JP2021120397A - Pharmaceutical composition containing dimethyl fumarate for administration at a low daily dose - Google Patents

Abstract

To provide a pharmaceutical composition having a lowered daily dose of dimethyl fumarate in an effective oral formulation, for use in the treatment of psoriasis (including moderate to severe plaque psoriasis).SOLUTION: The present invention provides a pharmaceutical composition for oral treatment of psoriasis by administering dimethyl fumarate at a low daily dose in range of 375 mg±5%. The pharmaceutical composition is in the form of an erosion matrix tablet.SELECTED DRAWING: None

Description

The present invention relates to pharmaceutical compositions containing dimethyl fumarate (DMF). More specifically, the present invention is for oral treatment of psoriasis (including moderate to severe psoriasis vulgaris) by administering a low daily dose of dimethyl fumarate in the range of 375 mg ± 5%. The present invention relates to a pharmaceutical composition, wherein the pharmaceutical preparation is in the form of an erosion matrix tablet.

Fumarate ester, dimethyl fumarate, has been used for many years in the treatment of psoriasis in combination with ethyl fumarate. The combination is sold under the registered trademark of Fumarate®. The combination takes the form of an oral enteric coated tablet.

Fumarate® is commercially available with two different active ingredient contents (Fumarate® initials and Fumarate®):

The contents of the two active ingredients are applied to the individual dosing regimens, starting with Fumarate® initials, gradually increasing the dose and then switching to Fumarate® after, for example, 3 weeks of treatment. The purpose is. However, due to the high frequency of side effects, some patients discontinue early in treatment. It is believed that side effects of the gastrointestinal tract and at least part of flushing can be explained by the release properties of the preformation, which results in high topical drug concentrations on the intestinal mucosa, followed by high plasma concentrations of drug metabolites.

In order to reduce side effects, Patent Document 1, Patent Document 2 and Patent Document 3 recommend that a microtablet containing DMF and / or MMF be produced.

Another method of reducing unwanted side effects is to produce the controlled release formulation disclosed in Patent Document 4.

Further, a specific controlled release preparation is disclosed in Patent Document 5. The controlled release formulation contains one or more fumaric acid esters in the erosion matrix tablet, which has a thinner enteric coating than the common enteric coatings in the art. The pharmaceutical preparation disclosed in Patent Document 6 exhibits excellent pharmacokinetic parameters.

DMF preparations and administration methods tried in clinical trials include gastrointestinal (GI) side effects such as red tide, diarrhea, abdominal pain (stomach ache, stomach pain, abdominal pain), abdominal spasm, nausea, flatulence, swelling, bloating. (Meteorism), increased bowel movements, bloating, and / or upper abdominal cramps.

European Patent No. EP-A-1 131 065 European Patent No. EP-A-1 059 920 European Patent No. EP-A-1 123 092 International Publication WO 2006/037342 A2 International Publication WO 2010/079222 Al International Publication WO 2010/079222

Considering the above, the problem to be solved by the present invention is to reduce the daily dose of dimethyl fumarate in an effective oral preparation used for the treatment of psoriasis (including moderate to severe psoriasis vulgaris). be.

Surprisingly, it has become clear that as a means to solve the above problems, an erosion matrix tablet containing dimethyl fumarate as a single active ingredient at a dose of 375 mg ± 5% per day can be used.

The erosion matrix formulation will allow the active ingredient DMF to be slowly and controlledly released within the intestinal lumen. This slow release allows the intestinal immune system to be exposed to the active ingredient for extended periods of time before and even during the absorption process into the systemic circulation. This local exposure induces local immunoregulation in addition to systemic pharmacological effects. These locally regulated immune cells regulate this systemic pharmacological effect in addition to the possible systemic effects. This slow, controlled release enhances the activity of DMF on cells in the local immune system, allowing pharmacological activity of the drug at unexpectedly low dose levels of 375 mg ± 5% per day.

More specifically, the present invention relates to the following aspects:

According to a first aspect, the invention is a pharmaceutical composition for the oral treatment of psoriasis, which is in the form of a tablet core and an erosion matrix tablet comprising one or more coatings. The tablet core
i) contains 10 to 80% by weight of dimethyl fumarate as the active substance, and ii) 1 to 50% by weight of the rate-determining substance, and at least one of the above 1 or more coatings is 1. It is an enteric coating applied at a level of 5 to 3.5% by weight and is intended for pharmaceutical compositions in which the dose of dimethyl fumarate administered is 375 mg ± 5% per day.

According to another preferred embodiment of the present invention, the tablet core of the pharmaceutical composition of the above embodiment is:
i) 30-60% by weight dimethyl fumarate, and ii) 3-40% by weight 1 or more rate-determining material.

It is preferable that the rate-determining substance is a water-soluble polymer. It is even more preferable that the rate-determining substance is a cellulose polymer, a cellulose derivative, or a mixture thereof.

According to another preferred embodiment of the invention, the rate-determining material is selected from the group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HMPC), methyl cellulose, carboxymethyl cellulose, and mixtures thereof. Most preferably, the rate-determining substance is hydroxypropyl cellulose.

According to another preferred embodiment of the invention, the tablet core of any one of the above aspects of the pharmaceutical composition comprises a binder. According to a preferred embodiment, the binder is lactose.

According to a more specific aspect of the present invention, the tablet core of any one of the above aspects of the pharmaceutical composition is:
i) 35-55% by weight dimethyl fumarate,
It contains ii) 3-12% by weight hydroxypropyl cellulose, and ii) 40-60% by weight lactose.

More preferably, the tablet core is
i) 40-50% by weight dimethyl fumarate,
It contains ii) 3-12% by weight hydroxypropyl cellulose, and ii) 45-55% by weight lactose.

The tablet core
i) 42-48% by weight dimethyl fumarate,
It is even more preferred to include ii) 3-10% by weight hydroxypropyl cellulose and ii) 45-52% by weight lactose.

In another aspect of the invention, the amount of hydroxypropyl cellulose in the tablet core defined above is 3-6% by weight.

According to a more preferred embodiment of the present invention, the tablet core of the pharmaceutical composition in any one of the above embodiments further comprises 0.15 to 0.7% by weight magnesium stearate, optionally from 0.05 to 0.05%. It may contain 0.25% by weight of silicon dioxide.

In certain aspects of the invention, the pharmaceutical composition is for administration once, twice or three times daily.

The pharmaceutical composition of any one of the above embodiments is for the treatment of psoriasis, including moderate to severe psoriasis vulgaris.

Furthermore, the present invention relates to the following aspects:

1. 1. A pharmaceutical composition in the form of a tablet core and an erosion matrix tablet comprising one or more coatings, wherein the tablet core is:
i) Containing 10 to 80% by weight of dimethyl fumarate as the active substance, and ii) 1 to 50% by weight of the rate-determining substance, and at least one of the above 1 or more coatings is 1. A pharmaceutical composition which is an enteric coating applied at a level of 5 to 3.5% by weight, wherein the erosion matrix tablet contains 375 mg ± 5% dimethyl fumarate.

2. The tablet core
The pharmaceutical composition according to Item 1 above, which comprises 30 to 60% by weight of dimethyl fumarate and ii) 3 to 40% by weight of a rate-determining substance of 1 or more.

3. 3. Item 2. The pharmaceutical composition according to Item 1 or 2, wherein the rate-determining substance is a water-soluble polymer.

4. Item 8. The pharmaceutical composition according to any one of Items 1 to 3, wherein the rate-determining substance is a cellulose polymer, a cellulose derivative, or a mixture thereof.

5. Item 4. The pharmaceutical composition according to Item 4, wherein the rate-determining substance is selected from the group containing hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose, and a mixture thereof.

6. Item 5. The pharmaceutical composition according to Item 5, wherein the rate-determining substance is hydroxypropyl cellulose.

7. The pharmaceutical composition according to any one of the preceding paragraphs, wherein the tablet core further comprises a binder.

8. Item 7. The pharmaceutical composition according to Item 7, wherein the binder is lactose.

9. The tablet core
i) 35-55% by weight dimethyl fumarate,
The pharmaceutical composition according to any one of the preceding paragraphs, which comprises ii) 3 to 12% by weight of hydroxypropyl cellulose and iii) 40 to 60% by weight of lactose.

10. The tablet core
i) 40-50% by weight dimethyl fumarate,
Item 9. The pharmaceutical composition according to Item 9, which comprises ii) 3 to 12% by weight of hydroxypropyl cellulose, and iii) 45 to 55% by weight of lactose.

11. The tablet core
i) 42-48% by weight dimethyl fumarate,
Item 10. The pharmaceutical composition according to Item 10, wherein ii) contains 3 to 10% by weight of hydroxypropyl cellulose, and ii) 45 to 52% by weight of lactose.

12. The tablet core
i) 35-55% by weight dimethyl fumarate,
The pharmaceutical composition according to any one of the preceding paragraphs, which comprises ii) 3 to 6% by weight of hydroxypropyl cellulose and iii) 40 to 60% by weight of lactose.

13. The tablet core
i) 40-50% by weight dimethyl fumarate,
Item 12. The pharmaceutical composition according to Item 12, which comprises ii) 3 to 6% by weight of hydroxypropyl cellulose and iii) 45 to 55% by weight of lactose.

14. The tablet core
i) 42-48% by weight dimethyl fumarate,
Item 13. The pharmaceutical composition according to Item 13, which comprises ii) 3 to 5.5% by weight of hydroxypropyl cellulose and iii) 45 to 52% by weight of lactose.

15. The tablet core further contains 0.15 to 0.7% by weight of magnesium stearate and may optionally contain 0.05 to 0.25% by weight of silicon dioxide, according to any one of the preceding paragraphs. Pharmaceutical composition.

16. The pharmaceutical composition according to any one of the preceding paragraphs, wherein the erosion matrix tablet contains about 375 mg of dimethyl fumarate.

17. The pharmaceutical composition according to any one of the preceding paragraphs, wherein dimethyl fumarate takes the form of a crystalline powder.

18. A method of treating psoriasis in a subject in need of treatment, wherein the method administers the subject in the form of an erosion matrix tablet comprising a tablet core and one or more coatings. And the tablet core
i) Containing 10 to 80% by weight of dimethyl fumarate as the active substance, and ii) 1 to 50% by weight of the rate-determining substance, and at least one of the above 1 or more coatings is 1. A method of treatment, wherein the enteric coating is applied at a level of 5 to 3.5% by weight, and the dose of dimethyl fumarate administered is from 375 mg ± 5% per day.

19. The tablet core
Item 18. The method of item 18, comprising i) 30-60% by weight dimethyl fumarate, and ii) 3-40% by weight one or more rate-determining material.

20. Item 18. The method according to Item 18 or 19, wherein the rate-determining substance is a water-soluble polymer.

21. Item 8. The method according to any one of Items 18 to 29, wherein the rate-determining substance is a cellulose polymer, a cellulose derivative, or a mixture thereof.

22. Item 2. The method of Item 21, wherein the rate-determining substance is selected from the group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose, and mixtures thereof.

23. Item 22. The method of Item 22, wherein the rate-determining substance is hydroxypropyl cellulose.

24. Item 8. The method according to any one of Items 18 to 23, wherein the tablet core further comprises a binder.

25. Item 24. The method of Item 24, wherein the binder is lactose.

26. The tablet core
i) 35-55% by weight dimethyl fumarate,
iii) The pharmaceutical composition according to any one of Items 18 to 25, which comprises 3 to 12% by weight of hydroxypropyl cellulose and iii) 40 to 60% by weight of lactose.

27. The tablet core
i) 40-50% by weight dimethyl fumarate,
Item 26. The pharmaceutical composition according to Item 26, which comprises ii) 3 to 12% by weight of hydroxypropyl cellulose, and iii) 45 to 55% by weight of lactose.

28. The tablet core
i) 42-48% by weight dimethyl fumarate,
Item 27. The pharmaceutical composition according to Item 27, which comprises ii) 3 to 10% by weight of hydroxypropyl cellulose, and iii) 45 to 52% by weight of lactose.

29. The tablet core
i) 35-55% by weight dimethyl fumarate,
Item 6. The method according to any one of Items 18 to 25, which comprises ii) 3 to 6% by weight of hydroxypropyl cellulose and iii) 40 to 60% by weight of lactose.

30. The tablet core
i) 40-50% by weight dimethyl fumarate,
Item 29. The method of item 29, comprising ii) 3-6% by weight hydroxypropyl cellulose, and iii) 45-55% by weight lactose.

31. The tablet core
i) 42-48% by weight dimethyl fumarate,
Item 30. The method of item 30, comprising ii) 3 to 5.5% by weight of hydroxypropyl cellulose, and iii) 45 to 52% by weight of lactose.

32. Any one of Items 18-31, wherein the tablet core further comprises 0.15-0.7% by weight magnesium stearate and optionally 0.05-0.25 wt% silicon dioxide. The method described in the section.

33. Item 6. The method according to any one of Items 18 to 32, wherein the dose of dimethyl fumarate to be administered is about 375 mg of dimethyl fumarate per day.

34. Item 8. The method according to any one of Items 18 to 27, wherein dimethyl fumarate takes the form of a crystalline powder.

35. Item 8. The method according to any one of Items 18 to 34, wherein the composition is administered once, twice or three times a day.

36. Item 35. The method of item 35, wherein the erosion matrix tablet comprises 375 mg ± 5% dimethyl fumarate, and the erosion matrix tablet is administered once daily.

37. 36. The method of item 36, wherein the erosion matrix tablet comprises about 375 mg of dimethyl fumarate.

38. Item 18. The method according to Item 1, wherein the erosion matrix tablet according to Item 1 is administered to a subject in need of treatment, and after the erosion matrix tablet is orally administered in a fasted state. When dimethyl fumarate is hydrolyzed, monomethyl fumarate appears in the plasma of the subject, and the Cmax of monomethyl fumarate in the plasma of the subject is between about 0.3 mg / L and about 2 mg / L. ..

39. Item 18. The method according to Item 1, wherein the erosion matrix tablet according to Item 1 is administered to a subject in need of treatment, and the erosion matrix tablet is orally administered in a fasted state and then fumaru. A method in which when dimethyl fumarate is hydrolyzed, monomethyl fumarate appears in the plasma of the subject, and the Tmax of monomethyl fumarate in the plasma of the subject is between about 1.5 hours and about 4.5 hours.

40. Item 18. The method according to Item 1, wherein the erosion matrix tablet according to Item 1 is administered to a subject in need of treatment, and the erosion matrix tablet is orally administered in a fasted state and then fumaru. When dimethyl fumarate is hydrolyzed, monomethyl fumarate appears in the subject's plasma, and the circulating plasma concentration of monomethyl fumarate in the subject's plasma begins within 1 hour after administration, approximately 1 hour to 4 hours. A method that has at least 50% of the Cmax obtained over 5 hours and can be measured over a total of about 5-8 hours.

41. Item 40. The method of item 40, wherein the subject in need of treatment suffers from mild to moderate psoriasis vulgaris, moderate to severe psoriasis vulgaris, or severe psoriasis vulgaris.

(Detailed description of the invention)
The pharmaceutical composition in the form of a matrix tablet of the present application is a controlled release preparation that continuously releases the active ingredient, that is, dimethyl fumarate. More specifically, the erosion matrix was at 37 ° C. and a paddle rate of 100 rpm with 0.1 N hydrochloric acid as the elution test solvent for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the elution test solvent. Performing an in vitro dissolution test with, preferably results in the release of dimethyl fumarate:
Within the first 2 hours after the start of the test, the total amount of dimethyl fumarate contained in the pharmaceutical composition is about 0% w / w to about 10% w / w, preferably 0% w / w to about 5% w / w. , More preferably 0% w / w to <2% w / w.
Within the first 2.5 hours after the start of the test, about 2% w / w to about 20% w / w of the total amount of dimethyl fumarate contained in the pharmaceutical composition was released.
Within the first 3.5 hours after the start of the test, about 35% w / w to about 65% w / w of the total amount of dimethyl fumarate contained in the pharmaceutical composition was released.
Within the first 6 hours after the start of the test, > 85% w / w of the total amount of dimethyl fumarate contained in the pharmaceutical composition is released.

In the context of the present invention, the terms "API" (abbreviation for "active pharmaceutical ingredient") and the term "active substance" are used interchangeably to refer to the fumaric acid ester released from the pharmaceutical formulation of the present invention.

For in vitro methods, well-established methods are available, in particular those described by official monographs, such as the United States Pharmacopeia (USP) or the European Pharmacopoeia. One of ordinary skill in the art will understand which method to choose and how to choose specific conditions for conducting in vitro studies. For example, the USP specifies that in vitro tests should be performed at 37 ± 1.0 ° C, for example 37 ± 0.5 ° C. In some embodiments, a suitable dissolution test uses an dissolution profile at 37 ° C. and a paddle elution device at 100 rpm, as described in the US Pharmacy, and 0.1 N as the elution test solvent for the first 2 hours of the test. Hydrochloric acid is then measured using 0.05 M phosphate buffer pH 6.8 as the elution test solvent for the rest of the test time. One of ordinary skill in the art will understand how to adjust applicable conditions such as temperature, pH, paddle speed, duration and the like. In a further embodiment, the in vitro dissolution test is performed using a USP device II (paddle) with a: 1 liter container. Set the bath temperature to 37 ° C ± 0.5 ° C and the paddle speed to 100 rpm. One tablet is placed in one container containing 750 ml of 0.1N HCl (pH 1.2) for 2 hours. The pH is then changed to 6.8 by adding 220-250 ml of 0.2 M sodium phosphate buffer. After at least 2, 2.5, 3.5, and 6 hours, 2.5 ml of sample is taken, immediately stored at 2-8 ° C., and DMF analyzed by HPLC. The HPLC parameters are set as follows: Column: Phenomenex Luna C18, 50x4.6 mm, 3 μm; Column oven temperature 30 ° C .: Mobile phase: Methanol: 20 mM phosphate buffer pH 3.0 (35: 65 V / V), injection Capacity: 5 μl, flow velocity: 0.8 ml / min, detector wavelength: 210 nm, operation time 5 minutes, DMF retention time 3.5 minutes.

In vivo release can be tested by measuring plasma concentration of dimethyl fumarate, or its metabolites, if any, at a given time, thereby obtaining a plasma concentration-to-time profile. In addition, metabolism is believed to have already occurred in the gastrointestinal tract or during passage through the gastrointestinal mucosa. Therefore, the relevant component in plasma examined when administering dimethyl fumarate may be a monomethyl ester rather than a dimethyl ester of fumaric acid.

Another test can also be used to determine or measure the release of the active substance in vivo. Therefore, animals (eg, mini pigs, dogs, monkeys, etc.) can be used as models. The composition under test is administered to the animal, and after a certain period of time, a blood sample is taken to measure the content of the active ingredient (or its metabolite, 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, which device has two compartments (donor and receiver) separated by the fragment, and is being tested in a suitable medium in one of the compartments (donor compartment). Add the composition. The composition releases the active substance, which then permeates the intestinal fragment. Therefore, at appropriate time intervals, the concentration of active substance (or metabolites, if relevant) in the receiver compartment is measured.

Those skilled in the art will be able to adapt the above methods to specific compositions.

In the context of the present invention, the term "relative bioavailability" refers to a comparison of the amount of drug absorbed in vivo (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 its metabolites. 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, Cmax 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 ratio of the standard deviation to the mean. Here, PK parameter values, such as Cmax and Tmax, refer to average values obtained from human clinical trials in dieted or fasted subjects.

In the context of the present invention, the term "tolerability" refers to the potential of a drug tolerated by a subject and / or patient. In some embodiments, "tolerance" is defined as the initial stage of treatment, eg, within the first 3 months after the start of treatment, eg, within the first month after the initiation of treatment, eg, within the first 2 weeks after the initiation of treatment, eg, first after the initiation of treatment. Within 1 week of treatment, eg, within the first 3 days after the start of treatment, eg, within the first day after the start of treatment, eg, after administration of the first dose of treatment, the potential of the drug tolerated by the subject and / or patient. Determined as sex. Tolerable drugs result in fewer side effects to the subject and / or patient than tolerant drugs.

In the context of the present invention, the term "substantial lack" refers to a level of less than about 1%, such as less than about 0.5%, such as less than about 0.3%, 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 polymer matrix materials" are used interchangeably to sustain and / or prolong in vivo and / or in vitro release of an active substance. Refers to substances that can be produced.

As mentioned above, the in vivo and / or in vitro release of the active substance is "controlled", i.e., longer and / or slower than the commercially available Fumaderm® compositions. In the context of the present invention, the term "controlled" means that the active ingredient is longer than Fumarate®, eg, at least 1.2 times longer than Fumarate®, eg, at least 1.5 times longer. It is intended to indicate that it is released for at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold longer. Thus, 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 be suitable for the test. It will be released at least 3.6 hours after the start.

The formulations of the present invention have improved tolerability, such as reduced gastrointestinal (GI) side effects and / or reduced severity, such as reduced redness and / or reduced severity, such as reduced flushing and /. Or it is thought to bring about a decrease in severity.

In the use of the present invention, side effects of the gastrointestinal tract (GI) include, but are not limited to, diarrhea, vomiting, abdominal pain (stomach ache, stomach pain, abdominal pain), abdominal spasm, nausea, flatulence, swelling, etc. Meteorism, increased bowel movements, bloating, and upper abdominal cramps may be included.

In the context of the present invention, the reduction of GI-related side effects compares the GI side effects seen after administration of the formulations of the invention to the GI side effects seen after administration of Fudamerm® among a given group of treated patients. By doing so, it is intended to indicate that the severity and / or incidence is reduced. Thus, a reduction in GI-related side effects by this definition 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%. , Or even more preferably, a reduction greater than at least 30% of the incidence. A reduction in GI-related side effects is a substantial reduction in the severity of any of the above GI side effects, such as diarrhea, vomiting, abdominal pain (stomach ache, stomach pain, abdominal pain), abdominal spasm, nausea, flatulence, swelling. , Meteorism, increased bowel movements, nausea, or decreased severity and / or frequency of upper abdominal cramps. As mentioned above, the reduction of GI-related side effects can be monitored in clinical trials by directly comparing the formulations of the present invention with administration of Fumarate® or placebo. 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 studies comparing Fumarate® with placebo (Altmeyer). et al., J. Am. Acad. Dermatol. 1994; full reference: Altmeyer PJ et al., Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J. Am. Acad. Dermatol. 1994; see 30: 977-81).

In a further embodiment, oral administration of the formulations of the present invention reduces (GI) side effects (frequency and / or severity) compared to the results produced after oral administration of the same dose of Fumaderm® tablets. ..

WO 2010/07922 Al has undesired side effects, especially flushing (frequency and / /), compared to the consequences of oral administration of the erosion matrix formulation after oral administration of the same dose of Fumaderm® tablets. Or the severity) is disclosed to be reduced. The frequency and extent of these and other side effects is further reduced given the low daily dose of 375 mg ± 5%.

In the context of the present invention, the term "flushing" refers to a sudden redness of the skin on the face and / or neck, and, less frequently, on the upper trunk and upper abdomen, or with a warm or crunchy sensation throughout the body. Represents. Flushing is distinguished from photosensitivity or persistent erythema of acute contact reactions in that the seizures are transient. 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, eds. Rook. / Wilkinson / Ebling textbook of dermatology, 6th ed., Vol. 3. Oxford, UK: Blackwell Scientific, 1998: 2099-2104).

In the context of the present invention, the decrease in flushing is severe compared to the flushing seen after administration of the formulations of the invention to the flushing seen after administration of Fudamerm® among a given group of treated patients. It is intended to indicate a decrease in degree and / or incidence / frequency, eg, measured as described in O'Toole et al. Cancer 2000, 88 (4): p. 770-776. Can be done. Therefore, a decrease in flushing by this definition could be interpreted as a decrease in the incidence and / or severity of flushing. In one aspect of the invention the incidence of red tide 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 incidence is at least about 1. It is reduced by 2/2, and in a further aspect of the present invention, the incidence of red tide 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, in another aspect of the invention at least about 1/3, in another aspect of the invention at least 1/2, a further aspect of the invention. Is reduced by at least about 2/3. A 100% reduction in the incidence and severity of flushing is most preferred, but not necessary. As mentioned above, the decrease in flushing can be monitored in clinical trials, for example, by comparing the administration of the compounds of the invention with, for example, administration of Fumarate®. For clinical trials using Fumarate® as a control, the incidence of flushing defined as mild, moderate, or severe in patients receiving the compounds of the invention compared to the Fumarate® group. And the severity can be compared.

In some embodiments, the severity of flushing is determined as the affected body surface area. In some embodiments, such clinical trials can be performed as described in the "Clinical Trials in Patients" section above. In another embodiment, such a clinical trial can be performed as described in the section "Clinical Trials in Healthy Persons" above.

In a further embodiment, oral administration of the pharmaceutical product of the present invention reduces redness (frequency and / or severity) as compared to the results produced after oral administration of the same dose of Fumarate® tablets.

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

In the context of the present invention, the reduction in redness is more severe than the redness seen after administration of the pharmaceutical product of the present invention compared to the redness seen after administration of Fumaderm® among a given group of treated patients. It is intended to indicate that the degree and / or incidence / frequency is reduced and can be evaluated, for example, by a doctor or nurse.

Therefore, a reduction in redness by this definition could be interpreted as a reduction 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 incidence is at least about 1. It is reduced by 2/2, 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, in another aspect of the invention at least about 1/3, in another aspect of the invention at least 1/2, a further aspect of the invention. Is reduced by at least about 2/3. A 100% reduction in the incidence and severity of redness is most preferred, but not necessary. As mentioned above, the reduction in redness can be monitored in clinical trials, for example, by comparing the administration of the compounds of the invention with, for example, administration of Fumarate®. For clinical trials using Fumarate® as a control, the incidence of mild, moderate, or severe redness in patients receiving the compounds of the invention compared to the Fumarate® group. And the severity can be compared.

In some embodiments, the severity of redness is determined as the affected body surface area.

In some embodiments, such clinical trials can be performed as described in the "Clinical Trials in Patients" section above.

In another embodiment, such a clinical trial can be performed as described in the section "Clinical Trials in Healthy Persons" above.

In some embodiments, the relative bioavailability of the formulations of the invention as compared to Fumarate® 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 the context of the present invention, the term "erosion matrix" refers to a matrix that releases the API as a result of the erosion rate of the matrix rather than by the inherent diffusion process. By removing the matrix layer that can be eroded in a well-controlled manner, a predetermined amount of API is obtained, and the release of API is the swelling and elution or erosion rate of the matrix, as well as the elution rate, solubility, and diffusion of API. Depends on speed.

In certain aspects of the invention, the rate-determining substance is a water-soluble polymer. As used herein, the term "water-soluble polymer" refers to a conventional pharmaceutical polymer 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. According to one preferred embodiment, the water soluble polymer is hydroxypropyl cellulose.

As used herein, the term "water-insoluble polymer" refers to a conventional pharmaceutical polymer having a solubility in water of less than 10 mg / ml.

In a further aspect of the invention, the erosion matrix is substantially free of water-insoluble polymers. In a further embodiment, 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 less than about 1%, such as less than about 0.5%, such as less than about 0.3%, such as about 0.0%. ..

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

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

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

In the most preferred embodiment of the present invention, the rate-determining substance is hydroxypropyl cellulose.

For example, there are many different grades of hydroxypropyl cellulose, depending on their molecular weight, degree of etherification, viscosity, and so on. Non-limiting typical embodiments of commercially available hydroxypropyl cellulose are, for example, from Aqualon or Nippon Soda, registered trademarks such as Klucel® HPC-L, HPC-SL, HPC-SSL, HPC-M, HPC-H. Available at. In some embodiments 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 wt% dry HPC at 20 ° C. Is. In some embodiments of the invention, the rate-determining material is HPC-SL.

According to the present invention, the rate-determining material is 1 to 50% by weight, 1 to 40% by weight, for example, 3 to 35% by weight, for example, about 4 to 15% by weight, for example, about 4 to 10% by weight, for example, 3 to 15% by weight. %, For example 3-12% by weight, for example 3-10% by weight, for example 3-6% by weight, for example 3-5% by weight, for example 4-6% by weight.

In some embodiments, the present invention is a pharmaceutical formulation comprising an erosion matrix, wherein the erosion matrix is:
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% to 55%, eg 40% -50%, eg 44% -55%, eg 42% -48% weight% dimethyl fumarate, and ii) 1% -50%, eg 1% -40%, eg 3% It relates to a pharmaceutical formulation containing from 1 to 40%, for example 3% to 20% by weight, one or more rate-determining substances, wherein erosion of the erosion matrix allows controlled release of the active substance.

The amount of rate-determining substance depends on the specific rate-determining substance used, the intended release profile, all excipients present in the core tablet, and the level and nature of the additive.

According to a preferred embodiment of the invention, the pharmaceutical composition further comprises a binder.

Non-limiting examples of binders include water-soluble sugars and sugar alcohols such as lactose, sucrose, glucose, sorbitol, mannitol and the like. In a particularly preferred embodiment, the binder is lactose. Lactose has a wide particle size, particle size distribution, etc., depending on the production method, and is commercially available in many different grades. Examples of lactose include, but are not limited to, anhydrous lactose, lactose made from alpha-lactoose monohydrate, aggregated lactose, granular lactose, crystalline lactose, crystalline sieve lactose, sieved lactose (eg, PrismaLac). PrismaLac® such as (Registered Trademark) 40), crystallized lactose (eg, GranuLac® 70, GranuLac® 140, GranuLac® 200, GranuLac® 230, and GranuLac. GranuLac® such as (registered trademark) 400), improved lactose, aggregated lactose (eg, Tablettose® 70, Tablettose® 80, and Tablettose® such as Tablettose® 100). ), Improved lactose, spray-dried lactose (FlowLac® such as FlowLac® 90 and FlowLac® 100). Lactose is, for example, from Meggle Pharma, Capsulac® such as PrismaLac®, Capsulac® 60, SacheLac®, SpheroLac®, Inhalac®, GranuLac®. ) 70, GranuLac® 140, GranuLac® 200, GranuLac® 230, and GranuLac® 400, etc. GranuLac®, SorboLac®, Tablettose® Obtained under registered trademarks of Tabletose® such as 70, Tablettose® 80, and Tablettose® 100, and 25 FlowLac® such as FlowLac® 90 and FlowLac® 100. can.

In some embodiments, the lactose is aggregated lactose. In another embodiment, the lactose is spray-dried lactose. In another embodiment, the lactose is abrasive lactose.

In certain aspects of the invention, the tablet core of the pharmaceutical composition of the invention is:
i) 40-60% by weight dimethyl fumarate and ii) 40-60% by weight, preferably 45-55% by weight of binder, preferably lactose, are included as active substances.

According to a preferred embodiment of the present invention, the tablet core of the pharmaceutical composition of the present invention may be:
i) 35-55% by weight dimethyl fumarate as an active substance,
ii) 3-12% by weight rate-determining substance,
iii) Contains 40-60% by weight of binder.

In an even more preferred embodiment, the tablet core of the pharmaceutical composition of the present invention is:
i) 40-50% by weight dimethyl fumarate as active substance,
ii) 3-12% by weight, especially 3-6% by weight hydroxypropyl cellulose,
iii) Contains 45-55% by weight lactose.

In another preferred embodiment of the invention, the tablet core of the pharmaceutical composition of the invention is.
i) 42-48% by weight dimethyl fumarate,
ii) 3-10% by weight, especially 3-6% by weight hydroxypropyl cellulose,
iii) Contains 45-52% by weight lactose.

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

In certain preferred embodiments, the pharmaceutical composition of the present invention further comprises one or more lubricants and / or one or more flow regulators.

More specifically, in certain aspects of the invention, the tablet core of the pharmaceutical composition of the invention is:
i) 35-55% by weight dimethyl fumarate as an active substance,
ii) 3-12% by weight rate-determining material, such as hydroxypropyl cellulose,
iii) 40-60% by weight binder, such as lactose,
iv) It may contain 0.15 to 0.7% by weight of a lubricant, such as magnesium stearate, and optionally 0.05 to 0.25% by weight of a flow regulator, such as silicon dioxide.

In an even more preferred embodiment of the invention, the tablet core of the pharmaceutical composition of the invention is:
i) 40-50% by weight dimethyl fumarate as active substance,
ii) 3-12% by weight rate-determining material, such as hydroxypropyl cellulose,
iii) 45-55% by weight binder, such as lactose,
iv) It may contain 0.15 to 0.7% by weight of a lubricant, such as magnesium stearate, and optionally 0.05 to 0.25% by weight of a flow regulator, such as silicon dioxide.

In an even more preferred embodiment of the invention, the tablet core of the pharmaceutical composition of the invention is:
i) 42-48% by weight dimethyl fumarate as active substance,
ii) 3-10% by weight rate-determining material, such as hydroxypropyl cellulose,
v) 45-52% by weight binder, such as lactose,
vi) 0.15 to 0.7% by weight of a lubricant, for example magnesium stearate, and optionally 0.05 to 0.25% by weight of a flow regulator, such as silicon dioxide, may be included.

In another preferred embodiment of the invention, the tablet core of the pharmaceutical composition of the invention is.
i) 35-55% by weight dimethyl fumarate as an active substance,
ii) 3-6% by weight rate-determining material, such as hydroxypropyl cellulose,
iii) 40-60% by weight binder, such as lactose,
iv) Contains 0.2-0.5% by weight of lubricant, eg magnesium stearate,
v) A flow regulator of 0.05 to 0.2% by weight may be appropriately contained, for example, silicon dioxide.

In an even more preferred embodiment of the invention, the tablet core of the pharmaceutical composition of the invention is:
i) 35-55% by weight dimethyl fumarate as an active substance,
ii) 3-6% by weight rate-determining material, such as hydroxypropyl cellulose,
iii) 45-55% by weight binder, such as lactose,
iv) Contains 0.2-0.5% by weight of lubricant, eg magnesium stearate,
v) A flow regulator of 0.05 to 0.2% by weight may be appropriately contained, for example, silicon dioxide.

In the most preferred embodiment of the present invention, the tablet core of the pharmaceutical composition of the present invention is:
i) 35-55% by weight dimethyl fumarate as an active substance,
ii) 3 to 5.5% by weight rate-determining material, such as hydroxypropyl cellulose,
iii) 45-52% by weight binder, such as lactose,
iv) Contains 0.2-0.5% by weight of lubricant, eg magnesium stearate,
v) A flow regulator of 0.05 to 0.2% by weight may be appropriately contained, for example, silicon dioxide.

According to the present invention, any pharmaceutically acceptable lubricant commonly used in the art can be used in the pharmaceutical composition of the present invention. Magnesium stearate can be preferably used as a lubricant.

According to the present invention, any pharmaceutically acceptable flow rate regulator common in the art can be used in the pharmaceutical composition of the present invention. Silicon dioxide can be preferably used as a flow rate regulator.

In some embodiments, the pharmaceuticals of the invention are selected from the group comprising a lubricant, a flow accelerator, a disintegrant, a flow regulator, a solubilizer, a pH regulator, a surfactant, and an emulsifier. May contain acceptable excipients and additives. The amounts of the excipient and the additive can be adjusted so as not to impair the properties of the pharmaceutical composition.

In some embodiments, the formulations of the present invention are produced without the use of disintegrants, i.e., the pharmaceutical compositions of the present invention preferably do not contain any disintegrants. However, small amounts of disintegrant are acceptable as long as the presence of the disintegrant does not disintegrate the erosion matrix tablet.

According to the present invention, at least one of one or more coatings is an enteric coating.

The enteric coating material can be selected from any of the many 30 coating materials on the market. Non-limiting examples thereof include Eudragit® E, L, S, L30 D-55, Kollicaat® 30D, cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropylmethyl cellulose phthalate. According to a preferred embodiment, the solution used as the coating solution for making a basic enteric coating comprises Eudragit® L30 D-55, triethyl citrate, glycerol monostearate, and Polysorbate 80.

According to the present invention, this basic enteric coating is 1.5-3.5% by weight of the tablet core, eg 2.0-3.5% by weight of the tablet core, eg 2-3% by weight of the tablet core. It is given at the% level. According to one particularly preferred embodiment, the coating is typically about 2.0 mg / cm ² to about 3.5 mg / cm ² for the core tablet, eg, about 2.5 mg / cm ² to about 3. for the core tablet. It further satisfies the condition that it is applied at a level of 5 mg / cm ² , for example, about 2.8 mg / cm ² to about 3.3 mg / cm ^{2 of the core tablet.}

Enteric coating is a well-established approach for preventing or minimizing the release of drugs in the stomach and releasing them in the small intestine. The enteric polymer coating works on the principle of pH-dependent solubility. That is, it is insoluble under low pH conditions in the stomach, but soluble in a near-neutral pH environment of the adjacent small intestine, where the pH is in the range 5-6.

This means that the drug that needs to be absorbed in the small intestine is, for example, about 6 hours, for example, about 5 hours, for example, about 4 hours, for example, about 3 hours, while the enteric coating is eluted and the API is released from the preparation. It only leaves a small chance of release in a few hours. It has been found that rapid dissolution of the enteric coating is possible by applying a relatively thin coating, i.e., an enteric coating in an amount of 1.5-3.5 wt% on the tablet core, while Surprisingly, this relatively thin coating still obtains the required protection against the acidic environment of the stomach, for example, a 2-hour in vitro dissolution test using 0.1N hydrochloric acid as the dissolution test solvent. When this is carried out, the fumaric acid ester contained in the preparation is released at less than 10%, for example, less than 5%, for example, less than 2%, for example, about 0%.

In certain aspects of the invention, the formulations of the invention comprise an enteric coating and the in vivo release of dimethyl fumarate is faster than the prior art formulation Fumaderm®, eg, in the fasted state, from Fumaderm®. Indicates initiation of release 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. ..

In certain aspects of the invention, the pharmaceutical product of the invention comprises an enteric coating and the in vivo release of dimethyl fumarate has a delay time of 15 minutes to 2 hours in the fasted state, eg, up to 120 minutes in the fasted state. Maximum 110 minutes, maximum 100 minutes, maximum 90 minutes, maximum 80 minutes, maximum 70 minutes, maximum 60 minutes, maximum 50 minutes, maximum 40 minutes, maximum 30 minutes, maximum 20 minutes, Alternatively, it indicates a delay time of up to 15 minutes.

According to a preferred embodiment of the present invention, the release of dimethyl fumarate uses 0.1N hydrochloric acid as the elution test solvent for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the elution test solvent. Then, when the in vitro dissolution test is performed, it becomes as follows:
Within the first 2 hours after the start of the test, the total amount of dimethyl fumarate contained in the pharmaceutical composition is about 0% w / w to about 10% w / w, preferably 0% w / w to about 5% w / w. , More preferably 0% w / w to <2% w / w.
Within the first 2.5 hours after the start of the test, about 2% w / w to about 20% w / w of the total amount of dimethyl fumarate contained in the pharmaceutical composition was released.
Within the first 3.5 hours after the start of the test, about 35% w / w to about 65% w / w of the total amount of dimethyl fumarate contained in the pharmaceutical composition was released.
Within the first 5 hours after the start of the test,> 85% w / w of the total amount of dimethyl fumarate contained in the pharmaceutical composition is released.

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

According to one preferred embodiment, the pharmaceutical composition is for administration once a day. In this case, the pharmaceutical composition of the present invention may preferably contain 375 mg ± 5%, preferably about 375 mg of dimethyl fumarate as the active substance.

According to another preferred embodiment of the present invention, the pharmaceutical composition is for administration three times a day. In this case, the pharmaceutical composition preferably comprises 125 mg of total amount of dimethyl fumarate.

The daily dose of the controlled release pharmaceutical composition of the invention administered to treat a patient depends on many factors, some of which are, but not limited to, body weight and age, as well as medical conditions. It is the underlying cause or the disease to be treated, and it is within the skill of the physician to determine the daily dose.

According to the present invention, the daily dose of dimethyl fumarate is in the range of 375 mg ± 5%, ie 356.25 to 393.75 mg. The daily dose can be administered in 1 to 3 divided doses, for example.

The erosion matrix tablet of the present invention can be produced by granulation, subsequent tableting, and enteric coating, and the obtained core tablet may be film-coated as appropriate. The core can be produced, for example, by conventional wet or continuous granulation, eg extruding, and then compressing the granulated material into tablets. The core can then be coated using a suitable technique, preferably 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 and carries out any or all of the following steps at a temperature such that the product temperature is 45 ° C. or lower.
a) Dissolve (or suspend) one or both of the fumaric acid ester and the rate-determining substance in the form of a polymer matrix substance in water to obtain an aqueous suspension thereof. b) Use the aqueous suspension as fumaric acid. Spray for a sufficient time to apply a uniform coating on the granules of the ester and / or binder c) Dry the resulting granules d) Sift or grind the granules as appropriate. E) All pharmaceutically acceptable excipients and additives are mixed by a method known per se to obtain a tablet product f) The tablet product is enteric coated by a method known per se. It may be film-coated as appropriate.

In certain aspects of the invention, any or all of the above steps are carried out at a temperature such that the product temperature is 40 ° C. or lower, for example 35 ° C. or lower, for example 30 ° C. or lower. Therefore, surprisingly, it has been shown that the pharmaceutical product of the present invention can be produced by using only water as a solvent, and thus does not require any organic solvent. In addition, all steps can be carried out at even lower temperatures. Therefore, any sublimation of the active pharmaceutical ingredient is minimized or reduced, resulting in an energy efficient process and reduced API loss, thus reducing costs and environmental and worker safety. Gender improves.

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

The average particle size of the active pharmaceutical ingredient (dimethyl fumarate), eg, by sieving or grinding, prior to step a) above, at least 50% of the particles are less than 800 μm, eg less than 600 μm, eg less than 500 μm, eg 400 μm. It is preferable to reduce the particle size so that the particle size is less than, for example, less than 300 μm, for example, less than 200 μm.

In another preferred embodiment, the average particle size of the active pharmaceutical ingredient (dimethyl fumarate) is such that at least 80% of the particles are less than 800 μm, eg less than 600 μm, prior to step a) above, eg, by sieving or grinding. For example, the particle size is reduced so that the particle size is less than 500 μm, for example, less than 400 μm, for example, less than 200 μm.

According to a preferred embodiment, the average particle size of the crystalline active pharmaceutical ingredient dimethyl fumarate, eg, by sieving or grinding, is at least 90% of the particles less than 800 μm, eg less than 600 μm, prior to step a) above. For example, the particle size is reduced so that the particle size is less than 500 μm, for example, less than 400 μm, for example, less than 200 μm.

In certain aspects of the invention, the average particle size of the crystalline active pharmaceutical ingredient dimethyl fumarate can be reduced, for example by sieving or milling, which sifting or milling suppresses the generation of a minimum amount of heat. Is done. Therefore, any sublimation of the active pharmaceutical ingredient is minimized or reduced, resulting in an energy efficient process and reduced API loss, thus reducing costs and environmental and worker safety. Gender improves. Sieving or grinding can be performed as a one-step sieving or grinding step, or may optionally be repeated several times to obtain the required particle distribution.

In certain aspects of the invention, sieving or grinding can be performed as a two-step process.

In certain aspects of the invention, where sieving or grinding is performed in multiple steps, a substance that reduces agglomeration is added during the steps.

In some embodiments, the lower amount of rate-determining material contains at least 35%, 40%, 45%, 50%, 55%, or 60% dimethyl fumarate, based on high drug content, eg, total tablet weight. Allows the production of tablets containing.

In some aspects of the invention, step b) is performed in 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 and carries out any or all of the following steps at a temperature such that the product temperature is 45 ° C. or lower.
a) A rate-determining substance in the form of a polymer matrix substance is dissolved (or suspended) in water to obtain an aqueous suspension thereof. b) The aqueous suspension is uniformly coated on a granulated product of fumaric acid ester. C) Dry the resulting granules d) The granules may be screened or ground as appropriate e) Any pharmaceutically acceptable excipient and Additives may be mixed by a method known per se to obtain a tablet product f) The tablet product may be enteric coated by a method known per se and film coated as appropriate. In certain aspects of the invention, any or all of the above steps are carried out at a temperature such that the product temperature is 40 ° C. or lower, for example 35 ° C. or lower, for example 30 ° C. or lower. Therefore, any sublimation of the active pharmaceutical ingredient is minimized or reduced, resulting in an energy efficient process and reduced API loss, thus reducing costs and environmental and worker safety. Gender improves.

In some aspects of the invention, step b) is performed in 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 and carries out any or all of the following steps at a temperature such that the product temperature is 45 ° C. or lower.
a) Sifting and / or grinding the crystals of fumaric acid ester b) The crystals of fumaric acid ester, rate-determining substances in the form of polymer matrix material as appropriate, and any pharmaceutically acceptable excipients and additives. C) The tablet product may be enteric coated by a method known per se and film-coated as appropriate.
In certain aspects of the invention, any or all of the above steps are carried out at a temperature such that the product temperature is 40 ° C. or lower, for example 35 ° C. or lower, for example 30 ° C. or lower. Therefore, any sublimation of the active pharmaceutical ingredient is minimized or reduced, resulting in an energy efficient process and reduced API loss, thus reducing costs and environmental and worker safety. Gender improves.

Another aspect of the present invention is a method for producing a pharmaceutical product of the present invention, which comprises the following steps and carries out any or all of the following steps at a temperature such that the product temperature is 45 ° C. or lower.
a) Mix crystals of fumaric acid ester, rate-determining material in the form of polymer matrix material as appropriate, and any pharmaceutically acceptable excipients and additives b) Grind the mixture and add additional additives , A tablet preparation is obtained by direct compression. C) The tablet preparation may be enteric coated by a method known per se and appropriately film coated.
In certain aspects of the invention, any or all of the above steps are carried out at a temperature such that the product temperature is 40 ° C. or lower, for example 35 ° C. or lower, for example 30 ° C. or lower. Therefore, any sublimation of the active pharmaceutical ingredient is minimized or reduced, resulting in an energy efficient process and reduced API loss, thus reducing costs and environmental and worker safety. Gender improves.

Another aspect of the present invention is a method for producing a pharmaceutical product of the present invention, which comprises the following steps:
a) Crystals of fumaric acid ester may be screened or ground as appropriate b) The crystals of fumaric acid ester take the form of any pharmaceutically acceptable additional excipient and optionally polymer matrix material. Mix with the rate-determining substance in a manner known per se to obtain a tablet formulation c) Roller compress the mixture and sieve / grind it to obtain granulation d) Any pharmaceutically acceptable additives The excipient of the above is mixed with a granulated product to obtain a final mixture to be used for tableting. E) Compressed into a tablet f) The tablet may be enteric coated and appropriately film-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 determined by measuring the initial in vitro dissolution profile of the tablet and the in vitro dissolution profile after storage for various periods of time and comparing the obtained in vitro dissolution profiles. In certain aspects of the invention, the tablets are 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, eg 36 months.

The stability of the pharmaceutical product of the present invention can also be determined, for example, by analysis, standardization methods for measuring any change in color or degradation products.

In certain aspects of the invention, the stability of the pharmaceutical product is released at a predetermined time point during a standardized in vitro dissolution test when comparing objective criteria, eg, initial test time point and later test time point, of the API. It can be defined by a certain maximum amount of change. In one embodiment of the invention, an in vitro dissolution test is performed using 0.1N hydrochloric acid as the dissolution test solvent for the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 as the dissolution test solvent. ICH conditions (eg, ° C./) for a period of time (eg, at least 1 month, eg, at least 3 months, eg, at least 6 months, eg, at least 9 months, eg, at least 12 months, eg, at least 18 months, eg, at least 24 months, eg, at least 36 months). The amount of API released from the formulation stored at 60% RH, eg 30 ° C./65% RH, eg 40 ° C./75% RH) is higher than at the initial time point (time = 0, at the start of the stability test). , Is as follows:
One hour after the start of the test, the amount of active pharmaceutical ingredient released from the formulation is less than 10 percent, for example less than 9 percent, for example less than 8 percent, for example less than 6 percent, for example less than 4 percent, for example 2 percent. Differences below the point, eg less than 1 percent point, are observed and / or
Two hours after the start of the test, the amount of active pharmaceutical ingredient released from the formulation is less than 10 percent, for example less than 9 percent, for example less than 8 percent, for example less than 6 percent, for example less than 4 percent, for example 2 percent. Differences below the point, eg less than 1 percent point, are observed and / or
Three hours after the start of the test, the amount of active pharmaceutical ingredient released from the formulation is less than 10 percent, for example less than 9 percent, for example less than 8 percent, for example less than 6 percent, for example less than 4 percent, for example 2 percent. Differences below the point, eg less than 1 percent point, are observed and / or
4 hours after the start of the test, the amount of active pharmaceutical ingredient released from the formulation is less than 10 percent, for example less than 9 percent, for example less than 8 percent, for example less than 6 percent, for example less than 4 percent, for example 2 percent. Differences below the point, eg less than 1 percent point, are observed and / or
Five hours after the start of the test, the amount of active pharmaceutical ingredient released from the formulation is less than 10 percent, for example less than 9 percent, for example less than 8 percent, for example less than 6 percent, for example less than 4 percent, for example 2 percent. Differences below the point, eg less than 1 percent point, are observed.

The pharmaceutical preparation of the present invention is for the treatment of psoriasis including mild to moderate, moderate to severe, or severe psoriasis vulgaris.

It should be understood that the present invention is not limited to the particular embodiments described and can of course vary in itself. Since the scope of the present invention is limited only by the appended claims, the terminology used herein is for the purpose of describing a particular embodiment only and is not intended to be limiting. Should be understood. If a range of values is given, each intervening value between the upper and lower limits of the description (up to one tenth of the lower limit unit unless otherwise specified in the context), and its. Any other specified or intervening value within the stated range is understood to be included in the present invention. These narrower upper and lower limits may independently be included in the narrower range and are also subject to any boundary values that are included in the invention and expressly excluded within the stated range. .. If the stated range includes one or both of the boundary values, then the range excluding one or both of the boundary values including these is also included in the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. Any method and material similar to or equivalent to that described herein can also be used in the practice or testing of the present invention, but preferred methods and materials are described. All publications described herein are incorporated herein by reference to disclose and describe methods and / or materials in connection with the publication being cited. As used herein and in the appended claims, the singular "a", "an" and "the" shall include the plural referent unless otherwise specified in context. You need to be careful.

The above invention has been described in a little more detail with figures and examples for the sake of clarity, but in view of the teachings of the present invention, any modifications and modifications thereof may be made without departing from the gist and gist of the appended claims. It is clear to those with ordinary skills in the art that improvements can be made.

Take necessary precautions (outside air-introduced protective clothing, double gloves, arm covers, breathing masks, etc., and / or containment devices while performing all of the following steps in the examples: Must).

Example 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 polymeric hydroxypropyl cellulose HPC-SL was dissolved by stirring in 2753 g of purified water and sprayed onto DMF for 2.5-3 hours. The granulated product was dried at 29 ° C. for 3 minutes. Several batches were mixed and sieved through an 800 μm sieve.
Using a barrel blender at 20 rpm for 15 minutes, 1730.7 g of granulated product was dried and further sieved through a 500 μm sieve to 25 781.3 g of granular lactose (Tabrettose® 100). , 66.7 g of HPC-SL, and a premixture of Aerosil® and Barreltose®. The premix was prepared with 4 g of colloidal silicic acid (Aerosil®) and 390.6 g of Tablettose® in a polyethylene bag and sieved through a 500 μm sieve. Finally, 26.7 g of magnesium stearate was added. The final mixture was compressed into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 2. Film and enteric coating of the core tablets of Example 1 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. In a fluidized bed chamber, about 66% of the suspension was sprayed onto the core tablets over a 20 minute period. The product temperature never exceeded 40 ° C. After the coating process, a drying period of 9 minutes at 30 ° C. was continued. The resulting coating gained less than 0.7% by weight compared to the core tablet weight.

Enteric coating 350 ml of purified water is heated to 70-80 ° C., 9.5 g of triethyl citrate, 1.9 g of glycerin monostearate (Cutina GMS V), and 0.7 g of Tween 80 are added to add UltraTurrax. 1 kg of gastric acid resistant coating solution was prepared by stirring for 10 minutes using the mixture to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 210 g of Eudragit L30 D 55 dispersion. In a fluidized bed chamber, about 66% of the resulting gastric acid resistant coating was sprayed onto 780 g of film-coated tablets. Due to the high loss during this process, the substantially applied coating level was a weight gain of about 2.2% compared to the core lock.

Example 3.
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 by stirring in 2753 g of purified water and sprayed onto DMF for 2.5-3 hours. The granulated product was dried at 29 ° C. for 3 minutes, sieved through a 500 μm sieve and sieved.
Using a barrel blender at 20 rpm for 15 minutes, 964 g of dried and sieved granules were combined with 565.5 g of granular lactose (Tabrettose® 100), 37.4 g of HPC-SL, and It was mixed with a premixture of Aerosil® and Tablettose®. The premix was prepared with 2.3 g of colloidal silicic acid (Aerosil®) and 282.7 g of Tablettose® in a polyethylene bag and further sieved through a 500 μm sieve. Finally, 14.9 g of magnesium stearate was added. The final mixture was compressed into 30 biconvex tablets 8 mm in diameter and 250 mg in weight.

Example 4.
The film and enteric coating of the core tablet of Example 3 Film coating The film coating of 800 g of the core tablet is prepared and applied as a 15% suspension of opadry as disclosed in Example 2.

Enteric coating 350 ml of purified water is heated to 70-80 ° C., 9.5 g of triethyl citrate, 1.9 g of glycerin monostearate (Cutina GMS V), and 0.7 g of Tween 80 are added to add UltraTurrax. 1 kg of gastric acid resistant coating solution was prepared by stirring for 10 minutes using the mixture to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 210 g of Eudragit L30 D 55 dispersion. In a fluidized bed chamber, about 66% of the resulting gastric acid resistant coating was sprayed onto 780 g of film-coated tablets at 30 ° C. for about 2.5 hours. A drying period of 30 minutes at 30 ° C. and a further 15 curing period of 30 minutes at 35 ° C. were continued. Due to the high loss during this process, the substantially applied coating level was a weight gain of about 2.2% compared to the core lock.

Example 5.
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 by stirring in 2753 g of purified water and sprayed onto DMF for 2.5-3 hours. The granulated product was dried at 29 ° C. for 3 minutes. Several batches were mixed and sieved through an 800 μm sieve.
Using a barrel blender at 20 rpm for 15 minutes, 1416 g of granulated product dried and further sieved through a 500 μm sieve to 1002.9 g of granular lactose (Tavelttose® 100), 54.6 g of HPC-. It was mixed with SL and a premixture of Aerosil® and Barreltose®. The premix was prepared with 3.3 g of colloidal silicic acid (Aerosil®) and 501.4 g of Tablettose® in a polyethylene bag and sieved through a 500 μm sieve. Finally, 21.8 g of magnesium stearate was added. The final mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight.

Example 6.
The film and enteric coating of the core tablet of Example 5 Film coating 800 g of the core tablet film coating was applied by preparing a 15% suspension of opadry as disclosed in Example 2.

Enteric coating 350 ml of purified water is heated to 70-80 ° C., 9.5 g of triethyl citrate, 1.9 g of glycerin monostearate (Cutina GMS V), and 0.7 g of Tween 80 are added to add UltraTurrax. 1 kg of gastric acid resistant coating solution was prepared by stirring for 10 minutes using the mixture to obtain a uniform mixture. 427.8 g of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 210 g of Eudragit L30 D 55 dispersion. In a fluidized bed chamber, about 66% of the resulting gastric acid resistant coating was sprayed onto 780 g of film-coated tablets at 30 ° C. for about 2.5 hours. A drying period of 30 minutes at 30 ° C. and a curing period of an additional 30 minutes at 35 ° C. were continued. Due to the high loss during this process, the substantially applied coating level was a weight gain of about 2.2% compared to the core lock.

Example 7.
Film Coating of Core Tablets of Example 2 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. In a fluidized bed chamber, about 66% of the suspension was sprayed onto the core tablets over 35 minutes. The product temperature never exceeded 40 ° C. After the coating process, a drying period of 16 minutes at 30 ° C. was continued. The resulting coating gained less than 2% by weight compared to the core tablet weight.

Example 8.
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 into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 9.
This study is a single-center study and is a randomized, non-randomized study to determine the plasma concentration, pharmacokinetics, safety and tolerability of the pharmaceutical formulation of the present invention compared to the reference commercial formulation Fumarate®. Followed the blind cross design. According to a randomization of 20 healthy Caucasian male subjects, tablets were administered as a single oral dose of 240 mg (2 tablets each containing 120 mg) 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: at least 21 to 2 days prior to initial dosing: inclusion / exclusion criteria checks, demographic data (age, height, weight, body mass index (BMI),). And tribal origin), health checkup, total medical history, 12-lead electrocardiogram, life signs (blood pressure (BP), pulse rate (PR), and body temperature (BT)), laboratory parameters (hematology, 20 serums) Chemistry and urinalysis), comorbidities and concomitant medication documentation.

Every four treatment periods, the subject is visited on the night of the first day, a 24-hour blood sample for PK analysis is taken, and all safety tests are performed (= morning of the second day). , The test facility was allowed to stay.
Subject was fasted overnight. One oral dose (of 2 tablets) of one of the formulations of the present invention (Examples 2, 4, or 6), or 2 tablets of reference agent Fudamerm® containing 120 mg of dimethyl fumarate each. Enteric coated tablets (total volume 240 mg dimethyl fumarate) were 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:
Detailed recording of side effects during pre-dose and pre-planned post-dose times during pre-dose and pre-planned post-dose times during blood sampling studies for plasma concentration and PK parameter measurements. Urine was collected

At least 7 days after the last dose (treatment period 4), follow-up tests including: health examination, signs of life (BP, PR, and BT), body weight, 12-lead ECG, laboratory test parameters (blood) were performed, including: (Study, serum biochemistry, and urinalysis), concomitant medications and documentation of side effects.

Example 10.
Preparation of core tablets Dimethyl fumarate was sieved through a 500 μm hand sieve. 29.3 g of sieved dimethyl fumarate, 2.93 g of HPC-SL, 22.17 g of granular lactose (Tabrettose® 100), and 0.07 g of Aerosil®, 0.49 g. It was mixed with magnesium stearate for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 225 mg in weight.

Example 11.
Preparation of core tablets Dimethyl fumarate was sieved through a 500 μm hand sieve.
Using a barrel blender at 20 rpm for 15 minutes, 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®. Mixed. Finally, 4 g of magnesium stearate was added and the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Enteric 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, using UltraTurrax. A uniform mixture was obtained by stirring for 10 minutes to prepare a gastric acid resistant coating solution. 495 g of purified water was added and the mixture was stirred using 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 lock in a perforated drum coating machine. The amount of solution sprayed onto the tablets was 2.5% solid w / w, resulting in a 1.8% weight increase of the coated tablets compared to the core tablets.

Example 12.
Preparation of core tablets Dimethyl fumarate was sieved through a 500 μm hand sieve.
Using a barrel blender at 20 rpm for 15 minutes, mix 500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of granular lactose (Tabrettose® 100), and 1.2 g of Aerosil®. bottom. Finally, 4 g of magnesium stearate was added and the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Enteric coating 99 g of purified water is heated 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 are added to UltraTurrax. A gastric acid-resistant coating solution was prepared by stirring for 10 minutes using the above to obtain a uniform mixture. 198 g of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 224 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core lock in a perforated drum coating machine. The solution was sprayed to give a 3% weight gain on the core tablets.

Example 13a.
Preparation of core tablets Dimethyl fumarate was sieved through 1143 μm and 610 μm sieves and ground.
Using a barrel blender at 20 rpm for 15 minutes, mix 500 g of sieved dimethyl fumarate, 48 g of HPC-SL, 447 g of granular lactose (Tabrettose® 100), and 1.2 g of Aerosil®. bottom. Finally, 4 g of magnesium stearate was added and the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight.

Enteric 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, using UltraTurrax. A uniform mixture was obtained by stirring for 10 minutes to prepare a gastric acid resistant coating solution. 495 g of purified water was added and the mixture was stirred using 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 lock in a perforated drum coating machine. The amount of solid sprayed onto the tablets was 2.5% solid w / w, resulting in a 1.5% weight increase of the coated tablets compared to the core tablets.

Example 13b.
The core tablet was produced as described in Example 13a.
Enteric 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, using UltraTurrax. A uniform mixture was obtained by stirring for 10 minutes to prepare a gastric acid resistant coating solution. 495 g of purified water was added and the mixture was stirred using 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 lock in a perforated drum coating machine. The amount of solid sprayed onto the tablets was 3.5% solid w / w, resulting in a 2% weight increase of the coated tablets compared to the core tablets.

Example 14.
Preparation of core tablets 2500 g of dimethyl fumarate was sieved through 1575 μm and 813 μm sieves and ground. Prior to the second grinding step, 6 g of Aerosil® was added. The obtained particle size distribution was about 3% for> 500 μm, about 65% for> 250 μm, and about 6% for <100 μm. The average particle size was 290 μm.
Using a barrel blender at 20 rpm for 15 minutes, the ground material was further mixed with 240 g HPC-SL and 2714 g granular lactose (Tavelttose® 100). Finally, 20 g of magnesium stearate was added and the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. Core tablets may be enteric coated as described in Example 16a or b.

Example 15.
Preparation of core tablets 2500 g of dimethyl fumarate was sieved through 1575 μm and 813 μm sieves and ground. Prior to the second grinding step, 6 g of Aerosil® was added. The obtained particle size distribution was about 3% for> 500 μm, about 50% for> 250 μm, and about 10% for <100 μm. The average particle size was 250 μm.
Using a barrel blender at 20 rpm for 15 minutes, the ground material is further mixed with 240 g HPC-SL and 2714 g granular lactose (Tavelttose® 100). Finally, 20 g of magnesium stearate is added and the mixture is mixed again at 20 rpm for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. The core tablets were appropriately enteric coated as described in Example 16b.

Example 16a.
Enteric coating 1193 g of purified water is heated to 70-80 ° C., then 45 g of triethyl citrate, 13.5 g of glycerin monostearate (Cutina GMS V), and 5.4 g of Tween 80 are added, using UltraTurrax. A uniform mixture was obtained by stirring for 10 minutes to prepare a gastric acid resistant coating solution. 2385 g of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 1500 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core lock in a perforated drum coating machine. The amount of solid sprayed onto the tablets was 3.0% w / w, resulting in a 2.5% weight increase of the coated tablets compared to the core tablets.

Example 16b.
Enteric coating 1193 g of purified water is heated to 70-80 ° C., then 45 g of triethyl citrate, 13.5 g of glycerin monostearate (Cutina GMS V), and 5.4 g of Tween 80 are added, using UltraTurrax. A uniform mixture was obtained by stirring for 10 minutes to prepare a gastric acid resistant coating solution. 2385 g of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 1500 g of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core lock in a perforated drum coating machine. The amount of solid sprayed onto the tablets was 3.5%, resulting in a 3% weight increase of the coated tablets compared to the core tablets.

Example 17.
Preparation of core tablets 2500 g of dimethyl fumarate was sieved through 1575 μm and 813 μm sieves and ground. Prior to the second grinding step, 6 g of Aerosil® was added. The obtained particle size distribution was about 3% for> 500 μm, about 63% for> 250 μm, and about 6% for <100 μm. The average particle size was 290 μm.
Using a barrel blender at 20 rpm for 15 minutes, the ground material was further mixed with 240 g HPC-SL and 2234 g granular lactose (Tavelttose® 100). Finally, 20 g of magnesium stearate was added and the mixture was mixed again at 20 rpm for 10 minutes. The mixture was compressed into biconvex tablets 8 mm in diameter and 250 mg in weight. Core tablets may be enteric coated as described in Example 16a or b.

Example 18.
Production of core tablets 2500 g of dimethyl fumarate is sieved through 1575 μm and 813 μm sieves and ground. Prior to the second grinding step, 6 g of Aerosil® is added.
Using a barrel blender at 20 rpm for 15 minutes, the ground material is further mixed with 240 g HPC-SL and 1714 g granular lactose (Tavelttose® 100). Finally, 20 g of magnesium stearate is added and the mixture is mixed again at 20 rpm for 10 minutes. The mixture is compressed into biconvex tablets 8 mm in diameter and 225 mg in weight. Core tablets may be enteric coated as described in Example 16a or b.

Example 19.
2.500 g of DMF was sieved through 1575 μm and 813 μm sieves and ground. Add 240 g HPC-SL, 2.734 g Tablettose® 100, and 6 g Aerosil and mix with DMF. The mixture is roller compressed and passed through a 1 mm sieve to obtain granules. 20 g of magnesium stearate is mixed to give the final mixture for tableting. The mixture is compressed into tablets with a tablet weight of 275 mg. Core tablets may be enteric coated as described in Example 16a or b.

Example 20.
2500 g of DMF is mixed with 6 g of Aerosil and subsequently ground by sieving at 1575 μm and 813 μm. 240 g of HPC-SL and 2.734 g of Tablettose® 100 are added and mixed with DMF and Aerosil. The mixture is roller compressed and passed through a 1 mm sieve to obtain granules. 20 g of magnesium stearate is mixed to give the final mixture for tableting. The mixture is compressed into tablets with a tablet weight of 275 mg. Core tablets may be enteric coated as described in Example 16a or b.

臨床試験の以上の結果は、Ｆｕｍａｄｅｒｍ（登録商標）に比べ、試験製剤が、より小さい変動性（表Ｉ参照）と共に、顕著に少ない有害作用の頻度を有することを示している（表ＩＩ）。従って、この例は、先行技術Ｆｕｍａｄｅｒｍ（登録商標）製剤に対して、浸食マトリックス錠が、ＡＵＣおよびＣｍａｘの変動性の大きな減少を有することを示している。 Example 21.
The tablets disclosed in Examples 18 and 22 were tested and compared with the corresponding data of the prior art formulation Fudamerm®, as disclosed in Example 25. The research results are shown in Tables I and II below.

The above results of the clinical trial show that the test product has a significantly lower frequency of adverse effects with less variability (see Table I) compared to Fumarate® (Table II). Thus, this example shows that the erosion matrix tablets have a large reduction in AUC and Cmax variability compared to the prior art Fumaderm® formulation.

Example 22.
Preparation of core tablets 13.4 kg of dimethyl fumarate was sieved through 1575 μm and 813 μm sieves and ground. Prior to the second grinding step, 32 g of Aerosil® was added. The obtained particle size distribution was about 3% for> 500 μm, about 52% for> 250 μm, and about 6% for <100 μm. The average particle size was 255 μm. 12.8 kg of ground material was further mixed with 1.2 kg of HPC-SL and 13.9 kg of granular lactose (Tavelttose® 100). Finally, 0.1 kg of magnesium stearate was added and the mixture was mixed again. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. The core tablets were enteric coated as follows.

Enteric coating 7.2 kg of purified water is heated to 70-80 ° C., then 138 g of triethyl citrate, 41 g of glycerin monostearate (Cutina GMS V), and 17 g of Tween 80 are added and 10 using UltraTurrax. A gastric acid resistant coating solution was prepared by stirring for 1 minute to obtain a uniform mixture. 8.9 kg of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 4.58 kg of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core lock in a perforated drum coating machine. The tablets were then cured at 40 ° C. for 2 hours. The amount of solid sprayed onto the tablets corresponded to a weight increase of 2.75%, resulting in a substantial weight increase of the coated tablets by about 2.2% compared to the core tablets. Based on the shape of the tablet, this corresponded to an enteric coat of ^{2.6 mg / cm 2.}

Example 23.
Preparation of Core Tablets 1136 g of dimethyl fumarate was mixed with 2.73 g of Aerosil®, 109 g of HPC-SL, and 1242.7 g of granular lactose (Tavelttose® 100). The mixture was then sieved through a 613 μm sieve and ground. Finally, 9.1 g of magnesium stearate was added and the mixture was mixed again. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. Core tablets were enteric coated as appropriate based on the description of the above Examples.

Example 24.
Preparation of core tablets 14.7 kg of dimethyl fumarate was mixed with 36 g of Aerosil® and pulverized by sieving through a 613 μm sieve to disaggregate. > 500 μm was about 3%,> 250 μm was about 20%, and <100 μm was about 25%. The average particle size was 165 μm.
13.7 kg of ground material was further mixed with 1.3 kg of HPC-SL and 14.9 kg of granular lactose (Tavelttose® 100). Finally, 0.11 kg of magnesium stearate was added and the mixture was mixed again. The mixture was compressed into biconvex tablets 8 mm in diameter and 275 mg in weight. The core tablets were enteric coated as follows.

Enteric coating Heat 8.7 kg of purified water to 70-80 ° C., then add 166 g of triethyl citrate, 49 g of glycerin monostearate (Cutina GMS V), and 20 g of Tween 80, using UltraTurrax 10 A gastric acid resistant coating solution was prepared by stirring for 1 minute to obtain a uniform mixture. 10.7 kg of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 5.5 kg of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core lock in a perforated drum coating machine. The tablets were then cured at 40 ° C. for 2 hours. The amount of solid sprayed onto the tablets corresponded to a 2.75% weight increase, resulting in a substantial weight increase of the coated tablets by about 2.4% compared to the core tablets. Based on the shape of the tablet, this corresponds to an enteric coat of ^{2.9 mg / cm 2.}

Example 25.
Preparation of core tablets 13.3 kg of dimethyl fumarate was mixed with 32 g of Aerosil® and pulverized by sieving through a 613 μm sieve to disaggregate. > 500 μm was about 3%,> 250 μm was about 20%, and <100 μm was about 25%. The average particle size was 165 μm. 12.53 kg of ground material was further mixed with 1.2 kg of HPC-SL and 16.17 kg of granular lactose (Tavelttose® 100). Finally, 0.10 kg of magnesium stearate was added and the mixture was mixed again. The mixture was compressed into biconvex tablets with a diameter of 11.5 mm and a weight of 600 mg. The core tablets were enteric coated as follows.

Enteric coating Heat 8.7 kg of purified water to 70-80 ° C., then add 166 g of triethyl citrate, 49 g of glycerin monostearate (Cutina GMS V), and 20 g of Tween 80, using UltraTurrax 10 A gastric acid resistant coating solution was prepared by stirring for 1 minute to obtain a uniform mixture. 10.7 kg of purified water was added and the mixture was stirred using a propeller stirrer until the emulsion reached room temperature. The emulsion was then added slowly to 5.5 kg of Eudragit L30 D 55 dispersion. The obtained gastric acid resistant coating solution was sprayed directly onto the core lock in a perforated drum coating machine. The tablets were then cured at 40 ° C. for 2 hours. The amount of solid sprayed onto the tablets corresponded to a 2.3% weight increase, resulting in a substantial weight increase of the coated tablets by about 2% compared to the core tablets. Based on the shape of the tablet, this corresponded to an enteric coat of ^{2.8 mg / cm 2.}

Example 26.
For example, using the methods described in Examples 4, 6, 7, 10, 12, 13a, 13b, 16a, 16b, 20, and 24, 375 mg ± 5%, 250 mg ± 5%, 187.5 mg ± 5%. , Or 125 mg ± 5% dimethyl fumarate essentially to produce a unit dosage form formulated as an enteric coated erosion matrix tablet. In some embodiments, a 375 mg dose of dimethyl fumarate is administered once daily. In another embodiment, the 187.5% mg dose is administered twice daily. In yet another embodiment, the 125 mg dose is administered three times daily. Such low dose regimens are particularly convenient for reducing the side effects associated with dimethyl fumarate treatment.

Claims (19)

A pharmaceutical composition for the oral treatment of psoriasis, wherein the composition is in the form of a tablet core and an erosion matrix tablet comprising one or more coatings.
i) contains 10 to 80% by weight of dimethyl fumarate as the active substance, and ii) 1 to 50% by weight of the rate-determining substance, and at least one of the above 1 or more coatings is the core 2. A pharmaceutical composition which is an enteric coating applied at a level of 8 to 3.3 mg / cm ² and the dose of dimethyl fumarate administered is 375 mg once daily. The pharmaceutical composition according to claim 1, wherein the rate-determining substance is hydroxypropyl cellulose. The pharmaceutical composition according to claim 1 or 2, wherein the tablet core further comprises a binder. The pharmaceutical composition according to claim 3, wherein the binder is lactose. The tablet core
i) 35-55% by weight dimethyl fumarate,
The pharmaceutical composition according to claim 4, wherein ii) contains 3 to 12% by weight of hydroxypropyl cellulose, and iii) 40 to 60% by weight of lactose. The tablet core
i) 40-50% by weight dimethyl fumarate,
The pharmaceutical composition according to claim 5, wherein ii) contains 3 to 12% by weight of hydroxypropyl cellulose, and iii) 45 to 55% by weight of lactose. The tablet core
i) 42-48% by weight dimethyl fumarate,
The pharmaceutical composition according to claim 6, wherein ii) contains 3 to 10% by weight of hydroxypropyl cellulose, and ii) 45 to 52% by weight of lactose. Any of claims 5-7, wherein the tablet core further comprises 0.15 to 0.7% by weight magnesium stearate and optionally 0.05 to 0.25% by weight of silicon dioxide. The pharmaceutical composition according to paragraph 1. The pharmaceutical composition according to any one of claims 1 to 8, for the treatment of mild to moderate psoriasis vulgaris, moderate to severe psoriasis vulgaris, or severe psoriasis vulgaris. Use of a pharmaceutical composition for producing a drug for the treatment of psoriasis, wherein the composition is in the form of an erosion matrix tablet for oral administration, which comprises a tablet core and one or more coatings. The tablet core
i) contains 10 to 80% by weight of dimethyl fumarate as the active substance, and ii) 1 to 50% by weight of the rate-determining substance, and at least one of the above 1 or more coatings is the core 2. An enteric coating applied at a level of 0-3.5 mg / cm ^2.
Further, the pharmaceutical composition is formulated by containing dimethyl fumarate at a dose of 375 mg once a day for use. The use according to claim 10, wherein the rate-determining substance is hydroxypropyl cellulose. The pharmaceutical composition according to claim 10 or 11, wherein the tablet core further comprises a binder. The pharmaceutical composition according to claim 12, wherein the binder is lactose. The tablet core
i) 35-55% by weight dimethyl fumarate,
The use according to claim 13, which comprises ii) 3-12% by weight hydroxypropyl cellulose, and iii) 40-60% by weight lactose. The tablet core
i) 40-50% by weight dimethyl fumarate,
ii) The use according to claim 14, comprising 3-12% by weight hydroxypropyl cellulose, and ii) 45-55% by weight lactose. The tablet core
i) 42-48% by weight dimethyl fumarate,
ii) The use according to claim 15, comprising 3-10% by weight hydroxypropyl cellulose, and iii) 45-52% by weight lactose. 10. Use of. The use according to any one of claims 10 to 17 for the treatment of mild to moderate psoriasis vulgaris, moderate to severe psoriasis vulgaris, or severe psoriasis vulgaris. A pharmaceutical composition in the form of a tablet core and an erosion matrix tablet comprising one or more coatings, wherein the tablet core is:
i) contains 10 to 80% by weight of dimethyl fumarate as the active substance, and ii) 1 to 50% by weight of the rate-determining substance, and at least one of the above 1 or more coatings is the core 2. A pharmaceutical composition which is an enteric coating applied at a level of 8 to 3.3 mg / cm ² and the dose of dimethyl fumarate administered is 375 mg per day.