JP2008094845A - Pharmaceutical tablet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical tablet containing a compressed core of which the surface is covered with a light protective layer. <P>SOLUTION: In this invention, the compressed core comprises (i) a pharmaceutically acceptable salt of 1-ä9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl}-4-ethylamino-piperidine-4-amide carboxylate, (ii) at least an extender (i.e., a ductility extender (i.e., a microcrystalline cellulose)) and/or a fragility extender (i.e., a lactose-hydrate or mannitol), (iii) a disintegrant (i.e., a starch sodium glycolate), and (iv) a lubricant (i.e., magnesium stearate), and is covered with the light protective layer. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to 1- [9- (4-chloro-phenyl) -8- (2-chloro-), a pharmaceutical tablet having improved shelf life stability, in particular the resistance to degradation of pharmaceutically active substances. Phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide acid salt.

Certain purine compounds have been found to be CB ₁ receptor antagonists (eg, as described in US 2004/0092520 (WO 2004/037823) 1- [9- (4- Chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide and pharmaceutically acceptable salts thereof. CB1 antagonists include eating disorders (eg, bulimia, anorexia, and bulimia), weight loss or weight loss (eg, reduced calorie or food intake, and / or appetite suppression), obesity, behavioral addiction, reward-related Behavioral inhibition (eg, conditioned place avoidance, eg, cocaine-induced and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, alcoholism (eg, alcohol abuse, addiction and / or dependence ( Withdrawal of alcohol, including treatment to reduce craving and prevention of recurrence)), tobacco abuse (eg, smoking addiction, withdrawal and / or dependence (including treatment to reduce smoking craving and prevent recurrence)), Dementia (memory loss, Alzheimer's disease, dementia due to aging, vascular dementia, mild cognitive impairment, cognitive decline associated with aging, and mild neurocognitive impairment Useful in the treatment of diseases, conditions and / or disorders modulated by cannabinoid receptor antagonists, including attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD), and in the prevention of type II diabetes It has been found to be.

  The purine compound 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide is: It absorbs visible / UV light and is therefore sensitive to photolysis. Furthermore, ethylamino and amide groups bonded to the same carbon atom can be easily decomposed under certain conditions. 1- [9- (4-Chloro-phenyl) -8- (2) with improved shelf life stability, as excipients commonly used in the manufacture of pharmaceutical formulations often increase stability issues There is a need to identify dosage forms containing -chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide.

SUMMARY The present invention provides a pharmaceutical tablet (especially an immediate release tablet) comprising a compressed core having a photoprotective layer coated thereon. The compressed core is (i) 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid A pharmaceutically acceptable salt of an amide, (ii) at least one bulking agent (eg, a ductile bulking agent (eg, microcrystalline cellulose) and / or a brittle bulking agent (eg, lactose monohydrate or mannitol); (iii) Including a disintegrant (eg, sodium starch glycolate) and (iv) a lubricant (eg, magnesium stearate) The photoprotective layer comprises 1- [9- (4-chloro-phenyl) -8- (2- Chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide in an amount of light-absorbing material sufficient to reduce the rate of formation of photolysis products (eg If, containing light-scattering materials and / or light absorbing materials), and is preferably coated in the form of a film coat.

  In another embodiment of the invention, process steps for producing the above dosage forms are also provided.

Strong drugs administered at low strengths are formulated with excipients for handling, ease of processing, and patient convenience. A high concentration of excipients relative to the concentration of drug in the formulation ensures the physical and chemical stability of the active ingredient and its delivery from the dosage form during manufacture, processing and storage of the formulation. However, there are unique challenges. Significant drug degradation can occur, particularly during storage, due to excipients or even due to excipient impurities. Degradation can be further accelerated at high temperature and / or high humidity conditions. The possible degradation pathways may be theoretically elucidated from chemical structure considerations, but it is impossible to predict in advance whether a stable formulation will be formed with the drug that a given excipient can tolerate. . Desired attributes for product performance and processing (eg, fluidity and compressibility of formulation blends and tablet disintegration), as well as desired attributes for patient convenience (eg, product identification by ease of swallowing and color) The suitability of excipients to develop a stable formulation with: needs to be established for each given active ingredient. For example, J. et al. T.A. Carstensen, Drug Stability: Principles and Practices , 2 nd Ed, Marcel Dekker, NY, 1995,449-452: and K. Waterman et al. Pharm Dev. Tech. 2002, 7 (2), 113-146).

  1- [9- (4-Chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide has its structure (eg Based on the fact that it has visible / UV light absorption and contains ethylamino and amide groups bonded to the same carbon atom) and high potency. Applicants have discovered dosage forms that address these concerns. Pharmaceutical tablets are generally composed of a compressed core having a light protective layer coated thereon. Compositions used to produce compressed cores generally include active ingredients, bulking agents to impart bulk and mechanical properties (eg, ductile and / or brittle bulking agents), disintegration Agents, as well as lubricants.

  The active ingredient is 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide (general Used in the form of its pharmaceutically acceptable salt, preferably the hydrochloride salt), which is a synthetic method described in US 2004/0092520 (Example 20), Or may be prepared by alternative synthetic methods described in PCT Publication WO 2006/043175, both of which are incorporated herein by reference.

  The active ingredient can be used in a range of particle sizes. The average dimension is generally about 5 to about 140 microns; preferably about 5 to about 100 microns; more preferably about 10 to about 50 microns; and most preferably less than about 25 microns.

In addition to their physical characteristics, excipients were screened for their effect on active ingredient degradation. Even under high stress conditions of high temperature and high humidity (eg about 40 ° C. and about 75% relative humidity (RH); and about 50 ° C. and about 75% RH for 12 weeks) show little degradation of the drug (general In particular, less than about 5%; preferably less than about 3%; and more preferably less than about 2% degradant), based on the compatibility of the excipient / excipient combination with the active ingredient Excipients were screened. The most stable formulations use microcrystalline cellulose and lactose monohydrate or mannitol as primary and secondary diluents, respectively; sodium starch glycolate (Explotab ^™ ) or sodium salt of crosslinked carboxymethylcellulose (AcDiSol ^™ ) Was used as a disintegrant; and magnesium stearate was used as a lubricant. Preferred diluents are microcrystalline cellulose and lactose monohydrate. Suitable diluents include one or more commercial grade microcrystalline cellulose (eg, Avicel® PH 101, 102, 150 and 200 available from FMC BioPolymer, Philadelphia, PA) and lactose monohydrate. Japanese (e.g., NF Lactose 310, 312, 315 and 316 Fast Flo, available from Forestmost Farms USA, Rothschild, WI (both 315 and 316 are spray dried mixtures of crystalline and amorphous lactose)) Is mentioned. A preferred disintegrant is sodium starch glycolate. Anhydrous dicalcium phosphate causes a high degree of degradation of the active ingredient and is therefore not considered as a compatible secondary bulking agent. See Example 1 in the Example section below.

  In tablet manufacture, the active ingredient, diluent and disintegrant are generally blended together using a blender well known to those skilled in the art (eg, rotary blender, bottle blender or V-blender). . Proper dispersion of the active ingredients in the mixture is achieved by a variety of techniques, such as a combination of premixing and mixing steps that intermittently pass the material through a mesh screen. The mixture is blended with a suitable lubricant (eg, magnesium stearate).

  The active ingredient is generally present in an amount of a total weight percent of about 4.5 to about 5.5 for a theoretical 5% w / w formulation, depending on the potency of the active ingredient (eg, For 90-110% potency, the active ingredient is present in an amount of 4.55 to 5.45 wt%: For 95-105 potency, it is present in an amount of 4.9525 to 5.0475% wt%. : For 97-103% potency is present in an amount of 4.9515 to 5.485 wt%).

  Depending on the tablet content, the active ingredient is generally a total weight percent of about 6.44 to about 7.87 for a theoretical 7.15% w / w formulation, depending on the potency of the active ingredient. (Eg, for 90-110% potency, the active ingredient is present in an amount of 6.44-7.87 wt%: for 95-105 potency, 6.79-7.51 wt% Present: and present in an amount of 6.936-7.365 wt% for an efficacy of 97-103%).

  Diluents can be present in the formulation in various ratios. Suitable microcrystalline cellulose to lactose ratios include 1: 1, 2: 1, 3: 1, 1: 2, or 1: 3; preferably 1: 1 or 2: 1; more preferably 2 : 1.

  Various commercial grade disintegrants may be used in the formulation. A preferred disintegrant is sodium starch glycolate. Suitable grades of sodium starch glycolate include Glycolys® (available from Roquette America, Inc., Keokuk, IA) and Explotab® (available from JRS Pharma LP, Patterson, NY) .

  The disintegrant is generally present in an amount from about 1% to about 12% of the tablet core, preferably from about 1% to about 8%, more preferably from about 2% to about 6%. The disintegrant in the tablet formulation can be added intragranular (before granulation) and / or extragranular (for granulation before tableting). Intragranular addition of disintegrant is preferred for rapid dissolution of the active ingredient from the tablet.

Lubricants are generally added as pharmaceutical ingredients or as processing aids. A preferred lubricant is magnesium stearate. Magnesium stearate is generally from about 0.01% to about 2.0% total weight percent, preferably from about 0.1% to about 1.5%, more preferably from about 0.25% to about 1. It is present in an amount of 5%, most preferably from about 0.5% to about 1.0%. Lubricants can be added extragranularly and / or intragranularly. Preferably the lubricant is added as a mixture of extragranular and intragranular magnesium stearate. For example, intragranular magnesium stearate can be added to reduce sticking of the active ingredient to the roll surface during the roll compaction of the blend; and extragranular magnesium stearate is used to achieve the desired tablet properties. It can be added as a pharmaceutical ingredient.

  Surfactants (eg, cetyl alcohol, glycerol monostearate and sodium lauryl sulfate (SLS)), adsorbent carriers (eg, kaolin and bentonite), preservatives, sweeteners, colorants, flavors (eg, citric acid, Other additives such as menthol, glycine or orange powder), stabilizers (eg, citric acid, sodium citrate or acetic acid), dispersants, binders (eg, hydroxypropylcellulose) and mixtures thereof may also be included. . Typically, such additives are present at a level of about 10% or less of the core mass; and for many such additives, they are typically present at about 1% or less of the core mass. To do.

  Even if the mixture is directly pressed, dry granulation (for example, it may be tableted after roll compaction and pulverization of the molded product), preferably after dry granulation. For example, the blended mixture may be compacted into a ribbon or a molded body, which may be pulverized into granules. Suitable dry granulators include Gerteis Minipactor or 3W Polygran roller compactor (available from Gerteis Machines and Process Engineering AG, Jona, Switzerland) Alexanderwerk Inc., Horsham, PA) and mills. Various tablet presses well known to those skilled in the art can be used. Suitable tablet presses include the Fette / Korsch press.

After compression, a water permeable light protective coating is coated on the tablet core using standard procedures well known to those skilled in the art. The light protection layer generally contains a film-forming material in which a light scattering material or light absorbing material (eg, pigment (eg, titanium dioxide)) is incorporated. Suitable film-forming materials include any pharmaceutically acceptable film-forming polymer well known to those skilled in the art, such as polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC). The film coat composition may include plasticizers such as polyethylene glycol (PEG), soy lecithin, triacetin and mixtures thereof. Suitable commercially available photoprotective coatings include Opadry® II, Opaglos® 2, Opadry® fx ^™ , and Opadry® AMB colored coating (Colorcon, Inc., Charlotte, Available from PA). Preferred coating agents include HPMC-based coatings, PVA-based coatings (Opadry® II-85F and 85G grades commercially available from Colorcon, Inc.). Examples of the colorant include iron oxide, lake dye, and a combination of iron oxide and lake. Suitable pigments include bengara, yellow iron oxide and black iron oxide, titanium dioxide and talc (white), FD & C Blue # 2, and Yellow # 6. Other colorants may be added to provide a mark or identification that characterizes the tablet.

  The photoprotective coating is generally present in the range of about 2% to about 5% by weight of the compressed core tablet, more preferably in the range of about 3% to about 4%.

  The light protective coating can be coated on the compressed core using any means well known to those skilled in the art, such as compression in a tablet press, dipping, fluid bed coating, pan coating or spray coating. Preferably, the aqueous suspension is used to pan or spray coat the layer to obtain a thin and uniform coating. In the presence of a photoprotective coating, no photodegradation product was detected in any of the coated tablets; whereas the control (uncoated core tablet) was photodegraded after exposure to UV light for 7 days. It had physical impurities. See the examples below. As a result, the addition of a photoprotective layer reduces the need for special packaging (eg, storage in opaque bottles or encapsulation of tablets in foil packaging) to minimize or eliminate photodegradation.

  It may be desirable to apply one or more additional coatings inside or outside the light protective coating. The one or more additional coatings are preferably permeable to water. Such coatings function to improve the adhesion of the light protective coating to the tablet core, or to provide a chemical barrier between the core and the light protective coating and / or act as a physical barrier. Can do. The outer coating may clean the surface to assist in product identification and marketing and to improve mouth feel and swallowability (tablet swallowability). Such coating agents can also be functional, such as enteric coatings (ie, coatings designed to dissolve in specific areas of the gastrointestinal tract). Other product identification features can also be added to the surface of the coating. Examples include, but are not limited to, printing identification information and embossing. Additional coatings can also contain the same or different active pharmaceutical ingredients as in the core. This may provide combined drug delivery and / or allow specific pharmacokinetics (eg, pulsatile). Such a coating can be film coated onto the tablet core using a suitable binder.

  Tablets can be packaged in a variety of ways. In general, distribution articles include containers that hold tablets. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), plastic bags, foil packs and the like. The container may contain a tamper-proof assembly to prevent indiscriminate access to the package contents and a means for eliminating moisture and / or oxygen (eg, an oxygen absorber (eg, Multisorb) D Series FreshPax.TM packets available from Technologies Inc., Buffalo, NY, USA, or Ageles.TM. And ZPTJ.TM. sachets available from Mitsubishi Gas Corporation, Tokyo, JP). May be included. The container typically has a label on it that describes the contents of the container and any suitable warnings.

  The following examples illustrate the tablets of the present invention. To illustrate the general concept of the present invention, specific methods and specific excipients are used in the manufacture of tablets. However, those skilled in the art will understand that the methods and specific excipients used do not limit the scope of the invention and should not be so construed.

  Excipients used in the following experiments are available from corresponding sources.

Avicel PH102 (microcrystalline cellulose) FMC BioPolymer, Philadelphia, PA
Fast Flo (Lactose monohydrate) Foremost Farms USA, Rothschild, WI
Anhydrous dicalcium phosphate (DA) Rhodia, Cranbury, NJ
Pearlitol® (mannitol) Roquette Freres, Restrem, France
Explotab ^™ (sodium starch glycolate) JRS Pharma,
Patterson, NY
Glycolys® (sodium carboxymethyl starch) Roquette America, Inc. , Keokuk, IA
AcDiSol ^™ (sodium salt of crosslinked carboxymethylcellulose) FMC BioPolymer, Philadelphia, PA
Klucel® (hydroxypropylcellulose (HPC)) Hercules Incorporated, Aqualon Division, Wilmington, DE
Magnesium stearate (plant origin) Mallinckrodt, Inc. , St. Louis, MO
White Opadry II® (polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc) Colorcon, Inc. , Charlotte, PA
Example 1 demonstrates the effect of excipients on the formation of impurities during storage at various storage conditions (temperature and humidity).

Example 1
1% active ingredient (1- [9- (4-chloro-phenyl) -8- in the form of excipients and hydrochlorides outlined in Table 1 below in the specified percentages based on total tablet weight (2-Chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide) was used to prepare 8 different excipient blends. The ratio of diluent (eg lactose, microcrystalline cellulose, DA, mannitol) was adjusted to compensate for the efficacy of the active ingredient.

  Dry blends were prepared with each of the eight test blends shown in Table I above and 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl]- Prepared by mixing with 4-ethylamino-piperidine-4-carboxylic acid amide hydrochloride and compressed. To ensure proper contact between the components, individual formulation blends are formed into compacts by compacting with a single station compactor equipped with a 5/16 inch flat punch and die at 100 pounds force for 0.5 seconds. Compressed to produce a 100 mg shaped body.

Impurities for 8 tablets were analyzed after 12 weeks at 5 storage conditions:
(1) 5 ° C. at 75% relative humidity in a sealed container;
(2) 40 ° C. at 75% relative humidity in an open container;
(3) 40 ° C. at 75% relative humidity in a sealed container;
(4) 50 ° C. at 20% relative humidity in a sealed container; and (5) 50 ° C. at 75% relative humidity in an open container.

Degradants were identified using the HPLC-Model: Waters 2695 instrument under the following conditions:
Column: Waters Symmetry C18 (150 × 3.9 mm, 5 μm particle size)
Column temperature: 30 ° C
Injection volume: 20 μL
Flow rate: 1.0 mL / min Detection: UV @ 215 nm
Mobile phase: A: 20 mM KH ₂ PO ₄ , 100 mM NaClO ₄ , pH = 3
B: MeOH
Dissolving solvent: 50/50: H ₂ O / MeOH

A summary of total impurities observed after 12 weeks under 5 different conditions is shown in Table 2 below.

  Examples 1D and 1H produced the lowest amount of total impurities over 12 weeks in all five storage conditions. Example 1C was slightly inferior to Examples 1D and 1H, but was still better than the formulation containing anhydrous dicalcium phosphate (DA). Examples containing anhydrous dicalcium phosphate produced significantly higher impurities in some conditions when compared to formulations that did not contain anhydrous dicalcium phosphate.

  Example 2 illustrates the effect of adding a photoprotective layer on the surface of the compressed core.

Example 2
Core tablets corresponding to tablet content of 5 mg and 25 mg were produced using the compositions in Table 3 below.

These blends were treated with 5% w / w of the active ingredient in its hydrochloride form (1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] Compressed from a common blend of -4-ethylamino-piperidine-4-carboxylic acid amide (referred to as “API”) using a V-blender (Patterson Kelly, 1 ft ³ , 10 minutes, approximately 25 rpm). The blend was passed through Comil (Model 197) equipped with a 1.0 mm screen, followed by blending for 10 minutes (about 25 rpm). The mixture was lubricated by mixing with magnesium stearate (0.25%) for 3 minutes. This blend was dry granulated by roller compaction (Gerteis Minipactor; 5-7 kN force, 4 rpm) followed by grinding and passing through a 0.8 mm screen. The granules were blended for 10 minutes in a V blender and lubricated by mixing with extragranular lubricant (0.5% magnesium stearate) for 3 minutes. Granules were compressed into tablets with a rotary tablet press (Kilian T-100 rotary tablet press) (1/4 inch standard circular concave tablets with 5 mg content (target: 100 mg size, 6-10 Newton tablet hardness) and 25 mg tablets (13/32 inch diameter standard concave tablet, 500 mg size, about 15-25N tablet hardness).

Opadry II ^™ -85F (containing titanium dioxide pigment) prepared by dispersing a film coat (20 parts Opadry II ^™ powder in 80 parts water) supplied as a powder in deionized water at room temperature ) To coat the tablets. The core tablets were coated with the suspension in a coating pan (Vector-LDCS 20) to a 4% weight gain.

Core (uncoated) and coated tablet samples were exposed to light for 7 days at 25 ° C. and 60% relative humidity (13 watts / m ² UV light and 8 kilolux fluorescent lamp). Degradation levels were measured using a Waters HPLC (Model 2695). The photolysate impurity levels were 0.33% and 0.18%, respectively, in the 5 mg and 25 mg content tablets compared to the control (less than 0.05%). The process for producing tablets with 10 mg and 20 mg content is essentially the same as outlined for the 5 mg and 15 mg contents.

  Example 3 shows the synthesis of 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide. Illustrates the preparation of a storage stable 5 mgA dose immediate release tablet containing a hydrogen chloride salt and a light protective topcoat.

Example 3
Microcrystalline cellulose (60.56 units), 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4 -Carboxylic acid amide hydrochloride (5.36 units; based on 93.3% theoretical potency), lactose monohydrate (30.33 units) and sodium starch glycolate (3.00 units) bottled Add to blender and blend for 10-20 minutes at 12 rpm. The blend was then passed through a mill equipped with a 1.00 mm screen, collected in a bottle blender and mixed at 12 rpm for 5-15 minutes. Intragranular magnesium stearate (0.25 units) was then added to the mixture and blended for a further 2-5 minutes at 12 rpm. The lubricated blend was granulated by roller compaction (Gerteis Polygran 3W: force of 4-10 kN / cm; gap 2-4 mm, roll speed 4-10 rpm) and milled (0.8-1.00 mm screen) . The granules were collected in a bottle blender. After blending for 5-15 minutes at 12 rpm, extragranular magnesium stearate (0.50 units) was added to the bottle blender. The lubricated blend was then blended for an additional 2-5 minutes at 12 rpm. This mixture was compressed using a Korsch / Fette tablet press to a target mass of 100 mgW and a target hardness of 8 kP into tablets with a content of 5 mgA.

  A photoprotective coating was prepared by adding White Opadry II® (4 units) to purified water (16 units) and stirring to produce a uniform suspension (approximately 20 wt% solids). . The compressed tablets were then coated with an Opadry suspension in a perforated coating pan (Glatt 750-1500) at a bed temperature of 45 ° C. to 50 ° C., an inlet temperature of 80 ° C., and an outlet temperature of 45 (˜55 ° C.). The coated tablets were then allowed to cool to room temperature The total tablet target mass was 104 mg.

  Example 4 below illustrates tablets made with four different contents.

Example 4
5 mg, 10 mg, 15 mg and 20 mg tablets were prepared using the same procedure as described in Example 2 and the formulation described below.

Claims (8)

A pharmaceutical tablet comprising a compressed core coated with a photoprotective layer, wherein the compressed core comprises
(I) 1- [9- (4-Chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide pharmaceutical Acceptable salts;
(Ii) at least one bulking agent selected from microcrystalline cellulose, lactose monohydrate or mannitol;
(Iii) a disintegrant selected from sodium starch glycolate or a sodium salt of crosslinked carboxymethylcellulose; and (iv) a pharmaceutical tablet comprising a lubricant which is magnesium stearate.   The tablet of claim 1, wherein the at least one bulking agent is microcrystalline cellulose and lactose monohydrate and the disintegrant is sodium starch glycolate.   The tablet of claim 2, wherein the microcrystalline cellulose and lactose monohydrate are present in a ratio of about 1: 1 or about 2: 1.   The tablet of claim 3, wherein the microcrystalline cellulose and lactose monohydrate are present in a ratio of about 2: 1.   Pharmaceutically acceptable of 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide The possible salt is hydrochloric acid of 1- [9- (4-chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide The tablet according to any one of claims 1 to 4, which is a salt.   6. The tablet of claim 5, wherein the photoprotective layer is present in the range of about 3% to about 5% by weight of the compressed core.   The tablet of claim 6, wherein the photoprotective layer is present at about 4% by weight of the compressed core. A pharmaceutical tablet comprising a compressed core coated with a photoprotective layer, wherein the compressed core comprises
(I) 1- [9- (4-Chloro-phenyl) -8- (2-chloro-phenyl) -9H-purin-6-yl] -4-ethylamino-piperidine-4-carboxylic acid amide hydrochloride ;
(Ii) about 2: 1 ratio of microcrystalline cellulose and lactose monohydrate;
(Iii) sodium starch glycolate; and (iv) magnesium stearate;
Wherein the photoprotective layer is present at about 4% by weight of the compressed core.