TW200826975A - Pharmaceutical tablet formulation - Google Patents

Abstract

A pharmaceutical tablet is described herein which includes a compressed core having deposited thereon a light-protective layer. The compressed core comprises (i) a pharmaceutically acceptable salt of 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4-carboxylic acid amide, (ii) at least one filler (e.g., a ductile filler, such as microcrystalline cellulose and/or a brittle filler, such as lactose monohydrate or mannitol); (iii) a disintegrant (e.g., sodium starch glycolate) and (iv) a lubricant (e.g., magnesium stearate).

Description

200826975 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a pharmaceutical lozenge having improved shelf life stability, and in particular to a compound containing 1-[9-(4-gas-phenyl) )-8-(2-Gas-phenyl)-9H-indol-6-yl]-4-ethylamino-hexahydroindole-4-carboxylic acid decyl acid acid salt lozenge, this recording: It is resistant to degradation of the pharmaceutically active agent. [Prior Art] Certain guanidine compounds have been found to act as CB! receptor antagonists, such as 1-[9-(4-gas-phenyl) as set forth in US Publication No. 2004/0092520 (WO 2004/037823). _8_(2_gas-phenyl)_9H_嘌呤-6•yl]_4_ethylamino hexahydro. Bisidine_4_ decylamine and its pharmaceutically acceptable salts. d-Bactericides have also been found to be useful in the treatment of diseases, conditions and/or conditions mediated by cannabinoid receptor antagonists: eating disorders (eg, bulimia, anorexia and bulimia), weight loss or control ( Such as calories (or reduced food intake, and / or appetite suppression), obesity, behavioral addiction, inhibition of reward-related behavior (such as conditional site avoidance, such as inhibition of conditional location preferences induced by cocaine and 徘) , drug abuse, addictive disease, impulsive behaviour, alcohol abuse (eg alcohol abuse, addiction and/or dependence, including treatment for prohibition, loss of desire and prevention of relapse of alcohol intake), tobacco abuse (eg smoking addiction, cessation and / or dependence, including treatment for loss of desire and prevention of recurrence of smoking), dementia (including amnesia, Alzhelmer's disease, Alzheimer's disease, vascular dementia, mild cognitive impairment, Age-related cognitive decline and mild neurocognitive impairment), attention deficit disorder (ADD) or attention deficit hyperactivity disorder 124840. Doc 200826975 (ADHD) and prevention of type 2 diabetes. The compound '' 1-[9-(4-chloro-phenyl)-8_(2_chloro-phenyl)_9H_嘌呤_ 6-yl]- 4-Ethylamino-hexahydroacridine-4-carboxylic acid decylamine, which absorbs visible light/ultraviolet light, which makes it susceptible to photodegradation. In addition, ethylamine and hydrazine attached to the same carbon atom Amines can be easily degraded under certain conditions. Since excipients commonly used in the preparation of pharmaceutical formulations tend to exacerbate stability problems, it is necessary to characterize 1-[9- including improved shelf life stability. (4-Chloro-phenyl)-8-(2-chloro-phenyl)_9Η-嘌呤·6_yl]_4_ethylamino-hexahydropyridine· 4-carboxylic acid decylamine dosage form. The invention provides a pharmaceutical lozenge (especially an immediate release tablet) comprising a compression core having a photoprotective layer deposited on the surface. The compression core comprises (1) 1-[9-(4-va-phenyl)-8. (2. gas phenyl) _9 Η 嗓呤 ] ] ] ] ] ] ] ] 医药 医药 医药 医药 医药 医药 医药 医药 ; ; ; ; ; ; ; ; 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少Microcrystalline fiber And/or a brittle filler such as lactose monohydrate or mannitol; (iii) a disintegrant (such as sodium starch glycolate) and (iv) a lubricant (for example, magnesium stearate). The photoprotective layer comprises A sufficient amount of light absorbing material (eg, light scattering and/or light absorbing material) to reduce 1 _[9-(4-milo-phenyl)-8-(2-gas-phenyl)_9H_嗓呤- a photodegradation product formation ratio of 6-yl]-4_ethylamino-hexahydropyridine-4-carboxylic acid decylamine, and the photoprotective layer is preferably deposited as a thin film coating. Another embodiment of the present invention, The process step of producing the above dosage form is also provided. [Embodiment] 124840.doc 200826975 is easy to ♦, 曲,,,; processing, processing and convenient for patients, using excipients to low: degree and strong drugs Make the deployment. Excipients in the formulation relative to the drug's degree are a significant challenge to ensure the physical and chemical stability of the active ingredient and its delivery from the dosage form during formulation preparation and spear storage. Significant pharmaceutical degradation may occur due to the presence of excipients or even the presence of excipient impurities, which occurs especially during storage. Degradation may be further accelerated under conditions of high pulse and/or high humidity. Although the potential degradation pathway can be theoretically explained by considering the chemical structure, it is not possible to predict whether a given excipient and a drug will form a formulation with 5: stability. It is necessary for each given active ingredient to establish that the excipient has the desired product properties and processing attributes (eg, fluidity and compactability of the formulation blend and disintegration of the tablet). Stabilize the suitability of the formulation as well as patient convenience (eg, easy to swallow and identify products with color). See, for example, J T. Carstensen, Drug

Stability: Principles and Practicee Second Edition, Marcel Dekker,, NY, 1995, 449.452; and K. Waterman et al., Pharm Dev.

Tech·, 2002, 7(2), 113-146. 1-[9-(4-chlorophenyl) based on its structure (for example, absorption of visible light/ultraviolet light and containing ethylamine and guanamine groups attached to the same carbon atom) and its high efficiency -8-(2-Gas-phenyl)-9H-indol-6-yl]-4-ethylamino-hexahydrogen ratio σ疋-4-carboxylic acid decylamine has a number of problems in degradation. Applicants have discovered dosage forms that can address these issues. Pharmaceutical lozenges typically consist of a compressed core having a protective layer deposited on the surface. The compositions used to make the compressed core typically contain the active ingredients, the build-up properties, and the mechanical properties of the filler (e.g., ductile and/or brittle ^^^^1, brother J) and a lubricant. The active ingredient is 丨-[9-(4-gas·stupyl JV虱·benyl)-9H-嘌呤-6·土] 4·ethylamino-hexahydropyridine_4_carboxylic acid e (It is often used in its medicine Approved 2004/nn〇〇c 驮||, which can be described in the synthesis method described in US Publication No. 2004/0092520 (Example 20) or in PCT Publication WO 2006/043175 Another person is made into M, which is a sigma method, both of which are incorporated herein by reference. The active ingredient can be used in a variety of particle sizes. The averaging particle size of the oxime 1 is usually from about 5 to about 1, 40, from the rice, preferably from about 5 to about 1 〇〇i · ^ J UU imitation wood, more preferably from about 10 to about 50 microns; Most preferably less than about 25 microns. In addition to its physical properties, it is also screened for the effect of excipients on the degradation of the active ingredient. The choice of excipients is based on the compatibility of the excipient/excipient group mouth with the active ingredient, which exhibits little degradation (degradation is typically less than about 5%; preferably less than about 3%; and more preferably less than About 2%), even under high temperature and high humidity conditions (for example, at about 4 〇t and about 75% relative humidity (RH); and about 5 〇t and about 75% RH. When using microcrystalline cellulose and lactose monohydrate or mannitol as the first and second diluents respectively; using sodium starch glycolate (ExplotabTM) or croscarmellose sodium salt (AcDiSoKM) as a disintegrating agent; the most stable formulation is observed when magnesium stearate is used as a lubricant. Preferred diluents are microcrystalline cellulose and lactose monohydrate. Suitable diluents include one or more grades of the market. Microcrystalline cellulose (eg, Avicel® PH 101, 102, 150, and 200 are commercially available from FMC BioPolymer, Philadelphia, PA) and lactose monohydrate (eg, NF Lactose 310, 312, 315, and 316 Fast Fl® (315 and 316 124840.doc 200826975 Juice 匕 &) can be purchased from Foremost disintegrant glycolic acid starch higher Degradation, and therefore are spray-dried lactose-crystalline and amorphous

Farms USA, Rothschild, WI). Better. Anhydrous bismuth hydride causes the active ingredient to not appear as a compatible secondary filler. See the examples in the Examples section below. In the preparation of tablets, the active ingredients, diluents are used by "pushers (such as drum blenders, cartridge blenders or combiners) that are well known to those skilled in the art. The sufficient dispersion of the active ingredient in the mixture with the disintegrant is achieved by a variety of techniques, such as a premixing and mixing process combined with a batch passage of material through a mesh screen. The mixture is combined with a suitable lubricant (eg , stearic acid town) blending. Performance of the terminal active ingredient For theoretically about 5% by weight of the formulation, the active ingredient is typically present in a total weight percentage of from about 4.5 to about 5.5 (for example, for 90_110% potency, the active ingredient is present in an amount from 4 55 to 545 wt%; for 95-1 05% potency, the active ingredient is present in an amount from 4.9525 to 5.0475 wt%; and for 97-103% potency, activity The ingredient is present in an amount from 4.9515 to 5.485 wt%. The concentration of the end-tablet tablet, the efficacy of the end-active ingredient. For theoretically 6.1 wt% of the formulation, the active ingredient usually has a total weight of from about 6.44 to about 7.87. The percentage is present (for example, for a performance of 90-110%, the active ingredient is present in an amount from 6.44 to 7.87 wt%; for a performance of 95-105, the active ingredient is present in an amount from 6.79 to 7.5 wt%; For 97-103% efficacy, the active ingredient is present in an amount from 6.936 to 7.365 wt%. The diluent can be present in the formulation in varying ratios. Suitable ratios of microcrystalline cellulose to lactose include 1:1, 2: 1, 3:1, 1:2 or 1:3; preferably 1:1 or 124840.doc -10 - 200826975 2·.1; better 2:1. A variety of commercially available disintegrants can be used In the formulation, the preferred disintegrant is sodium starch glycolate. Suitable grades of glycolic acid powder include

Glycolys16 (available from R0qUette America, Keokuk, ΙΑ) and

Explotab® (available from JRS Pharma LP, Patterson, NY).

The disintegrant is typically present in an amount from about 1% to about 12% of the tablet core, more preferably from about 1% to about 8%, more preferably from about 2% to about 6%. The disintegrant in the tablet formulation can be added to the granules (before granulation) and/or to the granules (added to the granules after tableting). The addition of the disintegrant particles is preferred because the active ingredient can be rapidly dissolved from the tablet. Lubricants are usually added as a formulation component or as a auxiliaries. Preferably, the agent is magnesium stearate. The stearic acid town is usually from about 0.01% to about 2.0% by weight, preferably from about 0.1% to about h5%, more preferably from about 25% to about 1 part, most preferably from about 5%. To about 】. 〇% of the amount exists. Lubricants can be added to or into the granules. Preferably, the lubricant is added in the form of an extragranular and intragranular = mixture. For example, intragranular stearin can be added to reduce the sticking of the active ingredient to the surface of the roll during the rolling of the admixture and the extra-strength magnesium stearate can be used as a formulation for the formulation. State Μ 付 可 可 = force: agent: for example: surfactant (for example, sixteen carriers (for example, early:: acid 8: and sodium lauryl sulfate (SLS)), adsorbent, flavoring agent (eg, earthworm): preservatives, sweeteners, coloring stabilizers (eg p τ n 4 He yeast, glycine or orange powder), citric acid, sodium citrate or acetic acid), dispersants, Combine 124840.doc 200826975 (eg, propylcellulose) and mixtures thereof. Such additives are typically present in an amount of less than about 1% by weight of the core; for many such additives, they are typically present in an amount of less than about 1% by weight of the core. The mixture may be tableted directly or after dry granulation (e.g., rolling and honing the compact), and the ingot is preferably granulated after dry granulation. For example, the blended mixture can be compressed into a ribbon or compact and ground into pellets. Suitable dry granulation units include Gerteis Minipactor or 3W Polygran drum compressors (available from Gerteis Machines and Process Engineering AG, Jona, Switzerland), TF-Mini sturdy presses (available from Vector Corporation, Marion, ΙΑ), Alexanderwerk (Alexanderwerk, Horsham, PA) and the mill. A variety of tablet presses well known to those skilled in the art can be used, and suitable tablet presses include Fette/Korsch presses. After compression, a water permeable photoprotective coating is deposited on the tablet core using standard procedures well known to those skilled in the art. The photoprotective layer typically comprises a film forming material into which a light scattering or light absorbing material (e.g., a pigment such as titanium dioxide) has been incorporated. Suitable film-forming materials include any of the pharmaceutically acceptable film-forming polymers known to those skilled in the art, such as polyvinyl alcohol (PVA), propylmethylcellulose (HPMC). The film composition may also include plasticizers such as polyethylene glycol (PEG), soy lecithin, triacetin, and combinations thereof. Suitable commercially available photoprotective coatings include coatings colored with Opadry® II, Opaglos® 2, Opadry® fxTM and Opadry® AMB (available from Colorcon, Inc., Chalfont, PA). Preferred coatings include HPMC based coatings, PVA based coatings (Opadry® II - 85F and 8 5G available from Colorcon Corporation). Examples of the coloring agent include iron oxide, color 124840.doc -12-200826975 lake dye, and a combination of iron oxide and lake. Suitable pigments include red, yellow and zero color iron oxide, monomethicone and talc (white), FD&C blue #2 and yellow #6. Other colorants may be added to provide particular marking or identification characteristics of the tablet. The photoprotecting layer typically comprises from about 2% to about 5% by weight of the compressed core tablet; preferably from about 3% to about 4%. The light-shave coating can be deposited on the compressed s core, by any method known to those skilled in the art (for example, pressing, dip coating, fluidized bed coating, disk coating or spraying, etc.) in a tablet press. . (d) The layer is coated or sprayed with an aqueous suspension to provide a thin and uniform coating. The photodegradation product was not detected in the lozenge with the photoprotective layer after 7 days of exposure to ultraviolet light; however, the control lozenge (uncoated core tablet) produced photodegradation impurities. See the example below. Thus, the addition of a photoprotective layer reduces the need to use special packaging (e.g., storage in opaque bottles or sealing the tablet in a foil package) to minimize or eliminate photodegradation. Replenishment—or multiple additional coatings—on the inside or outside of the photoprotective layer can sometimes yield satisfactory results. The one-and-a-half coat outer coating has better water permeability. These coatings can increase the adhesion of the photoprotective coating to the core of the tablet, or can act as a chemical barrier between the core and the photoprotective coating, and/or act as a barrier. The outer coating can serve as a function of (4) to aid product identification and to improve Π 及 and 易 (4) (easy to swallow). The coatings may also be functional, for example, intestines, intestines, and coatings (i.e., the coating MS designed to dissolve in the gastrointestinal tract area may also add other products to the coating. Identification features. Not limited to) Printing of identification information and 124840.doc 200826975 Imprint. The additional coating may also comprise an active pharmaceutical ingredient that is the same or different from the active pharmaceutical ingredient in the core. It can provide combined drug delivery and/or achieve specific pharmacokinetic characteristics (e.g., pulsatile pharmacokinetic characteristics). This coating can be applied to the core of the tablet using a suitable binder film. Tablets can be packaged in a variety of ways. In general, the item for dispensing includes a container for holding a tablet. Suitable containers are well known to those skilled in the art and include articles such as bottles (plastic bottles or glass bottles), plastic bags, foil packages, and the like. The container may also include an anti-interference device that prevents inadvertent access to the contents of the package and components that remove moisture and/or oxygen (eg, an oxygen absorber such as the D Series FreshPax.TM. package, available from Multisorb Technologies, Buffalo, NY) , USA, or Ageles.TM. and ZPTJ.TM. sachets, purchased from Mitsubishi Gas, Tokyo, JP). A label indicating the contents of the container and any appropriate warnings is usually placed on the container. The following examples illustrate the lozenges of the present invention. To illustrate the general concept of the invention, specific processes and specific excipients are employed in the manufacture of tablets. However, it should be understood by those skilled in the art that the processes and specific excipients used are not limiting the scope of the invention and should not be construed as such. EXAMPLES The excipients used in the experiments below were obtained from the corresponding sources.

Avicel PH102 (microcrystalline cellulose) FMC BioPolymer, Philadelphia, PA

Fast Flo (Lactose Monohydrate) Foremost Farms USA5 Rothschild, WI Anhydrous Hydrogen Phosphate (DA) Rhc^Crartay,^

Pearlitol® (mannitol)

Roquette Freres, Lestrem, France 124840.doc 14- 200826975

ExplotabTM (sodium starch glycolate) Glycolys® (sodium carboxylate powder) AcDiSolTM (croscarmellose sodium salt) Klucel® (hydroxypropylcellulose (HPC)) Magnesium stearate (plant source)

White Opadry II® (polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc)

JRS Pharma, Patterson, NY

Roquette America, Keokuk, ΙΑ

FMC BioPolymer, Philadelphia, PA

Hercules, Aqualon Division, Wilmington, DE

Mallinckrodt, St. Louis, MO Colorcon, Chalfont, PA ί Example 1 demonstrates the effect of excipients on the formation of impurities under different storage conditions (temperature and humidity). Example 1

Using the specified percentage of excipients based on the total tablet weight as outlined in Table 1 below and 1% of (1-[9-(4-chloro-phenyl)-8-(2-chloro) in the form of the hydrochloride salt -Phenyl)-9H-indol-6-yl]-4-ethylamino-hexahydropyridine-4-carboxylic acid decylamine) Eight different admixtures of excipients were prepared. The ratio of diluent (e.g., lactose, microcrystalline cellulose, DA, mannitol) is adjusted to compensate for the effectiveness of the active ingredient. Table 1 Excipient No. Lactose Microcrystalline Cellulose Starch Sodium Glycolate DA Cross-linked Carboxymethyl Cellulose Sodium HPC Mannitol Magnesium Stearate 1A 46.5 46.5 5.0 1.0 1B 46.5 5.0 46.5 1.0 1C 46.5 46.5 5.0 1.0 1D 46.5 46.5 5.0 1.0 1E 46.5 46.5 5.0 1.0 1F 46.5 5.0 46.5 1.0 1G 45.5 45.5 5.0 2.0 1.0 1H 46.5 5.0 46.5 1.0 124840.doc -15 - 200826975 by using each of the eight test blends in Table I above with l-[9 -(4-Gas·Benyl)-8-(2·Gas-Phenyl)-9Η-σ吟-6-yl]_4-Ethylamino-hexanitrogen-precipitate-4_ decyl decanoate The acid salt is mixed to make a dry blend and compression is applied. The individual formulation blend is compressed into a compact to ensure adequate contact between the components by a single point compressor in a single point compressor equipped with a 5/16 pair of flat punches and a die. The force was carried out by performing a compression of 0.5 seconds to produce 100 mg of compact. The impurities of the eight lozenges were analyzed after 12 weeks of storage under five storage conditions: (1) 5 ° C, 75% relative humidity in a closed container; (2) 40 ° C, 75% relative humidity , in an open environment; (3) 40 ° C, 75% relative humidity in a closed container; (4) 50 ° C, 20% relative humidity in a closed container; and (5) 50 ° C , 75% relative humidity, in an open environment. The HPLC-Model Waters 2695 apparatus was used to identify the reduced I solution under the following conditions: Columns Waters Symmetry C18 (150 x 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 KH2PO4, 100 mM NaC 104, pH = 3 B: MeOH Solvent solvent 50/50: H20/MeOH 124840.doc -16· 200826975 The total amount of impurities observed after 12 weeks of placement under five different conditions is summarized below In Table 2. Table 2 Example No. 5〇C/75% Η (closed) 40〇C/75% Η (open) 40〇C/75% Η (closed) 50〇C/20% Η (closed) 50〇C/75% Η (open) 1A 0.04 1.71 0.16 0.64 1.99 1B 0.06 0.68 0.13 0.54 0.39 1C 0.06 0.25 0.11 0.48 0.29 1D 0.04 0.22 0.08 0.48 0.07 1E 0.05 1.60 0.14 0.83 1.09 1F 0.05 1.58 0.11 0.68 1.07 1G 0.02 0.36 0.17 0.70 0.44 1H 0.02 0.16 0.08 0.16 0.13 After 12 weeks of storage under all five storage conditions, the total amount of impurities present in Examples 1D and 1H was the least. Although Example 1C was slightly inferior to Examples 1D and 1H, it was still superior to formulations containing anhydrous calcium hydrogen phosphate (DA). Under the same conditions, the examples containing the anhydrous calcium hydrogen phosphate showed significantly higher impurities than the examples which did not contain anhydrous calcium hydrogen phosphate. Example 2 illustrates the effect of adding a photoprotective layer on the surface of the compressed core. tH2 Core binders corresponding to concentrations of 5 mg and 25 mg tablets were prepared using the compositions in Table 3 below. Table 3 Excipients 5 mg / bond (w / w%) 25 mg / tablet (w / w ° / 〇) API 5.48 27.40 microcrystalline cellulose, NF 60.52 302.60 lactose monohydrate, NF 30.25 151.25 glycolic acid Sodium starch, NF 3.00 15.00 Magnesium stearate, NF 0.75 3.25 Lozenges/batch weight (mg/g) 100 500 *mgA = potency (or recording: agent concentration) 124840.doc -17- 200826975 with V-type blender (Patters〇nKeUy,ift3,i〇_ ^5^ The active ingredient in the form of hydrochloride from % by weight (1_[9♦chloro-phenyl)_8_ 乱-本基)-9H-嗓呤_6_基] A common admixture dust blend of ice ethylamine _ hexahydro octazone _4_carboxylic acid amine (referred to as API)). The blend was passed through a C mil (type 197) equipped with a U millimeter sieve, followed by a (four) clock batch (about 25 rpm). The mixture was lubricated by a stearic acid town (Ο·.) by performing a 3 minute mixing. The pellets were dried granulated by means of a prior pressure (Gerteis Minipaetor; 5. kN, 4 rpm) and then through (four) millimeters of grinding. The granules were stirred for 1 Torr in a V-blender and lubricated by means of an extragranular lubricant (〇 5% magnesium stearate) by mixing for 3 minutes. The granules were compressed into tablets (5 mg 1/4 " standard round concave lozenge on a rotary tablet press (KiUan T_l 〇〇 rotary tablet press) (target: 100 mg size, 6· 1 〇 Newton tablet hardness) and is a milligram of tablets (13/32 " diameter standard concave lozenge, 5 〇〇 milligram size, about 15 _ 25 Newton tablet strength)). The tablets were coated with Opadry IITM_85F (comprising titanium dioxide pigment) by dispersing the film coating provided as a powder in deionized water (20 parts of Opadry πTM powder for 8 parts water) Got it. The core tablet was coated with this suspension in a coating pan (Vector-LDCS 20) until the weight gain was 4%. The core (uncoated) and coated tablets were subjected to 7 days of illumination (13 W/m2 of UV light and 8 Fantasy 1〇1 fluorescence) at 25 ° C and 60% relative humidity. . The concentration of the degradant was measured using a Waters HPLC (Model 2695). Relative to the control (less than or equal to 0.05%), the photodegradation impurity concentration was 5 mg 124840.doc -18 - 200826975 and the 25 mg concentration of the ingots were G33% & g (d), respectively. The preparation of the 1 (9) gram and gamma concentration tablets is basically the same as that outlined for the 5 mg and Μ mg concentration tablets.呤-6-yl]-4-ethylamino-hexahydropyridine_4_carboxylic acid decylamine hydrochloride and photoprotective topcoat and storage stable 5 mgA dose immediate release lozenge. Example 3 胄Microcrystalline cellulose (60.56 units), chlorophenyl)_8♦ gas-phenyl)-9H-嘌呤-6-yl]_4_ethylamino-hexahydroacridine_4_formic acid guanamine salt Acid salt (5.36 units; based on 93.3% theoretical potency), lactose monohydrate (3〇·33 units) and sodium starch glycolate (3·00 units) were added to the cartridge blender and mixed at 12 rpm. Up to 20 minutes. The blend was passed through a mill equipped with a 毫米 millimeter sieve, collected in a bin blender, and mixed at 12 rpm for 5 to 15 minutes. Magnesium stearate (〇.25 units) in the granules was added to the mixture' and mixed for another 2 to 5 minutes at 12 rpm. Lubricated blending by pressure (Gerteis P〇lygran 3W: 4_1 〇 kN / cm, 24 mm gap, 4-10 rpm) and honing (0.8 to 1.00 mm sieve) The granulation was carried out. The particles are collected in a bin blender. After mixing at 12 rpm for 5 to 15 minutes, extragranular magnesium stearate (〇·5〇 unit) was added to the cartridge blender. The lubricated blend was blended for an additional 2 to 5 minutes at 12 rpm. The mixture was compressed into a 5 mgA tablet using a Korsch/Fette tablet press to achieve a target weight of 1 〇〇 mgw and a standard hardness of 8 kP. A photoprotective coating was prepared by adding Opadry II® (4 units) to purified water (16 units) and stirring with 124840.doc -19-200826975 to produce a uniform suspension (about 20% by weight solids). (Glatt 750-1500) (bed temperature 45 to 50 ° C, inlet temperature 80 ° C, outlet temperature 45 to 55 ° C) These compressed tablets were coated with Opadry suspension. The coated tablet will then be allowed to cool to room temperature. The total tablet standard weight is 104 mg. Example 4 illustrates the preparation of tablets in four different concentrations. Example 4 5 mg, 10 mg, 15 mg, and 20 mg tablets were prepared using the same procedure as in Example 2 and the formulations were described below. Table 4 Injury tablet concentration 10 mg 20 mg 5 mg 15 mg APIa 10.723 21.447 5.36 16.08 Microcrystalline cellulose 88.206 176.412 60.56 181.68 Lactose monohydrate 45.445 90.891 30.33 90.99 Sodium starch glycolate 4.500 9.000 3.00 9.0 Magnesium stearate 1.125 2.25 0.75 2.25 Core lozenge weight 150.00 300.000 100.00 300.00 Opadry II® 6.000 12.000 4.00 12.0 film coating color white yellow white white total weight 156.000 312.000 104.00 312.00

a based on the theoretical performance of 93.3%. ''ΑΡΓ refers to 1-[9-(4·gas-phenyl)-8-(2-chloro-phenyl)-9H-indol-6-yl]-4-ethylamino) as the hydrochloride salt Hexahydropyridine-4-carboxylic acid decylamine. b Weight for API performance correction 124840.doc -20·

Claims (1)

200826975 X. Patent application scope: 1 · A pharmaceutical bond comprising a compression core having a photoprotective layer deposited thereon, wherein the compression core comprises (1) pharmaceutically acceptable 1-[9-(4-chloro-phenyl) a salt of 8-(2-chloro-phenyl)_ 9H-inden-6-yl; 1-4-ethylamino-hexahydropyridine_4-formic acid guanamine; (ii) at least one selected from the group consisting of microcrystalline fibers a filler of lactone, lactose monohydrate or mannitol; (iii) a disintegrant selected from sodium starch via sodium acetate or croscarmellose sodium salt; and (iv) a magnesium stearate lubricant. 2. The tablet of claim 1, wherein the at least one filler is microcrystalline cellulose and lactose monohydrate, and the disintegrant is sodium starch glycolate. 3. The lozenge of claim 2 wherein the ratio of microcrystalline cellulose to lactose monohydrate is about 1:1 or about 2:1. 4. The lozenge of claim 3, wherein the ratio of the microcrystalline cellulose to the lactose monohydrate is about 2:1. 5. A lozenge according to claim 1, 2, 3 or 4, wherein the pharmaceutically acceptable compound [9_(4·chloro-phenyl)_8_(2_gas_phenyl)>9Η_嘌呤基卜4 _Ethylamine·Hexahydropyridine-4. The salt of decylamine is i-[9-(4-chloro-phenyl)_8_(2-gas-phenyl)9H >呤-6_yl]_4_ The hydrochloride of ethylamine hexahydropyridinium decylamine. The agent of claim 5, wherein the photoprotective layer comprises from about 3 to about 5% by weight of the compressed core. 7 · 青青τ石 [, The photoprotective agent wherein the photoprotective layer comprises about 4 124840.doc 200826975 wt% of the compressed core. 8. A lozenge comprising a compressed core having a photoprotective layer deposited thereon, wherein the compressive core comprises (i) l- [9-(4- gas-phenyl)-8-(2- gas-phenyl)-9Η-σ吟-6-yl]-4_ethylamine-hexahydropyridine-4-carboxylic acid guanamine salt (ii) microcrystalline cellulose and lactose monohydrate in a ratio of about 2:1; (iii) sodium starch glycolate; and (iv) magnesium stearate; wherein the photoprotective layer occupies the core of the compression About 4% by weight. 124840.doc 200826975 VII. Designated representative map: (1) The representative representative of the case is: ( ) (Ii) of the present symbol elements representative diagram of a brief description: (reference numerals without description) 8, when the case if the formula, please reveal the best features of the invention show a chemical formula: (None) 124840.doc