GR1009654B - Pharmaceutical composition comprising an immunomodulatory agent and method for the preparation thereof - Google Patents

Abstract

The present invention relates to a stable pharmaceutical formulation of solid dosage forms for oral administration containing a therapeutically effective amount of Fingolimod HCΙ in combination with inorganic salts in order to avoid any interaction with the active ingredient and formation of degradation products. It also relates to a process for the preparation thereof.

Description

PHARMACEUTICAL PREPARATION CONTAINING AN IMMUNE MODULATING AGENT AND METHOD FOR PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical preparation for oral administration containing a therapeutically active amount of an immunomodulating agent, such as Fingolimod, as well as the method of preparing the above preparation.

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and loss of oligodendrocytes and neurons. S.K.P. it is the leading cause of non-traumatic neurological disability in young and middle-aged adults and has a very large physical, psychological, social and economic impact on patients and their families, friends and the bodies responsible for the provision of health services.

Recurrent S.C.P. is the most common clinical presentation of the disease. The majority of patients are women (female to male ratio 2:1) diagnosed with S.C.P. aged between 20 and 40 years. At the stage of diagnosis, approximately 85% of patients have relapsing-remitting S.C.P. (YDSCP) characterized by recurrent acute paroxysms (relapses) of neurological dysfunction followed by recovery. A significant proportion (42 - 57%) of relapses may lead to incomplete recovery of function and leave permanent disability and retardation. After 6 - 10 years, 30 - 40% of patients with YSCP develop secondary progressive CKD. (DSCP), in which the course of the disease is less inflammatory and more neurodegenerative. D.P.S.K.P. steadily progresses to disability with or without relapses.

Fingolimod is a sphingosine 1-phosphate receptor modulator. It is metabolized by sphingosine kinase to active Fingolimod phosphate. Fingolimod phosphate binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptors 1, 3, and 4 found on lymphocytes and readily crosses the blood-brain barrier to bind to S1P receptors 1, 3, and 5 found on nerve cells in Central Nervous System. By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate inhibits the ability of lymphocytes to be secreted from the lymph nodes, causing redistribution rather than depletion of lymphocytes. The above redistribution is thought to reduce the infiltration of pathogenic lymphocytes into the central nervous system where they could become involved in nerve inflammation and nerve tissue destruction.

Fingolimod hydrochloride was the first oral drug approved to reduce relapses and slow the progression of disability in patients with relapsing forms of multiple sclerosis (MS). Before its approval, drugs for S.C.P. commercially available were all given by regular injections, the frequency of which varied from once a day to once a week, depending on the drug.

The chemical name of Fingolimod hydrochloride is 2-amino-2-(2-(4-octylphenyl)ethyl)propane1,3-diol hydrochloride. Its molecular formula is C19H33NO2.HC1 corresponding to a molecular weight of 343.93. It is a white to practically white powder. In salt form, Fingolimod is freely soluble in water and a buffer solution with a pH of 1.0, very soluble in a buffer solution with a pH of 4.0 and practically insoluble in a buffer solution with a pH of 6.8.

Fingolimod is not a chiral molecule and therefore does not exhibit any specific cyclic rotation. However, fingolimod hydrochloride exhibits polymorphism. Various polymorphisms are reported in the literature. The polymorphic form of the active substance used in the preferred formulation of the present invention is Form I, which is stable and which is discussed in WO-A-2010/055028.

In the presence of various versions, Fingolimod is unstable. Especially at high temperatures or in humid conditions, many pharmaceutical acceptable excipients are not compatible with Fingolimod because when mixed with it they create impure impurities or degradation products at a level above the acceptable limit for pharmaceutical preparations according to the Health Regulatory Authorities.

The patent EP 1613288 B1 concerns a solid pharmaceutical preparation for oral administration that includes Fingolimod and some saccharoalcohol.

US 6277888 B1 relates to a pharmaceutical formulation comprising Fingolimod and a lecithin.

The patent WO 2011/131370 A1 concerns a method of preparing an intermediate product consisting of Fingolimod by a melting process with a matrix forming agent.

Despite the fact that each of the above patents is an attempt to circumvent the stability problems of pharmaceutical formulations that include Fingolimod, there continues to be a need for an improved pharmaceutical formulation that does not face such problems and ensures increased patient compliance.

SUMMARY OF THE INVENTION

Therefore, the objective of the present invention is to provide an improved stable solid pharmaceutical form for oral administration containing as active substance Fingolimod or a pharmaceutically acceptable salt thereof and which overcomes the difficulties of the previous technological generation.

Another objective of the present invention is to provide hard gelatin capsules that contain Fingolimod HC1 as an active substance, are bioavailable and have a satisfactory shelf life.

The main objective of the present invention is the selection of the optimal combination of the pharmaceutically acceptable versions and the preparation method in order to achieve the appropriate dissolution profile and the stability required for the final pharmaceutical form. The aforementioned formulation offers predictable and reproducible drug release rates to achieve better patient treatment.

A further aspect of the present invention is to provide a formulation in capsule form for oral administration comprising Fingolimod HC1 and prepared by a quick and simple process with a good cost-effectiveness ratio.

According to the above aspects of the present invention, a pharmaceutical formulation is provided containing Fingolimod as an active substance in combination with inorganic salts to avoid any interaction with the active substance and formation of degradation products that will alter the dissolution characteristics.

According to another aspect of the present invention there is provided a method for the preparation of a stable, solid pharmaceutical form for oral administration, which includes as an active substance Fingolimod or a pharmaceutically acceptable salt thereof in combination with inorganic salts to avoid any interaction with the active substance and formation of degradation products that will alter dissolution characteristics. The above method consists of the following steps:

- mixing Fingolimod HC1 with the fillers,

- lubrication of the powder mixture with the lubricant,

- filling in capsules.

Through the following detailed description, other advantages and objectives of the present invention will become apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention it is considered that a pharmaceutical preparation consisting of an active substance is "stable" if the above substance degrades less or more slowly than on its own and/or in known pharmaceutical preparations.

As already mentioned, the main objective of the present invention is to provide a stable pharmaceutical formulation of Fingolimod for oral administration, which is simple to prepare, bioavailable, with good cost-effectiveness and has good pharmaceutical properties.

Oral administration is a way of administering the medicine by swallowing it. Many drugs are taken orally because they are intended for a systemic effect, e.g. reaching various parts of the body through the circulatory system of the blood. Oral administration is the most common route of administration due to its ease and comfort, factors that increase patient compliance.

Capsules are solid pharmaceutical forms in which the drug is enclosed in either a hard or a soft soluble container or "shell". The casing is usually made of gelatin, but may also be of starch or other suitable substances. Hard gelatin capsules consist of two parts: telescopic cap and main body. There is generally a unique groove or indentation formed in the cap and main body portion to provide adequate closure when fully applied, which helps prevent accidental opening of the filled capsules during transportation and handling. Hard shell capsules are usually filled with powder, spherical granules or granular mixtures, but it is also possible to fill them with semi-solids or liquids.

Agitation or mixing of powdered ingredients is a very common method in industry in many industries, including pharmaceuticals. The main advantage of the dry mixing method is that less equipment and space is required. In addition, this method eliminates both the need for binder solution and heavy mixing equipment, as well as the time-consuming drying step required in wet granulation.

According to the approaches of the present invention the hard gelatin capsules are filled with the powder mixture.

To maintain the effects of a drug after oral administration it must be solubilized and then diffused into the body through the intestinal walls. The first step in this process is the comminution of the pharmaceutical form and then the dissolution of the active substance. Since the invention concerns an immediate release pharmaceutical form, the dissolution properties are extremely important for its performance.

The manufacture of pharmaceutical formulations often involves mixing the drug with various excipients in order to improve manufacturability and maximize the product's ability to deliver the drug dose effectively. Excipients are known to facilitate administration and regulate the release of the active substance. They can also stabilize its degradation due to environmental conditions. Most excipients do not have any direct pharmacological action but can provide useful properties to the formulation. However, they may also trigger unintended and/or unwanted effects, such as increased degradation of the drug. Physical and chemical interactions between drugs and excipients may affect the chemical structure, stability and bioavailability of pharmaceutical products and thus their therapeutic efficacy and safety.

Fingolimod is an aminodiol, which is likely to have adverse reactions with several excipients. Interactions between acidic and basic substances as well as Maillard reactions are the most commonly recorded reactions between active substance and excipients.

The excipients used in the present invention were chosen with a view to improving the dissolution, the physicochemical properties and the stability of the active drug in the final pharmaceutical form and were therefore subjected to a compatibility study with the active substance.

Diluents or fillers increase the volume of the solid pharmaceutical formulation and can make the use of a pharmaceutical form easier for both the patient and the caregiver. In addition, they improve fluidity and enable preparation through direct compression. For example, microcrystalline cellulose (MCC), dextrose, dextrates, fructose, mannitol, maltodextrin, maltitol, lactose, sucrose, calcium phosphate, maltose can be used as diluents for solid preparations.

In the presence of reducing sugars and Fingolimod a Maillard reaction is induced and therefore in the present invention the use of inorganic salts as fillers is preferred.

Inorganic salts generally do not have functional groups that can interact with the drug substance and cause the formation of unwanted by-products. In addition, they are stable during storage and retain their physical properties. Calcium salts, such as calcium phosphate and tricalcium citrate, are widely used as fillers in solid pharmaceutical forms and provide very good flow properties.

Calcium phosphate, which here includes the dihydrate and anhydrous form of dibasic calcium phosphate as well as tribasic calcium phosphate, is a granular insoluble material. The above are widely used as fillers for capsules and also as diluents for the preparation of tablets by liquid granulation or direct compression. They are also used in pharmaceutical products due to their compression properties and good flow properties of the coarse material. The bulk density of calcium phosphate is higher than that of organic fillers. It is widely used in vitamin and mineral preparations. Calcium phosphate is used both as an excipient and as a source of calcium in dietary supplements. It is chemically stable and compatible with many pharmaceutical substances.

In the present invention two different strengths of tricalcium phosphate (bulk density 0.25 g/ml & 0.5 g/ml) are preferably used as fillers in an amount between 90-99.5% by weight.

Lubricants prevent the granular mixes/powders from sticking to the walls of the die and facilitate injection from the die after compression. They also reduce the internal friction between the particles and improve the flow rate of the powder. Lubricants tend to be hydrophobic so their level needs improvement. Inadequately lubricated mixes do not flow easily and exhibit adhesion problems during compaction. Overlubricated mixes can adversely affect dissolution rate and strength. Common lubricants used in pharmaceutical formulations are talc, magnesium stearate, calcium stearate, sodium stearate fumarate, glycerin behenate, stearic acid.

In the present invention it is preferred to use stearic acid as a lubricant in an amount of 0.2-2% by weight.

A number of immediate release formulations consisting of various excipients were tested, the results of which are shown in the examples below. The aim was to achieve the optimal properties in terms of the objectives of the present invention.

EXAMPLES

As a first approach, various soluble diluents were tested to study their effect on the dissolution properties of the final Fingolimod formulation as well as their effect on its chemical stability.

In Table 1 below the Fingolimod HC1 and filler are sieved and geometrically mixed due to the very small percentage of active substance in the final mixture. The mixture is lubricated with magnesium stearate and then filled into capsules.

Table 1: Formulations 1-5

Formulations 1-5 showed acceptable dissolution profiles and were then stored under accelerated storage conditions to study their chemical stability. The table below shows the pilot stability data of Formulations 1-5 after 6 months storage at 40°C/75% RH.

Table 2: Pilot stability data after 6 months storage at 40°C/75% RH

Based on the results presented above it follows that the use of saccharides with Fingolimod hydrochloride results in the formation of many degradation products after 6 months of storage at 40°C/75% RH. For this reason, further test formulations were prepared using mineral salts as fillers to avoid any interaction with the active substance.

In table 3 below Fingolimod HC1 was mixed with inorganic salts used as fillers. Magnesium stearate was used in the final mixes for lubrication purposes. The powder was paid in capsules.

Table 3: Formulations 6 -8

The following table shows the dissolution profiles of test formulations 6-8

Table 4: Dissolution Profile in 0.2% SLS 0.1N HCL, Baskets at 100 rpm, 500 ml

Comparing the dissolution profiles of Formulations 6-8 shows that faster drug release is achieved in Formulation 8 at initial times.

The test formulations were also tested for their chemical stability. Capsules of test formulations 6-8 were stored under long-term and accelerated storage conditions for 6 months and analyzed for their degradation products.

Table 5: Stability data of test formulations 6-8 under long-term and accelerated storage conditions for 6 months

Based on the results, Formulation 8, in which tricalcium phosphate was used as a filler, gave the lowest level of degradation products. Since, among others, it showed the fastest dissolution profile, it was chosen to be used in the hard gelatin capsule formulation of fingolimod.

In the context of further optimization of the manufacturing process, two different strength forms of tricalcium phosphate were used in the formulation in order to achieve uniformity of the mixture with optimal flow properties. More specifically, tricalcium phosphate with a bulk density of 0.25 g/ml was initially mixed with Fingolimod HC1, since its physical properties (i.e. particle size, bulk density) are similar, which results in good uniformity in the mixture. The remaining amount of tricalcium phosphate added to the mixture had a higher bulk density (0.5 g/ml) thus providing very good flow properties to the final mixture. The result is shown in the table below (Formulation 9).

Table 6: Formulation 9

Based on Formulation 9, different types of lubricants were tested to study their effect on the uniformity of the powder mixture as well as their effect on chemical stability.

In addition to magnesium stearate, which is the most common lubricant for use in solid pharmaceutical forms, other lubricants were tested, such as talc, stearic acid, sodium stearate fumarate. The results of the above test formulations are presented in the table below:

Table 7: Formulations 10-13

Formulations 10 - 13 were prepared according to the following preparation method: - mixing Fingolimod HC1 with tricalcium phosphate (volume density 0.25), - mixing with tricalcium phosphate (volume density 0.5),

-lubrication of the powder mixture with the corresponding lubricant (only in Formulations 10-12), -filling in capsules.

Table 8: Results of Formulations 9-13

Table 9: Dissolution profile in 0.2% SLS 0.1N HCL, Baskets at 100 rpm, 500 ml

Comparing Formulations 9-12 containing different types of lubricants as well as Formulation 13 without lubricant showed that stearic acid was the most suitable in terms of mixture uniformity and chemical stability. Little differences were observed in dissolution properties. Accordingly, the preferred formulation of the present invention is Formulation 12.

While the present invention is described in terms of its specific approaches, those skilled in the art will appreciate that several changes and modifications may be made to the invention, without however departing from the spirit and object thereof, as set forth in the appendices of the claims.

Claims (13)

1. Pharmaceutical formulation for oral administration comprising Fingolimod HC1 in combination with inorganic salts as excipients to avoid any interaction with the active substance and the formation of impurities and/or degradation products. Pharmaceutical formulation according to claim 1, wherein the excipients are selected from anhydrous dibasic calcium phosphate, tricalcium citrate, tricalcium phosphate. 3. Pharmaceutical formulation according to claim 1, wherein the filler is preferably tricalcium phosphate. Pharmaceutical formulation according to claim 3 comprising two different types of tricalcium phosphate. A pharmaceutical formulation according to claim 4 comprising tricalcium phosphate with a bulk density of 0.25 g/ml and tricalcium phosphate with a bulk density of 0.5 g/ml. A pharmaceutical formulation according to any preceding claim, which comprises tricalcium phosphate in an amount between 90 and 99.5% by weight of the total weight of the formulation. 7. A pharmaceutical composition according to any preceding claim, which also includes lubricants. 8. Pharmaceutical formulation according to claim 7, wherein the lubricant is preferably stearic acid. Pharmaceutical formulation according to claim 8, which comprises stearic acid in an amount between 0.2 and 2% by weight of the total weight of the formulation. A pharmaceutical composition according to any preceding claim, which is in the form of hard gelatin capsules. 11. A method for the preparation of a pharmaceutical preparation for oral administration comprising Fingolimod HC1 in combination with inorganic salts as excipients to avoid any interaction with the active substance and the formation of impurities and/or degradation products, which method consists of the following stages: -mixing Fingolimod HC1 with tricalcium phosphate (volume density 0.25), -mixing with tricalcium phosphate (volume density 0.5), - lubrication of the powder mixture with stearic acid, - filling in capsules. 12. A method according to claim 11, comprising tricalcium phosphate ranging between 90 and 99.5% by weight of the total weight of the formulation. Method according to claim 11, comprising stearic acid, which ranges between 0.2 and 2% by weight of the total weight of the formulation.