minutes, up to 30 minutes Indicates a lag time of 20 minutes, or up to 15 minutes.

In some embodiments of the invention, the release of fumaric acid ester is subjected to an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 50% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 3.5 hours after the start of the test, a maximum of about 95% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 4 hours after the start of the test, a maximum of about 98% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 60% w / w of the fumaric acid ester contained in the formulation, for example, about 0% w / w to about 50% w / w, for example. About 0% w / w ~ about 40% w / w, for example about 0% w / w ~ about 30%, for example about 0% w / w ~ about 20%, for example about 0% w / w ~ about 10%, For example, about 0% w / w to about 5%, for example about 0% w / w, is released and / or about 15% w of the total amount of fumaric acid ester contained in the formulation within the first 3 hours after the start of the test. / w ~ about 95% w / w, for example about 20% w / w ~ about 95% w / w, for example about 20% w / w ~ about 75% w / w, for example about 25% w / w ~ about 75 % W / w, for example about 40% w / w to about 95% w / w, for example about 40% w / w to about 75% w / w, for example about 50% w / w to about 95% w / w, For example, about 50% w / w to about 75%, for example, about 60% w / w to about 95% w / w, for example, about 60% w / w to about 75%, for example, about 70% w / w to about 95%. For example, about 80% w / w to about 95%, for example, about 90% w / w to about 95% are released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 60% w / w of the fumaric acid ester contained in the formulation, for example, about 0% w / w to about 5% w / w, for example. About 0% w / w to about 10% w / w, or for example, about 15% w / w to about 35% w / w, or for example, about 35% w / w to about 55% w / w is released. , And / or about 15% w / w to about 95% w / w of the total amount of fumaric acid ester contained in the formulation within the first 3 hours after the start of the test, for example about 15% w / w to about 75% w. / w, for example about 20% w / w to about 75% w / w, for example about 15% w / w to about 35% w / w, or for example, about 35% w / w to about 55% w / w, Or, for example, about 55% w / w to about 75%, or, for example, about 65% w / w to about 85%, or, for example, about 70% w / w to about 80%, or, for example, about 75% w /. w ~ about 95%, or, for example, about 85% w / w ~ about 95% is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 1% w / w to about 25% w / w of the fumaric acid ester contained in the formulation is released, and / or within the first 3 hours after the start of the test. About 15% w / w to about 95% w / w, for example, about 15% w / w to about 75% w / w, for example, about 25% w / w to about 95% of the total amount of fumaric acid ester contained in the formulation. w / w, eg about 25% w / w to about 75% w / w, eg about 40% w / w to about 95% w / w, eg about 40% w / w to about 75% w / w, eg About 50% w / w to about 95% w / w, for example about 50% w / w to about 75%, for example about 60% w / w to about 95% w / w, for example about 60% w / w to about 75%, for example about 70% w / w to about 95% w / w, for example about 80% w / w to about 95% w / w, for example about 90% w / w to about 95% w / w is released. To.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 1% w / w to about 25% w / w of the fumaric acid ester contained in the formulation is released, and / or within the first 3 hours after the start of the test. About 15% w / w to about 95% w / w, for example, about 15% w / w to about 75% w / w, for example, about 15% w / w to about 35% of the total amount of fumaric acid ester contained in the formulation. w / w, or for example about 35% w / w to about 55% w / w, or for example about 55% w / w to about 75%, or for example about 65% w / w to about 85%, or for example about 70 % W / w to about 80%, or for example about 75% w / w to about 95%, or for example about 85% w / w to about 95% is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 3.5 hours after the start of the test, the total amount of fumaric acid ester contained in the formulation is up to about 100% w / w, for example about 30% w / w to about 100% w / w, for example about 30% w /. w ~ about 95% w / w, for example about 40% w / w ~ about 100% w / w, for example about 40% w / w ~ about 95% w / w, for example about 50% w / w ~ about 100% w / w, for example about 50% w / w to about 95%, for example about 60% w / w to about 100% w / w, for example about 60% w / w to about 95%, for example about 70% w / w ~ About 100% w / w, for example about 70% w / w ~ about 95%, for example about 80% w / w ~ about 100% w / w, for example about 80% w / w ~ about 95%, for example about 90 % W / w to about 100% w / w, for example about 90% w / w to about 95% w / w, is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 3.5 hours after the start of the test, the total amount of fumaric acid ester contained in the formulation is up to about 100% w / w, for example about 30% w / w to about 90% w / w, for example about 30% w /. w ~ about 50% w / w, or, for example, about 60% w / w ~ about 80%, or, for example, about 80% w / w ~ about 95% is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 4 hours after the start of the test, the total amount of fumaric acid ester contained in the formulation is up to about 100% w / w, for example about 35% w / w to about 100% w / w, for example about 35% w /. w ~ about 98% w / w, for example about 40% w / w ~ about 100% w / w, for example about 40% w / w ~ about 98% w / w, for example about 50% w / w ~ about 100% w / w, for example about 50% w / w to about 98%, for example about 60% w / w to about 100% w / w, for example about 60% w / w to about 98%, for example about 70% w / w ~ About 100% w / w, for example about 70% w / w ~ about 98%, for example about 80% w / w ~ about 100% w / w, for example about 80% w / w ~ about 98%, for example about 90 % W / w to about 100% w / w, for example about 90% w / w to about 98% is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 4 hours after the start of the test, the total amount of fumaric acid ester contained in the formulation is up to about 100% w / w, for example about 35% w / w to about 98% w / w, for example about 50% w /. w ~ about 70%, or for example about 85% w / w ~ about 95% w / w is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 4 hours after the start of the test, up to about 95% w / w, for example up to about 90% w / w, for example up to about 70% of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 15% w / w to about 35% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3.5 hours after the start of the test, about 30% w / w to about 50% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 50% w / w to about 70% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 15% w / w to about 35% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3.5 hours after the start of the test, about 30% w / w to about 50% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 50% w / w to about 70% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 30% w / w to about 55% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 60% w / w to about 80% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 80% w / w to about 95% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 30% w / w to about 55% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 60% w / w to about 80% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 80% w / w to about 95% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 5 hours after the start of the test, about 80% w / w to about 100% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 60% w / w to about 85% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3.5 hours after the start of the test, about 80% w / w to about 95% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 4 hours after the start of the test, about 85% w / w to about 100% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 60% w / w to about 85% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3.5 hours after the start of the test, about 80% w / w to about 100% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 85% w / w to about 100% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 15% w / w to about 35% w / w of the fumaric acid ester contained in the formulation is released.
Within the first 3 hours after the start of the test, about 55% w / w to about 80% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 70% w / w to about 90% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 80% w / w to about 100% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 10% w / w to about 30% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 15% w / w to about 40% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 30% w / w to about 50% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 10% w / w to about 30% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 15% w / w to about 40% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 30% w / w to about 50% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 6 hours after the start of the test, about 75% w / w to about 100% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 5% w / w to about 25% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 10% w / w to about 30% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 20% w / w to about 40% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 5% w / w to about 25% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 10% w / w to about 30% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 20% w / w to about 40% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 5 hours after the start of the test, about 30% w / w to about 50% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 2% w / w to about 20% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 5% w / w to about 20% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 5% w / w to about 25% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In one embodiment of the invention, the release of fumaric acid ester is performed in an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium. It is as follows:
Within the first 2 hours after the start of the test, about 0% w / w to about 5% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 3 hours after the start of the test, about 2% w / w to about 20% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 3.5 hours after the start of the test, about 5% w / w to about 20% w / w of the total amount of fumaric acid ester contained in the formulation is released.
Within the first 4 hours after the start of the test, about 5% w / w to about 25% w / w of the total amount of fumaric acid ester contained in the formulation was released.
Within the first 5 hours after the start of the test, about 10% w / w to about 30% w / w of the total amount of fumaric acid ester contained in the formulation is released.

In certain aspects of the invention, the emission has a zero-order, primary, or square root (Higuchi's) kinetic emission profile.

In a further embodiment, the in vitro release has a combination of zero-order, primary, or square root (Higuchi's) kinetic in vitro release profiles, a combination of zero-order and primary in vitro release profiles.

Various kinetic models, such as zero-order (1), first-order (2), square root (Higuchi's equation) (3), can be applied to the interpretation of drug release kinetics.
1: M _t = M ₀ + k _o * t
2: InM _t = InM + k ₁ * t
3: M _t = M ₀ + k _H * t ^1/2

In these equations, M _t is the amount of drug accumulated at any particular time point and M ₀ is the dose of active substance incorporated into the pharmaceutical composition. k ₀ , k ₁ , and k _H are the rate constants of the zero-order, first-order, and Higuchi equations, respectively.

One aspect of the invention relates to a zero-order lysis release profile. Another aspect concerns the primary lysis release profile. A further aspect relates to the square root (Higuchi's equation) dissolution and release profile.

The active substance in the formulation of the present invention is any fumaric acid ester.

In certain aspects of the invention, the fumarate ester is preferably dimethyl fumarate, diethyl fumarate, dipropyl fumarate, dibutyl fumarate, dipentyl fumarate, methyl ethyl fumarate, methyl propyl fumarate, methyl butyl fumarate, It is selected from the group consisting of methylpentyl fumarate, monomethyl fumarate, monoethyl fumarate, monopropyl fumarate, monobutyl fumarate, and monopentyl fumarate (including its pharmaceutically acceptable salts).

The pharmaceutically acceptable salts include metal salts such as salts selected from alkali metal salts and alkaline earth metal salts (including sodium, potassium, calcium, magnesium, strontium, or zinc salts), amino acid salts, and the like. included.

In another aspect of the invention, the fumaric acid ester exists in the form of its monosaccharide ester, eg, as described in EP06753340.6.

In another aspect of the invention, the fumaric acid ester exists in the form of its amino acid salt. Amino acids include natural amino acids such as glycine, alanine, valine, norvaline, isovaline, leucine, norleucine, isoleucine, methionine, phenylalanine, tryptophan, serine, threonine, cysteine, peniciramine, tyrosine, aspartic acid, glutamic acid, aspartic acid. , Glutamic acid, ornithine, lysine, arginine, histidine, proline, 4-hydroxyproline, and pipecoline acid.

In certain aspects of the invention, the fumaric acid ester is a mono- (C _1- C ₅ ) alkyl ester of fumaric acid present in the form of a pharmaceutically acceptable salt. Suitable salts are, for example, metal salts, such as salts selected from alkali metal salts and alkaline earth metal salts, including sodium, potassium, calcium, magnesium, strontium, or zinc salts.

The term (C _1- C ₅ ) alkyl is a branched or non-branched alkyl group with 1-5 (including) carbon atoms (eg, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2). -Butyl, 2-methyl-2-propyl, 2-methyl-l-propyl, and pentyl).

In another embodiment, the pharmaceutical product of the present invention comprises dimethyl fumarate as an active substance.

In a further embodiment, the pharmaceutical product of the present invention is monomethyl fumarate as an active substance, optionally in the form of a pharmaceutically acceptable salt thereof, such as, for example, sodium, potassium, calcium, magnesium, strontium, and / or zinc salts. including.

In a further aspect, the pharmaceutical product of the present invention comprises, as an active substance, monomethyl fumarate in the form of an amino acid salt thereof, if desired.

In another embodiment, the pharmaceutical product of the present invention consists essentially of dimethyl fumarate as the active substance.

In another embodiment, the pharmaceutical product of the present invention comprises dimethyl fumarate as an active ingredient.

In a further aspect, the pharmaceuticals of the invention are essentially in the form of pharmaceutically acceptable salts such as sodium, potassium, calcium, magnesium, strontium, and / or zinc salts thereof, optionally as the active ingredient. It consists of monomethyl fumarate.

In a further aspect, the formulations of the present invention optionally consist of, for example, monomethyl fumarate in the form of sodium, potassium, calcium, magnesium, strontium, and / or zinc salts thereof.

In a further embodiment, the formulations of the present invention, as active ingredients, have a weight ratio of about 1:10 to about 10: 1 dimethyl fumarate and monomethyl fumarate (if desired, eg, their sodium, potassium, calcium, magnesium, strontium). , And / or in the form of pharmaceutically acceptable salts such as zinc salts).

In a further aspect, the formulations of the present invention essentially, as active ingredients, have a weight ratio of about 1:10 to about 10: 1 dimethyl fumarate and monomethyl fumarate (if desired, eg, their sodium, potassium, calcium). , In the form of pharmaceutically acceptable salts such as magnesium, strontium, and / or zinc salts).

In a further embodiment, the formulations of the present invention, as active ingredients, have a weight ratio of about 1:10 to about 10: 1 dimethyl fumarate and monomethyl fumarate (if desired, eg, their sodium, potassium, calcium, magnesium, strontium). , And / or in the form of a pharmaceutically acceptable salt such as zinc salt).

In some embodiments, the formulations of the present invention are for administration once, twice, or three times daily.

In some embodiments, the formulation is for administration once daily.

In some embodiments, the formulation is for administration twice daily.

The daily dose of the controlled release pharmaceutical formulation of the invention administered to treat a patient depends on many factors, including, but not limited to, body weight, age, and the underlying cause of the medical condition or disease being treated. It is within the skill of the physician to determine this.

In one aspect of the invention, the daily dose may be, for example, 200-400 mg active ingredient (administering 1-3 doses), in another aspect, 300-500 mg active ingredient (administering 1-3 doses), separately. 400-600 mg active ingredient (dos 1-3 doses) in one aspect, 500-700 mg active ingredient (dos 1-3 doses) in another aspect, 600-800 mg active ingredient in another aspect (1 to 3 doses administered), 700 to 900 mg active ingredient (1 to 3 doses administered) in another aspect, 800 to 1000 mg active ingredient (1 to 3 doses administered) in another aspect, another 900 to 1100 mg active ingredient (1 to 3 doses administered) in one aspect, 1000 to 1200 mg active ingredient (1 to 3 doses administered) in another aspect, 1100-1300 mg active ingredient in another aspect With (1 to 3 doses), 1200 to 1400 mg active ingredient (1 to 3 doses) in another aspect, and 1300 to 2000 mg active ingredient (1 to 3 doses) in yet another aspect. It is possible.

One embodiment of the present invention is a pharmaceutical formulation comprising:
i) 40% -55% by weight dimethyl fumarate,
ii) 4-6% by weight hydroxypropyl cellulose,
iii) 35-55% by weight lactose.

One embodiment of the present invention is a pharmaceutical formulation comprising:
i) 30% -60% by weight dimethyl fumarate,
ii) 3-6% by weight hydroxypropyl cellulose,
iii) 35-65% by weight lactose.

One embodiment of the present invention is a pharmaceutical formulation in the form of an erosion matrix tablet comprising:
A) Tablet cores including:
i) as active substance, 40 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 4 to 6% by weight rate-determining substance,
iii) 35-55 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of the fumaric acid ester contained in the formulation is released, and / or within the first 3 hours after the start of the test. About 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

One embodiment of the present invention is a pharmaceutical formulation in the form of an erosion matrix tablet comprising:
A) Tablet cores including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

One embodiment of the present invention is a pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
A) Tablet cores including:
i) as active substance, 40 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 4 to 6% by weight rate-determining substance,
iii) 35-55 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released, and / or within the first 4 hours after the start of the test. About 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

One embodiment of the present invention is a pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
A) Tablet cores including:
i) as active substance, 30 to 60 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof,
ii) 3 to 6% by weight rate-determining substance,
iii) 35-65 wt% binder,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumar as follows. Causes the release of acid esters:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of the fumaric acid ester contained in the formulation is released and / or
Within the first 3 hours after the start of the test, about 20% w / w to about 75% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 4 hours after the start of the test, about 50% w / w to about 98% w / w of the fumaric acid ester contained in the formulation is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the fumaric acid ester contained in the formulation is released.

One embodiment of the present invention is a pharmaceutical formulation in the form of an erosion matrix tablet comprising:
A) Tablet cores including:
i) 40-55% by weight dimethyl fumarate,
ii) 4-6% by weight hydroxypropyl cellulose,
iii) 35-55% by weight lactose,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumal as follows. Causes the release of dimethyl acid:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of dimethyl fumarate contained in the formulation is released, and / or within the first 3 hours after the start of the test. About 20% w / w to about 75% w / w of dimethyl fumarate contained in the formulation is released to and / or the fumarate ester contained in the formulation within the first 4 hours after the start of the test. About 50% w / w to about 98% w / w is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the total amount of dimethyl fumarate contained in the preparation is released.

One embodiment of the present invention is a pharmaceutical formulation in the form of a monolithic erosion matrix tablet comprising:
A) Tablet cores including:
i) 40-55% by weight dimethyl fumarate,
ii) 4-6% by weight hydroxypropyl cellulose,
iii) 35-55% by weight lactose,
B) Enteric coating in an amount of about 1.5-3.5% by weight of the core;
Here, when an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium is performed, the erosion of the erosion matrix is fumal as follows. Causes the release of dimethyl acid:
Within the first 2 hours after the start of the test, about 0% w / w to about 10% w / w or less of dimethyl fumarate contained in the formulation is released, and / or within the first 3 hours after the start of the test. About 20% w / w to about 75% w / w of dimethyl fumarate contained in the formulation is released to and / or the fumarate ester contained in the formulation within the first 4 hours after the start of the test. About 50% w / w to about 98% w / w is released and / or
Within the first 5 hours after the start of the test, about 70% w / w to about 100% w / w of the total amount of dimethyl fumarate contained in the preparation is released.

The production of the erosion matrix tablets of the present invention is obtained by granulation, then tableting, and optionally a core tablet film and / or enteric coating. The core can be produced, for example, by conventional wet or continuous granulation, eg, extrusion molding, and then compressing the granules into tablets. The core can then be coated with suitable techniques, preferably by air suspension.

One aspect of the present invention is a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) Dissolve (or suspend) one or both of the fumaric acid ester and optionally the rate-determining substance in the form of a polymerization matrix substance in water to obtain an aqueous suspension thereof;
b) Spray the granules of fumaric acid ester with the aqueous suspension and / or binder on it for a time sufficient to obtain a homogeneous coating.
c) The resulting granules are dried and
d) If desired, the granules are sieved or ground and
e) Mix all pharmaceutically acceptable excipients and additives according to known methods to obtain tablets.
f) Film and / or enteric coating the tablets by a known method, if desired, where all or all of the above steps are carried out at a temperature such that the product temperature is 45 ° C. or lower. In some embodiments of the invention, any or all of the above steps are carried out at a temperature such that the temperature of the product is 40 ° C. or lower, for example 35 ° C. or lower, for example 30 ° C. or lower. That is, it was surprisingly found that the production of the pharmaceutical product of the present invention can be obtained by using only water as a solvent, that is, without the need for any organic solvent. In addition, all manufacturing processes can be carried out at fairly low temperatures, which minimizes or reduces sublimation of active pharmaceutical ingredients, provides an energy efficient method and reduces API loss. Lower costs and improve the environment and worker safety.

In the context of the present invention, particle size is measured by conventional sieving analysis known to those of skill in the art.

In some embodiments of the invention, the fumaric acid ester is such that at least 90% of the particles have a particle size of up to 50 μm, such as up to 30 μm, for example up to 10 μm, prior to step a). Finely pulverize.

In another embodiment, the average particle size of the active pharmaceutical ingredient (fumaric acid ester) is reduced by, for example, sieving or grinding, and at least 50% of the particles are less than 800 μm, eg less than 600 μm, prior to step a) above. For example, it has a particle size of less than 500 μm, for example, less than 400 μm, for example, less than 200 μm.

In another embodiment, the average particle size of the active pharmaceutical ingredient (fumaric acid ester) is reduced by, for example, sieving or grinding, and at least 80% of the particles are less than 800 μm, eg less than 600 μm, prior to step a) above. For example, it has a particle size of less than 500 μm, for example, less than 400 μm, for example, less than 200 μm.

In another embodiment, the average particle size of the active pharmaceutical ingredient (fumaric acid ester) is reduced by, for example, sieving or grinding, and at least 90% of the particles are less than 800 μm, eg less than 600 μm, prior to step a) above. For example, it has a particle size of less than 500 μm, for example, less than 400 μm, for example, less than 200 μm.

In another embodiment, crystals of fumaric acid ester are sieved or ground and 90% of the particles are in the range of particle size 5 to 1000 μm, eg 10 to 900 μm, eg 20 to before step a) above. 800 μm range, eg 30-750 μm range, eg 40-600 μm range, eg 50-500 μm range, eg 100-400 μm range, eg 200-300 μm range, eg 300-600 μm range, eg 300-400 μm It has a range of, for example, 400 to 600 μm, or, for example, 500 to 600 μm.

In another embodiment, the average size of the active pharmaceutical ingredient (fumaric acid ester) is in the range of 5 to 1000 μm, eg 10 to 900 μm, eg 20 to 800 μm, eg 30 to 750 μm, prior to step a) above. Range, eg 40-600 μm, eg 50-500 μm, eg 100-400 μm, eg 200-300 μm, eg 300-600 μm, eg 300-400 μm, eg 400-600 μm Range, or range, for example 500-600 μm.

In another embodiment, the particle size distribution of the active pharmaceutical ingredient (fumaric acid ester) is such that 0-5% of the particles have a particle size> 500 μm and 45-53% of the particles have a particle size prior to step a) above. It has a size> 250 μm. As this variant, 7-15% of the particles have a particle size <100 μm prior to step a) above.

In another embodiment, the particle size distribution of the active pharmaceutical ingredient (fumaric acid ester) is such that 0-7% of the particles have a particle size> 500 μm and 42-59% of the particles prior to step a). Particle size> 250 μm. As this variant, 3-12% of the particles have a particle size <100 μm prior to step a) above.

In another embodiment, the particle size distribution of the active pharmaceutical ingredient (fumaric acid ester) is such that 0% to 10% of the particles have a particle size> 500 μm and 40-65% of the particles have a particle size> 500 μm prior to step a) above. Particle size> 250 μm. As this variant, 2-10% of the particles have a particle size <100 μm prior to step a) above.

In certain aspects of the invention, the average particle size of the active pharmaceutical ingredient (fumaric acid ester) is reduced by, for example, sieving or milling, the sieving or milling is performed so that heat generation is minimized. This will minimize or reduce the sublimation of active pharmaceutical ingredients, provide an energy efficient method, reduce API loss, reduce costs and improve environmental and worker safety. The sieving or grinding can be performed as a single sieving or grinding step or repeated several times if desired to obtain a predetermined particle distribution. In certain aspects of the invention, the sieving or grinding is carried out as a two-step process. In certain aspects of the invention, if the sieving or grinding is done in several steps, a substance that reduces agglomeration is added between the steps.

Without being bound by theory, we found that an active pharmaceutical ingredient (fumaric acid ester) having a particle size distribution within the above range causes slower in vitro dissolution and a higher particle size distribution. A lower amount of rate-determining substance can be used compared to the formulation having, for example, 10% or more of the particles have a particle size> 500 μm and / or 65% or more of the particles have a particle size> 250 μm. ..

In some aspects, lower doses of rate-determining material are tablets with higher drug doses, eg, tablets with at least 40%, 45%, 50%, 55%, or 60% active pharmaceutical ingredient based on total tablet weight. Can be manufactured.

In some embodiments of the present invention, fluidized bed granulation is used in step b).

Another aspect of the present invention is a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) Dissolve (or suspend) a rate-determining substance in the form of a polymerization matrix substance in water to obtain its aqueous suspension.
b) Spray the aqueous suspension onto the granules for a time sufficient to obtain a uniform coating on the granules of fumaric acid ester.
c) The resulting granules are dried and
d) If desired, the granules are sieved or ground and
e) Mix all pharmaceutically acceptable excipients and additives according to known methods to obtain tablets.
f) Film and / or enteric coating the tablets by a known method, if desired.
Here, all or all of the above steps are carried out at a temperature at which the temperature of the product is 45 ° C. or lower. In certain embodiments of the invention, any or all of the above steps are carried out at a temperature such that the temperature of the product is below 40 ° C, for example below 35 ° C, for example below 30 ° C. It reduces or minimizes the sublimation of active pharmaceutical ingredients to provide an energy efficient process, reduces API loss, lowers costs, and improves environmental and worker safety.

In some embodiments of the invention, the fumaric acid ester is miniaturized so that at least 90% of the particles have a particle size of up to 50 μm, eg up to 30 μm, eg up to 10 μm, prior to step b) above. Get the particle size.

In another embodiment, the average particle size of the active pharmaceutical ingredient (fumaric acid ester) is reduced by, for example, sieving or grinding, and at least 90% of the particles have a particle size of up to 800 μm prior to step b) above. For example, the maximum is 600 μm, for example, the maximum is 500 μm, for example, the maximum is 400 μm, and the maximum is 200 μm.

In some embodiments of the present invention, step b) is performed on a fluidized bed granulator.

Another aspect of the present invention is a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) If desired, sieve or grind the crystals of fumaric acid ester and
b) Direct compression mixing of fumaric acid ester crystals, rate-determining material in the form of a polymerization matrix material, and any pharmaceutically acceptable excipients and additives to obtain tablets.
c) Film and / or enteric coating the tablets by a known method, if desired.
Here, all or all of the above steps are carried out at a temperature at which the temperature of the product is 45 ° C. or lower. In certain embodiments of the invention, all or all of the above steps are carried out at temperatures such that the temperature of the product is 40 ° C. or lower, for example 35 ° C. or lower, for example 30 ° C. or lower. It reduces or minimizes the sublimation of active pharmaceutical ingredients to provide an energy efficient process, reduces API loss, lowers costs, and improves environmental and worker safety.

Another aspect of the present invention is a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) If desired, sieve or grind the crystals of fumaric acid ester and
b) Fumarate crystals are mixed in a known manner with any pharmaceutically acceptable excipient and optionally rate-determining material in the form of a polymerization matrix material to obtain tablets.
c) The mixture is roller compressed and then sieved / ground to obtain granules.
d) The granules are mixed with any additional pharmaceutically acceptable excipient to give the final mixture ready for tableting.
e) Compress to tablets
f) If desired, the tablets are film and / or enteric coated.

In certain aspects of the invention, the fumaric acid ester is premixed with one or more pharmaceutically acceptable excipients prior to step a) above.

The stability of the pharmaceutical product of the present invention can be measured by measuring the initial in vitro dissolution profile of the tablet and the in vitro dissolution profile after various storage periods, and comparing the obtained in vitro dissolution profiles. In certain aspects of the invention, the tablet is stable for at least 6 months, eg at least 9 months, eg at least 12 months, eg at least 18 months, eg at least 24 months. The stability of the pharmaceutical product of the present invention can also be measured, for example, by an assay, a standard method for measuring any change in color, or degradation products.

In certain aspects of the invention, the stability of the pharmaceutical product is the amount of API released at a predetermined time point during a standard in vitro dissolution test when comparing objective criteria, eg, first and second time points. It can be defined by the constant maximum change of. In one embodiment of the present invention, an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium is performed at the first time point (stability). For a period of time (eg at least 1 month) under ICH conditions (eg 25 ° C / 60% RH, eg 30 ° C / 65% RH, eg 40 ° C / 75% RH) compared to test time = 0). The amount of API released from the drug stored, for example for at least 3 months, for example at least 6 months, for example at least 9 months, for example at least 12 months, is as follows:
One hour after the start of the test, less than 10 percentage points, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, 2 of the amount of active pharmaceutical ingredient released from the preparation. Differences of less than% points, such as less than 1 percentage point, are observed and / or less than 10 percentage points, eg, less than 9 percentage points, eg, 8 of the amount of active pharmaceutical ingredient released from the formulation 2 hours after the start of the study. Differences of less than% points, such as less than 6 percentage points, such as less than 4 percentage points, such as less than 2 percentage points, such as less than 1 percentage point, are observed and / or activity released from the formulation 3 hours after the start of the study. Differences in the amount of pharmaceutical ingredient less than 10 percentage points, eg less than 9 percentage points, eg less than 8 percentage points, eg less than 6 percentage points, eg less than 4 percentage points, eg less than 2 percentage points, eg less than 1 percentage point, are observed. , And / or 4 hours after the start of the test, less than 10 percentage points, eg, less than 9 percentage points, eg, less than 8 percentage points, eg, less than 6 percentage points, eg, 4 percentage points, of the amount of active pharmaceutical ingredient released from the formulation. Differences of less than, eg, less than 2 percentage points, eg, less than 1 percentage point are observed, and / or less than 10 percentage points, eg, 9 percentage points, of the amount of active pharmaceutical ingredient released from the formulation 5 hours after the start of the study. Differences of less than, eg, less than 8 percentage points, eg, less than 6 percentage points, eg, less than 4 percentage points, eg, less than 2 percentage points, eg, less than 1 percentage point are observed.

In some embodiments, the pharmaceutical formulations of the present invention include psoriasis, sciatica, neurodermatitis, inflammatory bowel diseases such as Crohn's disease and uveitis, polyarthritis, multiple sclerosis (MS), juvenile diabetes. , Hashimoto thyroiditis, SLE (systemic lupus erythematosus), Schegren's syndrome, malignant anemia, chronic active (Lupoid) hepatitis, rheumatoid arthritis (RA), lupus nephritis, severe myasthenia, uveitis, refractory uveitis , Spring catarrh, uveitis vulgaris, lupus, uveitis, pain, such as nerve root pain, nerve root disorder related pain, neuropathic pain, or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis , Lipoids necrosis, or rheumatoid arthritis.

In some embodiments, psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, multiple sclerosis (MS), juvenile diabetes, Hashimoto thyroiditis, Basedow's disease , SLE (systemic lupus erythematosus), Sjogren's syndrome, malignant anemia, chronic active (wick) hepatitis, rheumatoid arthritis (RA), lupus nephritis, severe myasthenia, sciatica, refractory lupus erythematosus, spring catarrh, vulgaris Lupus erythematosus, sclerosis, optic neuritis, pain, such as lupus erythematosus, radicular disorder-related pain, neuropathic pain, or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, lipoid necrosis , Or the use of the pharmaceutical formulations of the present invention to produce a medicament for treating lupus erythematosus.

Another aspect of the invention is psoriasis, lupus erythematosus, neurodermatitis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, polyarthritis, polysclerosis (MS), juvenile diabetes, Hashimoto thyroid. Flame, Basedow's disease, SLE (systemic lupus erythematosus), Schegren's syndrome, malignant anemia, chronic active hepatitis (rheumatoid arthritis), rheumatoid arthritis (RA), lupus nephritis, severe myasthenia, sciatica, refractory sciatica, Spring catarrh, lupus vulgaris, scleroderma, optic neuritis, pain, such as radiculopathy, radiculopathy-related pain, neuropathic pain, or sciatica / sciatica pain, organ transplantation (prevention of rejection), sarcoidosis, A method for treating lipoid radiculopathy or rheumatoid arthritis, which comprises orally administering an effective amount of the controlled release pharmaceutical composition of the present invention to a patient in need thereof.

In certain aspects of the invention, the formulations of the invention are for use in the treatment of psoriasis.

In certain aspects of the invention, the formulations of the invention are for use in the treatment of psoriatic arthritis.

In certain aspects of the invention, the formulations of the invention are for use in the treatment of multiple sclerosis or recurrent remission multiple sclerosis.

In certain aspects of the invention, the formulations of the invention are for use in the treatment of rheumatoid arthritis.

It should be understood that the present invention is not limited to the specific embodiments described and can therefore vary in course. As the scope of the invention is limited only by the claims, it should be understood that the terms used herein are for illustration purposes only and are not intended to be limiting. Is. When indicating a value in a range, each value between the upper and lower limits of the range (1/10 of the unit of the lower limit unless the context explicitly states otherwise), and any other within the stated range. Alternatively, it is understood that values in between are included in the present invention. The upper and lower limits of these smaller ranges are independently included within the smaller range, provided that there are any specifically excluded limits of the indicated range. If the range shown includes one or both of the limits, then a range that excludes either or both of the limits contained therein is also included in the invention. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Any method and substance similar to or equivalent to that described herein can be used in the practice or testing of the present invention, but will describe the preferred method and substance. All publications described herein form part of this specification and describe the method and / or material for quoting the publication. Note that as used herein and in the claims, the singular forms "a", "an", and "the" include references to the plural unless the context explicitly states otherwise. Should. The patents and publications described herein merely indicate their disclosure prior to the filing date of the present application. Nothing in this specification should be construed as recognizing that the prior invention does not allow the invention to precede such patents or publications. In addition, the dates of publications listed may differ from the actual publication dates and may need to be confirmed independently. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described herein is characterized by any of the various other embodiments without departing from the scope or spirit of the invention. It has separated elements and features that can be easily separated or combined. The drawings described herein are not necessarily on scale and certain elements and features are exaggerated for clarity. Although described in some detail with illustrations and examples to clarify the understanding of the invention, it is the present invention that some modifications and modifications may be made without departing from the spirit or scope of the claims. It is easy for those skilled in the art to understand in light of the disclosure.

Take necessary precautions during all of the following steps of Examples 1-24 and 26-42 (outside air introduction protective clothing, double gloves, arm covers, breathing masks, etc.).

Manufacture of core locks
540.5 g of pulverized dimethyl fumarate (average particle size 10 μm) and 31.5 g of hydroxypropyl cellulose HPC-SL were suspended in 1716 g of purified water. The suspension was sprayed onto 405.5 g of Granulac® 140 lactose in a fluidized bed granulator basket for approximately 2 hours. The granules were dried for 5 minutes. A seal coat was applied by spraying 22.5 g of a solution of HPC-SL in 2265.5 g of purified water for about 2 hours. The product temperature never exceeded 35 ° C. Various batches were mixed and sieved through a 1.1 mm sieve.

183.3 g of dry sieved granules were mixed with 58.7 g of spray dried lactose (FlowLac® 100) in a barrel blender at 30 rpm for 15 minutes. Finally, 2.4 g of magnesium stearate was added and mixed at 30 rpm for an additional 10 minutes. The final mixture was compressed into biconvex tablets with a diameter of 10 mm and a weight of 375 mg.

Manufacture of core locks
540.5 g of non-pulverized dimethyl fumarate and 405.5 g of Granulac® 140 were placed in the basket of the fluidized bed granulator. 62.1 g of hydroxypropyl cellulose HPC-SL was dissolved in 3043 g of purified water with stirring and sprayed onto DMF tablets for 2.5 hours. The granules were dried at 29 ° C. for 4 minutes and sieved through a 1.1 mm sieve. The product temperature never exceeded 30 ° C.

135 g of dried granules were mixed with 30.4 g of spray-dried lactose (FlowLac® 100), 24.4 g of HPC-SL, and 0.3 g of Aerosil in a barrel blender at 30 rpm for 15 minutes. Finally, 1.8 g of magnesium stearate was added and mixed at 30 rpm for an additional 10 minutes. The final mixture was compressed into biconvex tablets with a diameter of 10 mm and a weight of 315.5 mg.

Manufacture of core locks
621.5 g of non-pulverized dimethyl fumarate (average particle size 500 μm) was suspended in 1793.5 g of purified water and stirred with Ultra-turrax for 5 hours to reduce particle size. Next, 36.2 g of hydroxypropyl cellulose HPC-SL was added. The suspension was sprayed on 140 tablets of 405.5 g Granulac® in a fluidized bed granulator basket for approximately 2 hours. The granules were dried for 5 minutes. A seal coat made from 26.3 g of HPC-SL in 2605 g of purified water was then applied by spraying the solution onto the granules for approximately 2 hours. The product temperature never exceeded 30 ° C.

183.3 g of dried granules were mixed with 58.7 g of spray-dried lactose (FlowLacl® 100) and 0.5 g of Aerosil in a barrel blender at 30 rpm for 15 minutes. Finally, 2.2 g of magnesium stearate was added and mixed at 30 rpm for an additional 10 minutes. The final mixture was compressed into biconvex tablets 10 mm in diameter and 375.4 mg in weight.

Manufacture of core locks
1200 g of non-pulverized dimethyl fumarate was placed in the basket of a fluidized bed granulator. 75 g of hydroxypropyl cellulose HPC-SL was dissolved in 2925 g of purified water with stirring and sprayed onto DMF for approximately 2.5 hours until 70 g of HPC was sprayed. The granules were dried at 29 ° C. for 4 minutes and then sieved through a 1.1 mm sieve. The product temperature never exceeded 30 ° C.

378.2 g of dried granules were mixed with 400.6 g of spray-dried lactose (FlowLac® 100), 14.6 g of HPC-SL and 0.9 g of Aerosil in a barrel blender at 30 rpm for 15 minutes. Finally, 5.8 g of magnesium stearate was added and mixed at 30 rpm for an additional 10 minutes. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 275 mg in weight.

Film coating of the core lock of Example 4
Film coating :
To film coat 800 g of core tablets, a 15% suspension of Opadry was prepared by adding 36 g of Opadry to 204 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a fluidized bed chamber for 35 minutes. The product temperature did not exceed 40 ° C. Following the coating process, it was dried at 30 ° C. for 16 minutes.

Film and enteric coating of core tablets of Example 4
Film coating Film coating was applied to 800 g core tablets. A 15% suspension of Opadry was prepared by adding 18 g of Opadry to 102 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a fluidized bed chamber for 20 minutes. The product temperature never exceeded 40 ° C. Following the coating process, it was dried at 30 ° C. for 9 minutes.
Enteric coating

1 kg of gastric acid resistant coating, heat 350 ml of purified water to 70-80 ° C, add 20 g of triethyl citrate, 3 g of glycerin monostearate (Cutina GMS V), 1 g of Tween 80, then with Ultra Turrax 10 Prepared by stirring for minutes to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 210 g of Eudragit L30 D 55 dispersion. Approximately 66% of the resulting gastric acid resistant coating was sprayed onto 780 g of film-coated tablets in a fluidized bed chamber at 30 ° C. for approximately 2.5 hours. It was dried at 30 ° C. for 30 minutes and then cured at 35 ° C. for another 30 minutes.

Enteric coating of core tablets of Example 4
Enteric coating
A 1 kg gastric acid resistant coating solution was prepared and sprayed onto the core tablet described in Example 6.

Granules were produced as described in Example 4.

416 g of dried granules were mixed with 360.8 g of spray-dried lactose (FlowLac® 100), 16 g of HPC-SL and 1 g of Aerosil in a barrel blender at 30 rpm for 15 minutes. Finally, 6.4 g of magnesium stearate was added and mixed at 30 rpm for an additional 10 minutes. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight.

Film coating of the core lock of Example 8
Film coating A film coating was produced as described in Example 5.

Film and enteric coating of core tablets of Example 8
Film coating Film coating was applied to 800 g of the core locks described in Example 6.

Enteric coating
1 kg of gastric acid resistant coating solution was prepared and applied as described in Example 6.

Granules were produced as described in Example 4.

404.5 g of dried granules are mixed with 272.9 g of spray-dried lactose (FlowLac 100®), 15.5 g of HPC-SL, and 0.9 g of Aerosil in a barrel blender at 30 rpm for 15 minutes. Finally, add 6.2 g of magnesium stearate and mix at 30 rpm for 10 minutes. The final mixture is compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight.

Film coating of core tablets is performed according to Example 11.

Film coating For film coating, 800 g of core lock is coated as described in Example 5. Mix active tablets with colored placebo to make 800 g tablets available for coating.

The core tablet film and enteric coating according to Example 11.
Film coating The film coating was coated with 800 g of core tablets as described in Example 5. Active tablets were mixed with colored placebo to make 800 g tablets available for coating.

Enteric coating
1 kg of gastric acid resistant coating solution was prepared and applied as described in Example 6.

Granules were prepared as described in Example 4.

130 g of dried granules were mixed with 52.7 g of spray-dried lactose (FlowLac® 100), 40 g of HPC-SL, and 0.3 g of Aerosil in a barrel blender at 30 rpm for 15 minutes. Finally, 2.0 g of magnesium stearate was added and mixed at 30 rpm for an additional 10 minutes. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 225 mg in weight.

Film coating of the core lock according to Example 14.
Film coating The film coating was coated with 800 g of core tablets as described in Example 5. Active tablets were mixed with colored placebo to make 800 g tablets available for coating.

The core tablet film and enteric coating according to Example 14.
Film coating Film coating was applied to 800 g core tablets. Therefore, tablets containing API were mixed with colored placebo to obtain the required amount. A 15% suspension of Opadry was prepared and applied as described in Example 6.

Enteric coating
1 kg of gastric acid resistant coating solution was prepared and applied as described in Example 6.

Dissolution profiles of the films and enteric coated tablets of this example were obtained according to the United States Pharmacopeia (USP) in vitro study. The test was performed at 37 ° C. using a paddle lysing device (100 rpm) with 0.1N hydrochloric acid as the lysis medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the lysis medium for the remaining test time. It was done using. The results are shown in Figure 1.

1.2 kg of dimethyl fumarate was sieved through a 700 μm sieve and placed in the basket of a fluidized bed granulator. 70.6 g of polymer hydroxypropyl cellulose HPC-SL was dissolved in 2753 g of purified water with stirring and sprayed onto DMF for 2.5-3 hours. The granules were dried at 29 ° C. for 3 minutes. Various batches were mixed and sieved through an 800 μm sieve.

1730.7 g of dried and further 500 μm sieved granules, 781.3 g of granular lactose (Tablettose® 100), 66.7 g of HPC-SL, and Aerosil® and Tablettose®. The premix was mixed with a barrel blender at 20 rpm for 15 minutes. The premix was prepared from 4 g of colloidal silicic acid (Aerosil®) and 390.6 g of Tablettose® in a polyethylene bag and sieved at 500 μm. Finally, 26.7 g of magnesium stearate was added. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 225 mg in weight.

Film and enteric coating of core tablets of Example 17
Film coating
To film coat 800 g of core tablets, a 15% suspension of Opadry was prepared by adding 18 g of Opadry to 102 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a fluidized bed chamber for 20 minutes. The product temperature never exceeded 40 ° C. Following the coating process, it was dried at 30 ° C. for 9 minutes.

Enteric coating
1 kg of gastric acid resistant coating, 350 ml of purified water heated to 70-80 ° C, 9.5 g of triethyl citrate, 1.9 g of glycerin monostearate (Cutina GMS V), 0.7 g of Tween 80, then Ultra Turrax Stir for 10 minutes to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 210 g of Eudragit® L30 D 55 dispersion. Approximately 66% of the resulting gastric acid resistant coating was sprayed onto a 780 g film-coated tablet in a fluidized bed chamber.

The dissolution profile of the film and enteric coated tablets of this example was followed in accordance with the in vitro dissolution test described in Example 16 with 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test, followed by 0.05 M phosphate buffer pH 6. 8 was obtained using as a dissolution medium (see Fig. 1).

1.2 kg of dimethyl fumarate was sieved through a 700 μm sieve and placed in the basket of a fluidized bed granulator. 70.6 g of hydroxypropyl cellulose HPC-SL was dissolved in 2753 g of purified water with stirring and sprayed onto DMF for 2.5-3 hours. The granules were dried at 29 ° C. for 3 minutes and then sieved through a 500 μm sieve.

964 g of dried and sieved granules, 565.5 g of granular lactose (Tablettose® 100), 37.4 g of HPC-SL, and a premixture of Aerosil® and Tablettose® and barrel blender Mix at 20 rpm for 15 minutes. The premix was prepared from 2.3 g of colloidal silicic acid (Aerosil®) and 282.7 g of Tablettose® in a polyethylene bag and then sieved at 500 μm. Finally, 14.9 g of magnesium stearate was added. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight.

Film and enteric coating of core tablets of Example 19
Film coating
To film coat 800 g of core tablets, a 15% suspension of Opadry is prepared and applied as described in Example 18.

Enteric coating
1 kg of gastric acid resistant coating, 350 ml of purified water heated to 70-80 ° C, 9.5 g of triethyl citrate, 1.9 g of glycerin monostearate (Cutina GMS V), 0.7 g of Tween 80, then Prepared by stirring with Ultra Turrax for 10 minutes to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 210 g of Eudragit® L30 D 55 dispersion. About 66% of the obtained gastric acid resistant coating solution was sprayed on a 780 g film-coated tablet in a fluidized bed chamber at a temperature of 30 ° C. for about 2.5 hours. It was dried at 30 ° C. for 30 minutes and then cured at 35 ° C. for an additional 30 minutes.

The dissolution profile of the film and enteric coated tablets was according to the in vitro dissolution test described in Example 16 with 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium. (See Fig. 1).

1.2 kg of dimethyl fumarate was sieved through a 700 μm sieve and placed in the basket of a fluidized bed granulator. 70.6 g of hydroxypropyl cellulose HPC-SL was dissolved in 2753 g of purified water with stirring and sprayed onto DMF for 2.5-3 hours. The granules were dried at 29 ° C. for 3 minutes. Several batches were mixed and sieved at 800 μm.

1416 g of dried, further 500 μm sieved granules of 1002.9 g of granular lactose (Tablettose® 100), 54.6 g of HPC-SL, and Aerosil® and Tablettose® The premix was mixed with a barrel blender at 20 rpm for 15 minutes. A premix of 3.3 g of colloidal silicic acid (Aerosil®) and 501.4 g of Tablettose® was prepared in a polyethylene bag and sieved at 500 μm. Finally, 21.8 g of magnesium stearate was added. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 275 mg in weight.

Film and enteric coating of core tablets of Example 21
Film coating
To film coat 800 g of core tablets, a 15% suspension of Opadry was prepared and applied as described in Example 18.

Enteric coating :
1 kg of gastric acid resistant coating, 350 ml of purified water heated to 70-80 ° C, 9.5 g of triethyl citrate, 1.9 g of glycerin monostearate (Cutina GMS V), 0.7 g of Tween 80, then Prepared by stirring with Ultra Turrax for 10 minutes to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was then stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 210 g of Eudragit® L30 D 55 dispersion. About 66% of the obtained gastric acid resistant coating solution was sprayed onto a 780 g film-coated tablet in a fluidized bed chamber at a temperature of 30 ° C. for about 2.5 hours. It was dried at 30 ° C. for 30 minutes and then cured at 35 ° C. for another 30 minutes.

Films and enteric coated tablets using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05M phosphate buffer pH 6.8 as the dissolution medium according to the in vitro dissolution test described in Example 16. The dissolution profile is shown in Figure 1.

Film coating of the core lock of Example 18
Film coating
To film coat 800 g of core tablets, a 15% suspension of Opadry was prepared by adding 36 g of Opadry to 204 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a fluidized bed chamber for 35 minutes. The product temperature never exceeded 40 ° C. Following the coating process, it was dried at 30 ° C. for 16 minutes.

Figure 2 shows the dissolution profile of the film-coated tablets of this example that were subjected to an in vitro dissolution test using 0.1N hydrochloric acid as the dissolution medium for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution medium. ..

18 g of pure DMF (particle size 250-500 μm) was mixed with 6.3 g of HPC-SL, 9.1 g of spray-dried lactose (FlowLac® 100) and 0.045 g of Aerosil. Finally, 0.3 g of magnesium stearate was added and mixed. The final mixture was compressed to give a biconvex tablet 8 mm in diameter and 225 mg in weight.

This study is a one-center study of an open-label, randomized, cross-design, based on the commercially available Fumaderm®, the plasma concentration, pharmacokinetics, safety, and tolerability of the pharmaceutical product of the present invention. Sex was tested. A single oral dose of 240 mg (2 tablets each containing 120 mg) of the tablets was administered to 20 healthy Caucasian male subjects at random during each treatment period. The study was divided into four treatment periods (treatment periods 1, 2, 3 and 4) separated by a washout period of at least 7 days.

Subjects were screened for eligibility, including the following, at least 21-2 days prior to the first dose: Checking inclusion / exclusion criteria; Artificial statistical data (age, height, weight, body mass index (BMI), race) (Including); Health Examination; Overall Medical History; 12-Lead ECG (ECG); Life Signs (Blood Pressure (BP), Pulse Rate (PR), and Body Temperature (BT)); Laboratory Test Parameters (Hematology, Serum Biochemistry, and) Urinalysis); Supported by documentary records of comorbidities and drug treatment.

During each of the four treatment periods, subjects came to the study facility from the night of Day 1 until a 24-hour blood sample for PK analysis was taken and all safety tests were performed (= Morning of Day 2). stayed.

Subject was fasted overnight. One single oral dose (2 tablets) of the formulation of the invention (Examples 18, 20, or 22), or 2 enteric coated tablets of the standard drug drug Fumaderm® (120 mg each). The dimethyl-containing (total dose 240 mg dimethyl fumarate) was administered on day 1 (according to randomization). Fasted subjects were administered with 240 mL of tap water. A washout period of at least 7 days was maintained between each dose.

The following evaluations / measurements were performed: Blood was collected before administration and at pre-planned post-administration times to measure plasma concentrations and PK-parameters.

Adverse events were recorded in detail throughout the study.

Urine was collected before administration and at the time after administration planned in advance.

Follow-up studies including the following were performed at least 7 days after the final dose (treatment period 4): health examination; life signs (BP, PR, and BT); body weight; 12-lead ECG; laboratory parameters (hematology, Serum biochemistry and urinalysis); evidenced by concomitant medications and record of adverse events.

Preparation of core tablets Dimethyl fumarate was sieved through a 500 μm hand screen. 29.3 g of sieved dimethyl fumarate, 2.93 g of HPC-SL, 22.17 g of granular lactose (Tablettose® 100), 0.07 g of Aerosil®, and 0.49 g of magnesium stearate 10 Mix for minutes. The mixture was compressed to give a biconvex tablet with a diameter of 8 mm and a weight of 225 mg.

(Example 27a)
Preparation of core tablets Dimethyl fumarate was sieved through a 500 μm hand screen. 500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of spray-dried lactose (FlowLac® 100), and 1.2 g of Aerosil® were mixed in a barrel blender at 20 rpm for 15 minutes. .. Finally, 4 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight.

Enteric coated gastric acid resistant coating, heat 247 g of purified water to 70-80 ° C, then add 9 g of triethyl citrate, 1.8 g of glycerin monostearate (Cutina GMS V), and 0.72 g of Tween 80. , Ultra Turrax for 10 minutes to prepare a homogeneous mixture. 495 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 200 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater. The amount of solution sprayed onto the tablets was 1.5% solid w / w, and the weight of the coated tablets was increased by 1% as compared to the core tablets.

(Example 27b)
The core tablet was produced as described in Example 27a.

Enteric coated gastric acid resistant coating, heat 247 g of purified water to 70-80 ° C, then add 9 g of triethyl citrate, 1.8 g of glycerin monostearate (Cutina GMS V), and 0.72 g of Tween 80. , Ultra Turrax for 10 minutes to prepare a homogeneous mixture. 495 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 200 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater. The amount of solution sprayed onto the tablets was 2.5% solid w / w, and the weight of the coated tablets increased by 1.8% compared to the core tablets.

Preparation of core tablets Dimethyl fumarate was sieved through a 500 μm hand screen. 500 g of sieved dimethyl fumarate, 48 g of HPC-SL and 447 g of granular lactose (Tablettose® 100), and 1.2 g of Aerosil® were mixed in a barrel blender at 20 rpm for 15 minutes. .. Finally, 4 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight.

Enteric coated gastric acid resistant coating, heated 99 g of purified water to 70-80 ° C, then 10.1 g of triethyl citrate, 2.0 g of glycerin monostearate (Cutina GMS V), and 0.8 g of Tween 80. In addition, it was prepared by stirring with Ultra Turrax for 10 minutes to obtain a homogeneous mixture. 198 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 224 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater. The solution was sprayed so that the weight gain of the core tablets was 3%.

(Example 29a)
Preparation of core tablets Dimethyl fumarate was ground through a 1143 μm to 610 μm screen. Mix 500 g of sieved dimethyl fumarate, 48 g of HPC-SL, and 447 g of granular lactose (Tablettose® 100), and 1.2 g of Aerosil® in a barrel blender at 20 rpm for 15 minutes. did. Finally, 4 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight.

Enteric coated gastric acid resistant coating, heat 247 g of purified water to 70-80 ° C, then add 9 g of triethyl citrate, 1.8 g of glycerin monostearate (Cutina GMS V), and 0.72 g of Tween 80. , Ultra Turrax for 10 minutes to prepare a homogeneous mixture. 495 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 200 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater.
The amount of Eudragit sprayed onto the tablets was 2.5% solid w / w, and the weight gain of the coated tablets was 1.5% compared to the core tablets.

(Example 29b)
The core tablet was produced as described in Example 29a.

Enteric coated gastric acid resistant coating, heat 247 g of purified water to 70-80 ° C, then add 9 g of triethyl citrate, 1.8 g of glycerin monostearate (Cutina GMS V), and 0.72 g of Tween 80. , Ultra Turrax for 10 minutes to prepare a homogeneous mixture. 495 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 200 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater. The amount of Eudragit sprayed onto the tablets was 3.5% solid w / w, and the weight gain of the coated tablets relative to the core tablets was 2%.

Manufacture of core locks
2500 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. 6 g of Aerosil® was added prior to the second grinding step. The particle size distributions obtained were> 500 μm for about 11%,> 250 μm for about 70%, and <100 μm for about 7%. The average particle size was 358 μm.

The ground material was further mixed with 240 g of HPC-SL and 2714 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 20 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 275 mg in weight. The core tablets were optionally coated with an enteric coating as described in Example 33a.

Manufacture of core locks
2500 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 6 g of Aerosil® was added. The particle size distributions obtained were> 500 μm for about 3%,> 250 μm for about 65%, and <100 μm for about 6%. The average particle size was 290 μm.

The ground material was further mixed with 240 g of HPC-SL and 2714 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 20 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 275 mg in weight. The core tablet can be enteric coated as described in Example 33a or b.

Manufacture of core locks
2500 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 6 g of Aerosil® was added. The resulting particle size distribution was> 500 μm for about 3%,> 250 μm for about 50%, and <100 μm for about 10%. The average particle size was 250 μm.

The ground material was further mixed with 240 g of HPC-SL and 2714 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 20 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 275 mg in weight. Core tablets were optionally coated with enteric coated as described in Example 33b.

(Example 33a)
Enteric coated gastric acid resistant coating, heat 1193 g of purified water to 70-80 ° C, then add 45 g of triethyl citrate, 13.5 g of glycerin monostearate (Cutina GMS V), and 5.4 g of Tween 80. , Ultra Turrax for 10 minutes to obtain a homogeneous mixture. 2385 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 1500 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater. The amount of Eudragit sprayed onto the tablets was 3.0% w / w, and the weight gain of the coated tablets was 2.5% compared to the core tablets.

(Example 33b)
Enteric coated gastric acid resistant coating, heat 1193 g of purified water to 70-80 ° C, then add 45 g of triethyl citrate, 13.5 g of glycerin monostearate (Cutina GMS V), and 5.4 g of Tween 80. , Ultra Turrax for 10 minutes to prepare a homogeneous mixture. 2385 g of purified water was added and the mixture was stirred with a propeller stirrer until the emulsion reached room temperature. The emulsion was then gradually added to 1500 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core tablet in a perforated drum coater. The amount of Eudragit sprayed onto the tablets was 3.5% w / w, and the weight gain of the coated tablets was 3% compared to the core tablets.

Manufacture of core locks
2500 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 6 g of Aerosil® was added. The particle size distributions obtained were> 500 μm for 8%,> 250 μm for 80%, and <100 μm for 0%. The average particle size was 360 μm.

The ground material was further mixed with 240 g of HPC-SL and 2234 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 20 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight. The core tablet can be enteric coated as described in Example 33a or b.

Manufacture of core locks
2500 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 6 g of Aerosil® was added. The particle size distributions obtained were 6%> 500 μm, 65%> 250 μm, and 6% <100 μm. The average particle size was 305 μm.

The ground material was further mixed with 240 g of HPC-SL and 2234 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 20 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight. The core tablet can be enteric coated as described in Example 33a or b.

Manufacture of core locks
2500 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 6 g of Aerosil® was added. The particle size distributions obtained were> 500 μm for 3%,> 250 μm for 63%, and <100 μm for 6%. The average particle size was 290 μm.

The ground material was further mixed with 240 g of HPC-SL and 2234 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 20 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight. The core tablet can be enteric coated as described in Example 33a or b.

Manufacture of core locks
2500 g of dimethyl fumarate is ground through a 1575 μm-813 μm screen. Prior to the second grinding step, add 6 g of Aerosil®.

The ground material is further mixed with 240 g of HPC-SL and 1714 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, add 20 g of magnesium stearate and mix the mixture again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet with a diameter of 8 mm and a weight of 225 mg. The core tablet can be enteric coated as described in Example 33a or b.

2.500 g of DMF is ground through a 1575 μm-813 μm screen. Add 240 g HPC-SL, 2.734 g Tablettose 100, and 6 g Aerosil and mix with DMF. The mixture was rolled on a roller and granules were obtained through a 1 mm screen. Mix 20 g of magnesium stearate to obtain the final mixture ready for tableting. The mixture is compressed to give tablets weighing 275 mg. The core tablet can be enteric coated as described in Example 33a or b.

2.50 Og of DMF is mixed with 6 g of Aerosil and then ground through a 1575 μm-813 μm screen. Add 240 g HPC-SL and 2.734 g Tablettose 100 and mix with DMF and Aerosil. The mixture was rolled on a roller and granules were obtained through a 1 mm screen. Mix 20 g of magnesium stearate to obtain the final mixture ready for tableting. The mixture is compressed to give tablets weighing 275 mg. The core tablet can be enteric coated as described in Example 33a or b.

2000 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 4.8 g of Aerosil® was added.

475.3 g of ground material was further mixed with 519.8 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 3.8 g of magnesium stearate was added and then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet with a diameter of 8 mm and a weight of 263 mg. The core tablet can be enteric coated as described in Example 33a or b.

2000 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 4.8 g of Aerosil® was added.

468.2 g of ground material was further mixed with 15 g of HPC-SL and 512 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 3.7 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet with a diameter of 8 mm and a weight of 267 mg. The core tablet can be enteric coated as described in Example 33a or b.

2000 g of dimethyl fumarate was ground through a 1575 μm-813 μm screen. Prior to the second grinding step, 4.8 g of Aerosil® was added.

500 g of ground material was further mixed with 32 g of HPC-SL and 562,8 g of granular lactose (Tablettose® 100) in a barrel blender at 20 rpm for 15 minutes. Finally, 4 g of magnesium stearate was added, then the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed to give a biconvex tablet 8 mm in diameter and 250 mg in weight. The core tablet can be enteric coated as described in Example 33a or b.

A test similar to that described in Example 25 was performed on the tablets described in Examples 18 and 22 and compared with the corresponding data for the prior art formulation Fumaderm®. The test results are shown in Table I and Table II below.

The above results of the clinical trial show a marked reduction in adverse effects on Fumaderm® (Table II) and low variability (Table I) of the manufactured product. That is, this example shows that the formulation of the present invention provides an unexpectedly large reduction in _{AUC and C max variability as compared with the prior art Fumaderm® formulation.}

Claims (1)

Pharmaceutical formulation in the form of an erosion matrix tablet containing:
i) as active substance, 10 to 80 wt%, of fumaric acid di - (C ₁ -C ₅₎ alkyl esters and fumaric acid mono - (C ₁ -C _{5) 1} or more selected from alkyl esters Fumaric acid ester, or a pharmaceutically acceptable salt thereof, and
ii) 1 to 50% by weight of 1 or more rate-determining substances,
Here, erosion of the erosion matrix allows for controlled or sustained release of the active substance.

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