WO2008044111A1 - Cachet de formulation pharmaceutique - Google Patents

Cachet de formulation pharmaceutique Download PDF

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Publication number
WO2008044111A1
WO2008044111A1 PCT/IB2007/002921 IB2007002921W WO2008044111A1 WO 2008044111 A1 WO2008044111 A1 WO 2008044111A1 IB 2007002921 W IB2007002921 W IB 2007002921W WO 2008044111 A1 WO2008044111 A1 WO 2008044111A1
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WO
WIPO (PCT)
Prior art keywords
chloro
phenyl
tablet
light
compressed core
Prior art date
Application number
PCT/IB2007/002921
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English (en)
Inventor
Margaret Sue Landis
Jeffrey Francis Moriarty
Vidya Swaminathan
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2008044111A1 publication Critical patent/WO2008044111A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the present invention relates to a pharmaceutical tablet having improved shelf-life stability, in particular, a tablet containing an acid salt of 1-[9-(4-chloro- phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4-carboxylic acid amide which is resistant to degradation of the pharmaceutically active agent.
  • CBi receptor antagonists e.g., 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino- piperidine-4-carboxylic acid amide and its pharmaceutically acceptable salts described in US Publication No. 2004/0092520 (WO 2004/037823)).
  • CB1 antagonists have been found to be useful in treating diseases, conditions, and/or disorders modulated by cannabinoid receptor antagonists including eating disorders (e.g., binge eating disorder, anorexia, and bulimia), weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression), obesity, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, alcoholism (e.g.
  • eating disorders e.g., binge eating disorder, anorexia, and bulimia
  • weight loss or control e.g., reduction in calorie or food intake, and/or appetite suppression
  • obesity e.g., behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, alcoholism (e.
  • alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake
  • tobacco abuse e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking
  • dementia including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder
  • attention deficit disorders ADD
  • ADHD attention deficit hyperactivity disorders
  • the purine compound 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6- yl]-4-ethylamino-piperidine-4-carboxylic acid amide, absorbs visible/UV light which makes it susceptible to photodegradation.
  • the ethyl amino and amido groups which are attached to the same carbon atom can be easily degraded under certain conditions.
  • the present invention provides a pharmaceutical tablet (in particular, an immediate release tablet) including 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).
  • the light-protective layer contains a sufficient amount of light absorbing material (e.g., light-scattering and/or light- absorbing materials) to reduce the rate of formation of photodegradation products of 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4- carboxylic acid amide and is preferably deposited in the form of a film coat .
  • light absorbing material e.g., light-scattering and/or light- absorbing materials
  • Potent drugs for administration at low strengths are formulated with excipients for ease of handling, processing and patient convenience.
  • the high concentration of excipients relative to that of the drug in the formulation presents unique challenges in ensuring the physical and chemical stability of the active ingredient and its delivery from the dosage form during preparation, processing and storage of formulations.
  • Significant drug degradation can occur due to excipients or even due to excipient impurities, especially during storage. Degradation can be further accelerated at elevated temperature and/ or humidity conditions. While potential degradation pathways can be elucidated theoretically from consideration of chemical structures, it is not possible to predict a priori whether a given excipient will form an acceptably stable formulation with a drug.
  • the pharmaceutical tablet is generally composed of a compressed core having deposited thereon a light-protective layer.
  • the composition used for manufacturing the compressed core generally includes the active ingredient, fillers (e.g, ductile and/or brittle fillers) for conferring bulk and mechanical properties, a disintegrant, and a lubricant.
  • the active ingredient is 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6- yl]-4-ethylamino-piperidine-4-carboxylic acid amide (generally used in the form of its pharmaceutically acceptable salt, preferably the hydrochloride salt) which may be prepared by the synthetic process described in US Publication No. 2004/0092520 (Example 20) or an alternative synthetic process described in PCT Publication No. 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 size is generally from about 5 to about 140 microns; preferably, from about 5 to about 100 microns; more preferably, from about 10 to about 50 microns; and most preferably, less than about 25 microns.
  • excipients were screened for their effect on the degradation of the active ingredient. Excipients were chosen based on the compatibility of excipient/excipient combinations with the active ingredient which showed little degradation of the drug (generally, less than about 5%; preferably, less than about 3%; and more preferably, less than about 2% degradants), even under high-stress conditions of elevated temperature and humidity (e.g., about 4O 0 C and about 75% relative humidity (RH); and about 5O 0 C and about 75% RH for 12 weeks).
  • elevated temperature and humidity e.g., about 4O 0 C and about 75% relative humidity (RH); and about 5O 0 C and about 75% RH for 12 weeks.
  • microcrystalline cellulose and lactose monohydrate or mannitol were used as the primary and secondary diluents, respectively; sodium starch glycolate (ExplotabTM) or the sodium salt of cross-linked carboxymethylcellulose (AcDiSolTM) was used as the disintegrant; and magnesium stearate was utilized as the lubricant.
  • Preferred diluents are microcrystalline cellulose and lactose monohydrate.
  • Suitable diluents include one or more commercially available grades of microcrystalline cellulose (e.g., Avicel® PH 101 , 102, 150 and 200 available from FMC BioPolymer, Philadelphia, PA) and lactose monohydrate (e.g., NF Lactose 310, 312, 315 and 316 Fast Flo (315 and 316 are both spray-dried mixtures of crystalline and amorphous lactose), available from Foremost Farms USA, Rothschild, Wl).
  • Preferred disintegrant is sodium starch glycolate. Anhydrous dicalcium phosphate caused a higher degradation of the active ingredient and is therefore not considered a compatible secondary filler. See Example 1 of the Example section below.
  • the active ingredient, diluents and disintegrant are generally blended together using blenders well-known to those of skill in the art, e.g., tumbling blenders, bin blender or V-blender. Adequate dispersion of the active ingredient in the mixture is achieved by a variety of techniques such as combinations of premixing and mixing processes with intermittent passage of the material through a mesh screen.
  • the mixture is blended with a suitable lubricant (e.g., magnesium stearate).
  • the active ingredient is generally present in an amount from about 4.5 to about 5.5 total weight percent for a theoretical 5% w/w formulation depending upon the potency of the active ingredient, (e.g., for a potency of 90-110%, the active ingredient is present in an amount of 4.55 to 5.45 wt%: for a potency of 95 -105, 4.9525 to 5.0475% wt%: and for a potency of 97-103%, 4.9515 to 5.485 wt%).
  • the active ingredient is generally present in an amount from about 6.44 to about 7.87 total weight percent for a theoretical 7.15% w/w formulation depending upon the potency of the active ingredient, (e.g., for a potency of 90-110%, the active ingredient is present in an amount of 6.44 to 7.87 wt%: for a potency of 95-105, 6.79 to 7.51 wt%: and for a potency of 97-103%, 6.936 to 7.365 wt%).
  • the diluents may be present in the formulation in varying 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.
  • a variety of commercial grades of disintegrant may be used in the formulation.
  • a preferred disintegrant is sodium starch glycolate.
  • Suitable grades of sodium starch glycolate include Glycolys® (available form 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 intra- granulariy (prior to granulation) and /or extra-granularly (to the granulation prior to tableting). Intra-granular addition of the disintegrant is preferred due to rapid dissolution of the active ingredient from the tablet.
  • a lubricant is generally added as a formulation component or a processing aid.
  • a preferred lubricant is magnesium stearate.
  • the magnesium stearate is generally present in an amount 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 1.5%, most preferably, from about 0.5% to about 1.0%.
  • the lubricant can be added extra-granularly and/or intra-granularly.
  • the lubricant is added as a mixture of extra-granular and intra-granular magnesium stearate.
  • intra-granular magnesium stearate may be added to reduce sticking of the active ingredient to the roll surfaces during roll compaction of the blends; and extra- granular magnesium stearate may be added as a formulation component to achieve the desired tablet properties.
  • additives may also be included such as surface active agents (e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate (SLS)), adsorptive carriers (e.g., kaolin and bentonite), preservatives, sweeteners, coloring agents, flavoring agents (e.g., citric acid, menthol, glycine or orange powder), stabilizers (e.g., citric acid, sodium citrate or acetic acid), dispersing agents, binders (e.g., hydroxypropylcellulose) and mixtures thereof.
  • surface active agents e.g., cetyl alcohol, glycerol monostearate, and sodium lauryl sulfate (SLS)
  • adsorptive carriers e.g., kaolin and bentonite
  • preservatives e.g., kaolin and bentonite
  • sweeteners e.g., kaolin and bentonite
  • the mixture may be tableted directly or after dry granulation (e.g., roll compaction and milling of compacts), preferably after dry granulation.
  • dry granulation e.g., roll compaction and milling of compacts
  • the blended mixture may be compacted into ribbons or compacts, which are milled into granules.
  • Suitable dry granulation equipment include the Gerteis Minipactor or 3W Polygran roller compactors (available from Gerteis Machines and Process Engineering AG, Jona, Switzerland), TF-Mini roll compactor (available from Vector Corporation, Marion, IA), Alexanderwerk (Alexanderwerk Inc., Horsham, PA) and mills.
  • a variety of tablet presses may be used which are well-known to those of skill in the art. Suitable tablet presses include a Fette/Korsch press.
  • the light-protective layer generally contains a film-forming material(s) having incorporated therein a light-scattering or light-absorbing material, such as pigments (e.g., titanium dioxide).
  • Suitable film forming materials include any pharmaceutically acceptable film-forming polymer(s) well-known to those of skill in the art, such as polyvinyl alcohol (PVA), hydroxypropylmethylcellulose (HPMC).
  • Film-coat compostions may also include plasticizers such as polyethylene glycols (PEG), soy lecithin, triacetin, and combinations thereof.
  • Suitable commercial light-protective coatings include Opadry® II, Opaglos® 2, Opadry®fxTM, and Opadry® AMB pigmented coatings (available from Colorcon, Inc., Chalfont, PA).
  • Preferred coatings include HPMC -based coatings, PVA- based coatings (Opadry® Il - 85F and 85G grades available commercially from Colorcon, Inc.).
  • colorants include iron oxides, lake dyes and combinations of iron oxides and lakes.
  • Suitable pigments include red yellow and black iron oxides, Titanium dioxide and talc (white), FD&C Blue #2, and Yellow # 6. Other colorants may be added to provide distinctive markings or recognition of the tablet.
  • the light protective coat is generally present in a range of about 2% to about 5% by weight of the compressed core tablet, more preferably from about 3% to about 4%.
  • the light-protective coating may be deposited onto the compressed core using any means well-known to those of skill in the art, such compression in a tablet press, dipping, fluid bed coating, pan-coating, or spray-coating.
  • the layer is pan-coated or spray-coated using an aqueous suspension to provide a thin and uniform coating.
  • the light protective coat was present, no photodegradation product was detected in any of the coated tablets; whereas, the control (uncoated core tablets) had a photodegradant impurity after exposure to UV light for 7 days. See example below. Consequently, the addition of the light-protective layer reduces the need for special packaging (e.g., storage in opaque bottles or encapsulation of the tablets in foil wraps) to minimize or eliminate photodegradation.
  • the additional coating or coatings are preferably permeable to water. Such coatings can serve to improve adhesion of the light-protective coating to the tablet core, or to provide a chemical and/or act as a physical barrier between the core and the light-protective coating.
  • External coatings can be cosmetic to help with product identification and marketing, and improve mouth feel and swallowability (ease of swallowing the tablet).
  • Such coatings can also be functional, e.g., an enteric coating (i.e., coatings designed to dissolve in certain regions in the gastrointestinal tract).
  • Other product identifying features can also be added to the top of the coating. Examples include, but are not limited to, printing and embossing of identifying information.
  • the additional coating can also contain an active pharmaceutical ingredient, either the same or different from that in the core. This can provide for combination drug delivery and/or allow for specific pharmacokinetics (e.g., pulsatile).
  • Such a coating can be film coated with an appropriate binder onto the tablet core.
  • the tablets may be packaged in a variety of ways.
  • an article for distribution includes a container which holds the 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 also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package and a means for removing moisture and/or oxygen (e.g., oxygen absorbers such as D Series FreshPax.TM. packets available from Multisorb Technologies Inc., Buffalo, N.Y., USA, or Ageles.TM. and ZPTJ.TM. sachets available from Mitsubishi Gas Corporation, Tokyo, JP).
  • the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings.
  • Example 1 demonstrates the effect of excipients on the formation of impurities upon storage at various storage conditions (temperature and humidity).
  • Dry blends were prepared by mixing each of eight test blends indicated in Table I above with the hydrochloride salt of 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H- purin-6-yl]-4-ethylamino-piperidine-4-carboxylic acid amide and compressed.
  • the individual formulation blends were compressed into compacts to ensure adequate contact between the ingredients by compacting in a single station compactor equipped with a 5/16 inch flat face punch and dye at 100 pounds force for 0.5 seconds to produce 100 mg compacts.
  • Dissolving Solvent 50/50 : H 2 O/MeOH
  • Table 2 The total impurities observed after 12 weeks at the five different conditions are summarized in Table 2 below.
  • Examples 1 D and 1 H provided the least amount of total impurities over the 12 week period at all five storage conditions. Although Example 1C was slightly worse than Example 1D and 1H, it was still better than those formulations containing anhydrous dibasic calcium phosphate (DA). Those examples containing anhydrous dibasic calcium phosphate provided significantly higher impurites at some conditions as compared to those formulations that did not contain anhydrous dibasic calcium phosphate.
  • DA anhydrous dibasic calcium phosphate
  • Example 2 illustrates the effect of adding a light-protective layer on the surface of the compressed core.
  • the blends were compressed from a common blend of 5% w/w of the active ingredient (1-t9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino- piperidine-4-carboxylic acid amide (referred to as "API")) in the form of its hydrochloride salt using a V- blender (Patterson Kelly, 1 ft 3 , 10 minutes, about 25 rpm). The blend was passed through a Comil (Model 197) fitted with a 1.0 mm screen followed by blending at 10 minutes (about 25 rpm). The mixture was lubricated with magnesium stearate (0.25%) by mixing for 3 minutes.
  • the blend was dry granulated by roller compaction (Gerteis Minipactor; 5-7kN force, 4 rpm) followed by milling through a 0.8 mm screen.
  • the granulation was blended for 10 minutes in a V blender and lubricated with extra-granular lubricant (0.5% Magnesium stearate) by mixing for 3 minutes.
  • the granules were compressed into tablets (1/4" standard round concave tablets of 5mg strength (target: 100 mg size, 6-10 Newtons tablet hardness) and 25 mg tablets (13/32" diameter standard concave tablets, 500 mg size, about 15 - 25 N tablet hardness) on a rotary tablet press (Kilian T- 100 rotary tablet press).
  • the tablets were coated with Opadry IITM - 85F (containing Titanium dioxide pigment) which was prepared by dispersing the film coat supplied as a powder in de- ionized water at room temperature (20 parts of Opadry IITM powder to 80 parts of water).
  • the core tablets were coated with the suspension in a coating pan (Vector - LDCS 20) to a weight gain of 4%.
  • Example 3 illustrates the manufacture of a storage stable, 5 mgA dose immediate release tablet containing the hydrogen chloride salt of 1-[9-(4-chloro- phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4-carboxylic acid amide and a light-protective topcoat.
  • Microcrystalline cellulose 60.56 units
  • the hydrochloric acid salt of 1-[9-(4- chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4- carboxylic acid amide 5.36 units; based on 93.3% theoretical potency
  • lactose monohydrate 30.33 units
  • sodium starch glycolate 3.00 units
  • Intra-granular magnesium stearate (0.25 units) was then added to the mixture and allowed to blend an additional 2 to 5 minutes at 12 rpm.
  • the lubricated blend was granulated by roller compaction (Gerteis Polygran 3W: force at 4-10kN/cm; gap of 2-4 mm, roll speed 4-10 rpm) and milled (0.8 to 1.00 mm screen). The granules were collected in a bin blender. After blending for 5 to 15 minutes at 12 rpm, extra-granular magnesium stearate (0.50 units) was added to the bin blender. The lubricated blend was then blended an additional 2 to 5 minutes at 12 rpms. The mixture was compressed into 5 mgA strength tablets using a Korsch/Fette tablet press to a target weight of 100 mgW and target hardness of 8 kP.
  • the light-protective coating was prepared by adding White Opadry II® (4 units) to purified water (16 units) and stirred to produce a homogenous suspension (approximately 20% by weight solids).
  • the compressed tablets were then coated with the Opadry suspension in a perforated coating pan (Glatt 750-1500) at a bed temperature of 45° to 50 0 C, an inlet temperature of 80 0 C, and outlet temperature of 45° to 55°C.
  • the coated tablets were then allowed to cool to room temperature.
  • the total tablet target weight was 104 mg.
  • Example 4 illustrates tablets prepared at four different strengths.
  • Tablets at 5 mg, 10 mg, 15 mg and 20 mg were made using the same procedures described in Example 2 and the formulations described below.
  • API refers to 1-[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)- 9H-pur ⁇ n-6-yl]-4-ethylamino-p ⁇ perid ⁇ ne-4-carboxylic acid amide in the form of its hydrochloride salt b weight adjusted for potency of the API

Abstract

L'invention concerne un cachet pharmaceutique qui comprend un noyau comprimé sur lequel a été déposée une couche de protection vis-à-vis de la lumière. Le noyau comprimé comprend (i) un sel acceptable du point de vue pharmaceutique de l'amide d'acide 1-[9-(4-chloro-phényl)-8-(2-chloro-phényl)-9H-purin-6-yl]-4-éthylamino-pipéridine-4-carboxylique, (ii) au moins un agent de remplissage (par exemple, un agent de remplissage ductile, telle que la cellulose microcristalline et/ou un agent de remplissage fragile, telle que le lactose monohydraté ou le mannitol) ; (iii) un désintégrant (par exemple, le glycolate d'amidon sodique) et (iv) un lubrifiant (par exemple, le stéarate de magnésium).
PCT/IB2007/002921 2006-10-13 2007-10-01 Cachet de formulation pharmaceutique WO2008044111A1 (fr)

Applications Claiming Priority (2)

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US82941206P 2006-10-13 2006-10-13
US60/829,412 2006-10-13

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WO2008044111A1 true WO2008044111A1 (fr) 2008-04-17

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AR (1) AR063255A1 (fr)
TW (1) TW200826975A (fr)
WO (1) WO2008044111A1 (fr)

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