Dialkyl fumarate-containing pharmaceutical preparations

The present invention relates to the use of dialkyl fumarate to produce drug formulations for use in transplantation medicine or the treatment of autoimmune diseases and drug formulations in the form of microtablets or micropellets containing dialkyl fumarate. It is a thing.

Thus, the invention, on the one hand, is a drug formulation specifically for the treatment, mitigation or suppression of recipient rejection of a transplant, i.e., a host-to-graft reaction, or recipient rejection, i.e., a graft-versus-host reaction. It relates to the use of dialkyl fumarate to produce. On the other hand, the present invention presents polyarthritis, polysclerosis, juvenile early diabetes, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosus (SLE), Schogren's syndrome, pernicious anemia and chronic activity (pertussis-like). ) It relates to the use of dialkyl fumarate to produce drug formulations for the treatment of autoimmune diseases such as hepatitis.

Graft rejection and autoimmune diseases are based on medically undesirable reactions or dysregulation of the immune system. Cytokines such as interleukins or tumor necrosis factor α (TNF-α) are substantial mediators of action on the immune system. Generally, both are treated by administration of immunosuppressive agents such as cyclosporine.

In general, autoimmune diseases are found as a lack of resistance to endogenic substances or antigens. As a result, this resistance is maintained only when the antigen remains in contact with immunological cells. Loss of this resistance results in the formation of autoantibodies, i.e., a humoral immune response to internal tissues. The exact nature of how TNF-α is involved is unknown.

A transplant is a tissue or organ transplant, i.e. a transplant of tissue such as the cornea, skin, bone (bone fragments), blood vessels or myocardium; a transplant of an organ such as the kidney, heart, liver, lung, pancreas or intestine; or It is the transfer of individual cells such as islet cells, α-cells and hepatocytes, where the pancreas is the most important organ to be transplanted.

Depending on the degree of association between the donor and the beneficiary, auto transplantation (transfer to another part of the same individual), iso-transplantation (to another genetically identical individual) Transfer); and allogenic transplantation (transfer to other individuals of the same species). Depending on the organ and the site of transplantation, it is further divided into homotopic transplantation (transplantation to the same site) and heterotopic transplantation (transfer to different sites). Transplantation as described above is an important role in modern medicine.

The main problem in transplant medicine is graft rejection due to the recipient's immunological defense response after transplantation of tissue, organ or cell. Such graft rejection is also called a host-to-graft reaction. An organism's immunological defense response to a foreign protein often results in the rejection or lysis of the graft. Different stages are distinguished in the host-to-graft reaction. This reaction occurs at different rates depending on the degree of difference between the beneficiary and the donor and is therefore referred to as an acute, subacute or chronic reaction. The acute rejection process involves irreversible loss of transplantation as a result of arteritis or arterioleitis within 48 hours and cannot be affected by drug administration. Subacute rejection is a reversible dysfunction caused by graft vasculopathy and manifests as rejection within 12 days to 4 months. Finally, a condition in which the transplanted tissue loses its function due to vascular changes such as arterial damage due to obstruction that progresses over weeks or years and cannot be stopped by drugs is called chronic rejection.

In contrast, transplant rejection of recipients, the so-called graft-versus-host reaction, can occur when transplanting well-immune tissue, primarily bone marrow transplants. The severity of this reaction is also graded, resulting in the same complex problems as in the host-versus-graft reaction: arteriopathies and disruption.

In order to avoid such rejection, that is, host-to-graft reaction and graft-versus-host reaction, immunosuppression, that is, weakening of normal immune response, is performed in transplant medicine. For this purpose, anti-lymphocyte sera are often combined with corticosteroids and so-called antimetabolites to use purine homologues such as 6-mercaptopurine and thioguanines, which are nucleic acids and proteins. It acts on synthesis and thus blocks cell division and proliferation. This suppresses antibody production and cellular immune response. Immunosuppressants used for treatment are substances that specifically or non-specifically suppress or weaken the immune response in the body. Non-specific immunosuppressants are cytostatic agents such as alkylating agents or antimetabolites.

In addition, at least active ingredients that cause partially specific immunosuppression, such as corticosteroids, antisera, antibody FK-506, tacrolimus, mycophenolate mofetil and mainly cyclosporines such as cyclosporin A It is known. As a result of the use of cyclosporin, especially cyclosporin A, which is the most important representative of modern immunosuppressants, the results of transplantation have been significantly improved over the last few years. Currently, the survival rate after one year is about 60% for liver transplantation, about 80% for heart transplantation, and more than 90% for kidney transplantation. Autoimmune diseases in which the endogenic immune system attacks internal organs, tissues, and cells are comparable to graft-versus-host reactions. These are also medically undesirable reactions of the immune system, which can be treated with immunosuppressants.

<p><patcit num="1"><text>European Patent No. 0188549</text></patcit><patcit num="2"><text>German Patent No. 2530372</text></patcit><patcit num="3"><text>German Patent No. 2621214</text></patcit><patcit num="4"><text>European Patent No. 0312697</text></patcit></p>

<p><nplcit num="1"><text>Hautarzt (1987) 279-285 (Dermatologist (1987), pp. 279-285)</text></nplcit></p>

<p> The risk of using immunosuppressants is to weaken the body's defenses against an increased risk of infections and malignancies. Accordingly, an object of the present invention can be used to treat, particularly suppress, weaken and / or ameliorate a host-to-graft response and a graft-versus-host response, but without the aforementioned disadvantages. To provide a drug formulation used in transplantation medicine.</p><p> Another object of the present invention is an autoimmune disease, particularly polyarthritis, polysclerosis, juvenile early diabetes, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosus (SLE), Shogren's syndrome, pernicious anemia and chronic activity. To provide a drug formulation that can treat lupus-like hepatitis and does not have the disadvantage of immunosuppression.</p>

<p> An object of the present invention is the use of certain dialkyl fumarate for use in transplant medicine or for the treatment of autoimmune diseases, and the formulation of drugs in the form of microtablets and micropellets containing this dialkyl fumarate. Achieved by things. The individual subject matter of the present invention is characterized in detail in the claims. The formulations of the present invention do not contain free fumaric acid itself.</p><p> During post-dose biodegradation, the drug formulation that enters or is part of the citric acid cycle-especially at high doses-alleviates or treats potentially occurring illnesses. It is known to increase therapeutic importance.</p><p> Fumaric acid, for example, inhibits the growth of Ehrlich ascites tumors in mice, reduces the toxic effects of mitocin C and aflatoxin, and exhibits anti-psoriasis and anti-microbial activity. High doses of fumaric acid or as far as known fumaric acid derivatives, such as dihydroxyl fumaric acid, fumaramide and fumaronitrile, are often used by injection or when administered transdermally and especially orally. Has serious unacceptable side effects and high toxicity as previously had to abandon treatment.</p><p> Surprisingly, the study conducted by the applicant found that methyl hydrogen fumarate, a metabolite of dimethyl fumarate, was found in peripheral blood human mononuclear cells (peripheral blood mononuclear cells = PBMC cells) and isolated monocytes. It was shown that the increase was an early increase in intracellular toxin-stimulated TNF-α secretion. Furthermore, Applicants have been able to show that fumaric acid has an effect comparable to cyclosporine on in vitro and in vivo hemagglutination reactions.</p><p> Surprisingly, dialkyl fumarate has been found to be advantageous in producing drug formulations for use in transplant medicine and for the treatment of autoimmune diseases. This arises because the compositions containing dialkyl fumarate as described above allow for positive modulation of the immune system in host-to-graft reaction, graft-versus-host reaction and other autoimmune diseases.</p><p> Patent Document 1 has already described fumaric acid and a fumaric acid-containing drug composition for the treatment of psoriasis. A drug composition for treating psoriasis containing a mixture of fumaric acid and other fumaric acid derivatives is known from Patent Document 2. The inclusion of free fumaric acid is essential for these medicines.</p><p> Patent Document 3 describes a drug containing fumaric acid monomethyl ester and an inorganic salt thereof as an active ingredient for the treatment of psoriasis. Non-Patent Document 1 describes the use of fumaric acid monoethyl ester salt. A drug formulation for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regional Crohn containing a mixture of a monoalkyl fumarate salt and Diesel fumarate is known from Patent Document 4. ..</p><p> In particular, an object of the present invention is an expression.<chemistry num="1"><img file="JP2019123738A_D0001.tif" /></chemistry>(In the formula, R₁And R₂Are the same or different independent linear, branched or cyclic saturated or unsaturated C₁~₂₀Alkyl group, which is optionally halogen (Cl, F, I, Br), hydroxy group, C₁~₄Achieved by using one or more dialkyl fumarate represented by an alkoxy group (which may be substituted with an alkoxy group, a nitro group or a cyano group) for use in transplantation medicine or for the treatment of autoimmune diseases. Will be done.</p><p> C₁~₂₀Alkyl group, preferably C₁~₈Alkyl group, especially preferably C₁~₅Alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, second butyl group, tertiary butyl group, pentyl group, cyclopentyl group, 2-ethylhexyl group, hexyl group, cyclohexyl group, With heptyl group, cycloheptyl group, octyl group, vinyl group, allyl group, 2-hydroxyethyl group, 2- or 3-hydroxypropyl group, 2-methoxyethyl group, methoxymethyl group or 2- or 3-methoxypropyl group. is there. Preferably the group R₁Or R₂At least one of them is C₁~₅Alkyl groups, especially methyl or ethyl groups. More preferably R₁And R₂Are the same or different C₁~₅Alkyl groups such as methyl group, ethyl group, n-propyl group or tertiary butyl group, and methyl group and ethyl group are particularly preferable. Most preferred group R₁And R₂Are the same and are methyl or ethyl groups. Dimethyl fumarate, methyl ethyl fumarate and diethyl fumarate are particularly preferred.</p>

<p> Treatment with the fumaric acid derivatives of the invention for the listed uses has few significant side effects compared to prior art substances such as cyclosporine, which causes serious renal failure or disease of the lymphocyte proliferative system. It doesn't happen.</p><p> In particular, the immunosuppressive effect of cyclosporine is caused by inhibition of Th-1 cell formation. As shown by Applicant's test tube experiments, fumarate translocates Th-1 type cytokine patterns to Th-2 type cytokine patterns.</p><p> Unexpected effects of the use of dialkyl fumarate according to the invention, especially in view of the long-term treatment and prevention always required in graft-versus-host reaction and host-to-graft reaction or other autoimmune diseases such as multiple sclerosis. Is very important. In combination therapy with cyclosporine and fumaric acid derivatives, the toxic side effects of the previous compounds are substantially and unexpectedly reduced. Furthermore, the use of dialkyl fumarate according to the present invention is also important in that it replaces the treatment of corticosteroids for autoimmune diseases known to have significant side effects.</p>

The dialkyl fumarate used according to the present invention is produced by a method known to a technical level (see, for example, Patent Document 4).

Preferably the active ingredient is used to make oral formulations in the form of tablets, micro tablets, pellets or granules, optionally in capsules or bags. Formulations in the form of micro-tablets or pellets, optionally filled in capsules or bags, are also preferred and are the subject of the present invention. The oral formulation may be enteric coated. Capsules are soft or hard gelatin capsules.

The dialkyl fumarate used by the present invention is used alone or as a mixture of several compounds, optionally in combination with conventional carriers and excipients. The amount used is selected so that the resulting formulation contains an amount of active ingredient corresponding to 10-300 mg of fumaric acid.

The preferred formulation according to the invention contains a total of 10-300 mg of dimethyl fumarate and / or diethyl fumarate.

According to a preferred embodiment, the size or average diameter of the pellets or microtablets is in the range of 300-2000 μm, in particular in the range of 500-1000 μm, respectively.

In addition to the graft-versus-host reaction (see above), the following autoimmune diseases to be treated include: polyarthritis, multiple sclerosis, graft-versus-host reaction, juvenile early diabetes, Hashimoto thyroiditis, Graves. Diseases, systemic lupus erythematosus (SCE) Shogren's syndrome, pernicious anemia and chronic active (wolves-like) hepatitis. Broadly defined autoimmune diseases include psoriasis, psoriatic arthritis, neurodermatitis and localized cloned enteritis.

Besides micropellets, microtablets, capsules (eg soft and hard gelatin capsules), granules and tablets for oral administration as described above, suitable drug formulations are ointments, plasters, lotions or showers. Formulations for skin and transcutaneous administration in the form of formulations, and aqueous microdisperses for rectal administration such as crude drugs or micro-enemas, for enteral administration in the form of oil-in-water emulsions or oily solutions. It is a formulation. Drug formulations in the form of micro-tablets or micro-pellets are preferred for the treatment of all the autoimmune diseases described above, including psoriasis, psoriatic arthritis, neurodermatitis and localized cloned enteritis, and are also in the subject matter of the present invention. is there.

According to the present invention, treatment with dialkyl fumarate can also be performed in combination with a first or higher formulation of triple drug treatment commonly used in organ transplantation or cyclosporin A alone. To this end, the formulations administered can each contain a combination of active ingredients in known doses or in total amounts. Similarly, a combination of treatments consists of administering separate formulations in parallel by the same or different routes. In some cases, there is also an advantage that the dose of the active ingredient contained in addition to the fumaric acid derivative administered according to the present invention can be reduced.

In another embodiment of the use of dialkyl fumarate according to the present invention, application of the dialkyl fumarate is followed by drug treatment with an immunosuppressive agent such as cyclosporine. This means that the application of the fumaric acid derivative for one week or more is followed by one week or more of cyclosporine treatment. This will reduce the dose of cyclosporin A and significantly reduce the incidence of side effects in long-term treatment.

Administration of dialkyl fumarate in the form of preferred micro-tablets already reduces when regular tablets are administered, but the gastrointestinal irritation and side effects that are still observed are further reduced by the fumaric acid derivatives and salts.

When normal tablets are administered, the components of the tablets are likely to be released into the intestine at too high a concentration, causing local irritation of the intestinal mucosa. This local stimulus releases a very high concentration of TNF-α for a short period of time that can respond to gastrointestinal side effects. On the other hand, when an enteric coated microtablet in a capsule is applied, the local concentration of active ingredient in the intestinal epithelial cells can be significantly reduced. Microtablets are released by the stomach and pass through the small intestine by peristalsis, thus improving the distribution of active ingredients.

This means that the same dose of enteric coated microtablets are already dispersed in the stomach, which passes in small portions towards the intestine, where the active ingredient is released in small doses. This avoids local stimulation of intestinal epithelial cells and release of TNF-α. Thus, the resistance of micro tablets in the gastrointestinal system is improved as compared to normal tablets.

Furthermore, the dialkyl fumarate used by the present invention is not an active ingredient in itself, but a so-called prodrug that is converted to an active ingredient in the body, thus improving absorption.

<p> To illustrate the use of dialkyl fumarate according to the invention, various examples of preferred agents are described below.</p><p>Production Examples In principle, oral formulations in the form of tablets or micro tablets according to the invention can be produced by conventional tableting methods. Instead of such a conventional tableting method, other tablet manufacturing methods such as a direct tableting method and a method for producing a solid dispersion by a melting method and a spray drying method can be used.</p><p> The tablets can be enteric coated. The enteric coating is applied or sprayed in a conventional coating pan or applied in a fluidized bed device. The tablets can also be film coated.</p><p>Example 1 Production of enteric coated microtablets in capsules containing 120.0 mg of dimethyl fumarate, which corresponds to 96 mg of fumaric acid.</p><p> Take necessary precautions (breathing mask, gloves, protective clothing, etc.), grind 12.000 kg of dimethyl fumarate, mix and homogenize with sieve 800. Then make an excipient mixture with the following composition: Starch Derivatives (STA-RX)^R1500) 17.50kg, microcrystalline cellulose (Avicel)^RPH101) 0.30kg, PVP (Kollidon)^R120) 0.75kg, Primogel^R4.00 kg, colloidal silicic acid (Aerosil)^R) 0.25kg. The active ingredient is added to the whole powder mixture, mixed, homogenized by sieve 200 and polyvinylpyrrolidone (Kollidon).^RIt is processed by a conventional method using a 2% aqueous solution of k25) to obtain bound granules, and then mixed with other phases in a dry state. The other phase consists of 0.50 kg of magnesium stearate and 1.50 kg of talc.</p><p> The powder mixture is then pressed by conventional methods to give convex tablets with a total weight of 10.0 mg and a diameter of 2.0 mm.</p><p> Hydroxypropyl methylcellulose phthalate (HPMC, Pharmacoat) is an example of gaining resistance to gastric acid.^R HP50) Dissolve a small amount of 2.250 kg of solution in the following solvent mixture: 13.00 l of acetone, ethanol (94 wt%, modified with 2% ketone) 13.50 l Demineralized water 1.50 l. Castor oil (0.240 kg) as a plasticizer is added to the finishing solution and a small amount is applied to the tablet core by a conventional method:</p><p> After drying, apply the following composition as a film coating in the same device: talc 0.340 kg, titanium oxide (VI) Cronus RN 56 0.400 kg, colored lacquer L-Rot-lack 86837 0.324 kg, EudragitE 12.5% 4.800 kg , Polyethylene glycol 6000 mixed with solvent of the following composition, pH 11 XI: 2-propanol 8.170 kg, demineralized water 0.200 kg, glycerin triacetate (triacetin) 0.600 kg.</p><p> After this, the enteric coated microtablets are filled into hard gelatin capsules with a net weight of 400 mg and sealed.</p><p>Example 2 Production of enteric coated microtablets in capsules containing 120.0 mg of dimethyl fumarate, which corresponds to 96 mg of fumaric acid.</p><p> Grind 12.000 kg of dimethyl fumarate and homogenize in the same manner as above. Then make an excipient mixture with the following composition: Microcrystalline Cellulose (Avicel)^RPH200) 23.20kg, Croscarmellose Sodium (AC-Di-SOL-SP-711) 3.00kg, Talc 2.50kg, Anhydrous Silica (Aerosil) ^R200) 0.10kg, magnesium stearate 1.00kg. The active ingredient is then added to the whole powder mixture and mixed uniformly. By direct tableting, the powder mixture is then pressed into convex tablets with a total weight of 10.0 mg and a diameter of 2.00 mm.</p><p> After this, Eudragit^R Make a solution of isopropanol containing 0.94 g of L. This solution contains 0.07 kg of dibutyl phthalate. This solution is sprayed onto the tablet core. After this, Eudragit^R A mixture of 17.32 kg of LD-55 and 2.80 kg of microtalc, 2.00 kg of Macrogol 6000 and 0.07 kg of dimeticon is dispersed in water and sprayed onto the tablet core.</p><p> The enteric coated microtablets are then filled into hard gelatin capsules with a net weight of 650 mg and sealed.</p><p>Example 3 Production of micropellets in capsules containing 50.0 mg of dimethyl fumarate, which corresponds to 40 mg of fumaric acid.</p><p> Grind 5.000 kg of dimethyl fumarate and homogenize as described above. In addition, make 2 l of a 2% (m / v) solution of polyvinylpyrrolidone (Kollidon K30) in ethanol. Spray 7.250 kg of micropellets in a coated pan with some Kollidon K-30 solution until slightly warmed. The active ingredient is then added in small amounts until the pellets are dry. This wetting / drying process continues until all active ingredients have been added. Then continue to move the pellet until it is completely dry.</p><p> After this, the pellets are filled into hard gelatin capsules (126.5 mg pellets / capsules).</p><p>Example 4 Production of enteric coated capsules containing 110.0 mg of dimethyl fumarate equivalent to 88 mg of fumaric acid.</p><p> 11.000 kg of dimethyl fumarate, 14.00 kg of starch, 5.65 kg of lactose, microcrystalline cellulose (Avicel)^R) 2.00 kg, polyvinylpyrrolidone (Kollidon)^R25) 1.00 kg and Primogel^RMix vigorously in a mixture of 2.443 kg, take necessary precautions (breathing mask, gloves, protective clothing) and homogenize with sieve 800.</p><p> Polyvinylpyrrolidone (Kollidon)^RUsing a 2% aqueous solution of K25), the whole powder mixture is treated in bound granules by a conventional method and mixed with the outer phase when dried. This outer phase is colloidal silicic acid (Aerosil)^R) Composed of 0.350 kg, magnesium stearate 0.500 kg and talc 1.500 kg. A small amount of this homogeneous mixture is filled into a suitable 400 mg capsule, which is then routinely coated with an enteric coating of hydroxypropylmethylcellulose stearate and castor oil as a plasticizer. Instead of using hard gelatin capsules, capsules with a suitable enteric coating consisting of a mixture of cellulose acetate phthalate (CAP) and hydroxypropylmethyl cellulose phthalate (HPMCP) can also be filled.</p>