Classifications

• • 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
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
  • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K9/2009—Inorganic compounds
• • 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
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

• This invention relates to solid oral dosage forms of the HIV inhibitor darunavir and combination formulations thereof.
• HIV Human Immunodeficiency Virus
• AIDS acquired immunodeficiency syndrome
• NRTIs nucleoside reverse transcriptase inhibitors
• NRTIs non-nucleoside reverse transcriptase inhibitors
• NtRTIs nucleotide reverse transcriptase inhibitors
• PIs HIV-protease inhibitors
• a high pill burden is undesirable for many reasons, such as the frequency of intake, often combined with the inconvenience of having to swallow large dosage forms, as well as the need to store and transport a large number or volume of pills.
• a high pill burden increases the risk of patients not taking their entire dose, thereby failing to comply with the prescribed dosage regimen. As well as reducing the effectiveness of the treatment, this also leads to the emergence of viral resistance.
• the problems associated with a high pill burden are multiplied where a patient must take a combination of different anti-HIV agents or agents in combination with a so called booster to improve pharmacokinetic properties.
• HIV inhibitory therapy that reduces pill burden in that it involves the administration of dosage forms of a practical size and additionally does not require frequent dosing.
• darunavir One class of HIV drugs that is used in HAART is that of the PIs amongst which is darunavir (TMC114), approved in the U.S., the E.U. and a number of other countries and available under the trade name PrezistaTM.
• Darunavir currently marketed in the form of darunavir monoethanolate, has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)-propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C 27 H 37 N 3 O 7 S.C 2 H 5 OH, with a molecular weight of 593.73, and the following chemical structure:
• GS-9350 also known under the name Cobicistat.
• GS-9350 is loaded on silicon dioxide, preferably colloidal silicon dioxide, and has the following chemical name: 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R,6R,9S)—.
• Its molecular formula is C 40 H 53 N 7 O 5 S 2 , with a molecular weight of 776.023 g/mol, and the following chemical structure:
• a darunavir tablet containing 600 mg of active ingredient and having a total weight of 1250 mg per tablet is disclosed in WO/2009/013356.
• the oral dosage forms are formed by direct compression of the ingredients.
• the present invention is based on the unexpected finding that a high weight % load of darunavir per dosage form is facilitated by the granulation of darunavir before formulation.
• Granulation of darunavir according to the present invention thus facilitates a high loading of darunavir in a single dosage form (>80% (w/w)) or the combination of darunavir with other active ingredients and still having an acceptable size of the dosage form.
• the present invention thus provides anti-HIV therapy involving the administration of darunavir dosage forms of acceptable size, potentially as a combination formulation, thereby requiring less frequent dosing.
• present dosage forms are beneficial in terms of pill burden and drug compliance of the patient.
• the invention relates to an oral dosage form comprising about 0.4 to 0.6% by weight (w/w) of a lubricant, about 3% by weight (w/w) of a disintegrant, 17 to 20% by weight (w/w) of silicon dioxide, preferably colloidal silicon dioxide, loaded with GS-9350 corresponding to a total amount of about 150 mg free form equivalent of GS-9350 and about 50 to 60% by weight (w/w) of darunavir granulate, said darunavir granulate consisting of darunavir and/or a pharmaceutically acceptable salt or solvate thereof, Hypromellose and any residual water from the granulation.
• the Hypromellose is Hypromellose 2910 15 mPa ⁇ s.
• the invention relates to a process for preparing an oral dosage form according to the invention comprising the steps of:
• the present invention relates to an oral dosage form according to the invention for use in medicine, more specifically for use in the treatment of HIV infections
• the invention relates to a method for the treatment of an HIV infection in a subject which comprises administering to the subject an effective amount of an oral dosage form according to the invention.
• the present invention provides an oral dosage form of darunavir and GS-9350 that is manufactured by using a darunavir granulate.
• the weight percentage darunavir can be increased per dosage form, thus generating oral dosage forms with a high dose of free from equivalent of darunavir (e.g. 800 mg). Additionally, the size and weight of existing dosage forms (e.g. 400 or 600 mg) can be reduced by about 25%.
• the solid oral dosage forms can comprise additional active ingredients such as pharmacokinetic boosters, e.g. GS-9350 and still be of an acceptable size.
• the size of the dosage forms of the invention i.e. the total weight of the dosage forms, should be below a limit of convenience which is below the size at which a number of patients starts having difficulty taking in the dosage form.
• the total weight of the dosage forms of the invention preferably is below about 1700 mg, and in particular below about 1650 mg.
• the oral dosage forms of the present invention preferably are tablets.
• the term “darunavir” is meant to comprise the base form, any pharmaceutically acceptable acid addition salt thereof, as well as any pharmaceutically acceptable solvate thereof.
• the pharmaceutically acceptable addition salts as mentioned hereinabove the therapeutically active non-toxic acid addition salt forms, which darunavir is able to form.
• the term “darunavir” is meant to comprise the base form, as well as any pharmaceutically acceptable solvate thereof.
• pharmaceutically acceptable solvate comprises the hydrates and the solvent addition forms that darunavir can form.
• examples of such forms are e.g. hydrates, alcoholates, e.g. methanolates, ethanolates and propanolates, and the like.
• solvates are the ethanolate, e.g. the monoethanolate.
• free-form equivalent refers to that quantity of darunavir or GS-9350, whether present in free form (or base form), or as salt or solvate, that corresponds to a given quantity of free form darunavir or GS-9350.
• free-form equivalent For example 650 mg of darunavir monoethanolate corresponds to 600 mg of free-form equivalent darunavir.
• the dosage forms of the invention contain from about 500 to about 900 mg, in particular from about 600 mg to about 800 mg, for example about 800 mg, of free-form equivalent darunavir per unit of the dosage form.
• the darunavir in the dosage forms of the invention is added to the formulation process in the form of a darunavir granulate composition consisting of Darunavir or a pharmaceutically acceptable salt or solvate thereof, Hypromellose and any residual water from the granulation.
• the Darunavir is present in the form of its ethanolate and the Hypromellose is Hypromellose 2910 15 mPa ⁇ s.
• the amount of darunavir in the granulate composition may be in the range from about 95% to about 100%, in particular about 97% to about 99.9%, or about 98% to about 99%, by weight relative to the total weight of the granulate composition comprising darunavir and Hypromellose 2910 15 mPa ⁇ s.
• the granulate composition may additionally contain residual water that is not completely removed during processing.
• the average particle size of the granulate is between 100 and 500 ⁇ m, more preferably from 150 to 400 ⁇ m and even more preferably about 300 ⁇ m.
• the term average particle size has its conventional meaning as known to the person skilled in the art and can be measured by art-known particle size measuring techniques such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation.
• the average particle sizes mentioned herein may be related to weight distributions of the particles. In that instance, by “an average particle size of about 150 ⁇ m” it is meant that at least 50% of the weight of the particles have a particle size of less than average of 150 ⁇ m, and the same applies to the other particle sizes mentioned.
• the average particle sizes may be related to volume distributions of the particles but usually this will result in the same or about the same value for the average effective particle size.
• Granulation of darunavir preferably is performed in a fluid-bed granulator.
• darunavir is granulated by using Hypromellose. More preferably, Hypromellose 2910 15 mPa ⁇ s is used. According to the present invention, darunavir is granulated without any filler or other excipients before formulation of the tablet core.
• the oral dosage forms according to the present invention will comprise a pharmacokinetic booster such as a cytochrome P 450 inhibitor.
• a cytochrome P 450 inhibitor is GS-9350.
• GS-9350 is provided as loaded on silicon dioxide, preferably colloidal silicon dioxide.
• a suitable process for the preparation of silicon dioxide, preferably colloidal silicon dioxide, loaded with GS-9350 is described in WO 2009/135179, as incorporated herein by reference.
• the dosage forms of the invention comprise about 150 mg of free-form equivalent GS-9350 per unit of the dosage form.
• GS-9350 can be used in base form or as a pharmaceutically acceptable addition salt form, in particular as an acid addition salt form, or as a pharmaceutically acceptable solvate.
• the pharmaceutically acceptable addition salts are meant to comprise the therapeutically active non-toxic salt forms.
• the weight/weight ratio darunavir:GS-9350 may vary, but in one embodiment it is in the range from about 10:1 to about 4:5, in particular said ratio may be about 5:1.
• Oral dosage forms according to the present invention will preferably comprise pharmaceutically acceptable carriers and excipients.
• Such inactive ingredients are added to help hold the tablet together and give it strength, among others binders, fillers disintegrant glidants and lubricants.
• binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose and modified cellulose (for example hydroxymethyl cellulose).
• Other such materials are silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol.
• Such agents may sometimes also be referred to as “fillers”.
• Microcrystalline cellulose that can be used comprises the AvicelTM series of products available from FMC BioPolymer, in particular Avicel PH 105® (20 ⁇ m), Avicel PH 101® (50 ⁇ m), Avicel PH 301® (50 ⁇ m);
• microcrystalline cellulose products available from JRS Pharma in particular Vivapur® 105 (20 ⁇ m), Vivapur® 101 (50 ⁇ m), Emcocel® SP 15 (15 ⁇ m), Emcocel® 50M 105 (50 ⁇ m), Prosolv® SMCC 50 (50 ⁇ m); the microcrystalline cellulose products available from DMV, in particular Pharmacel®105 (20 ⁇ m), Pharmacel®101 (50 ⁇ m); the microcrystalline cellulose products available from Blanver, in particular Tabulose (Microcel)®101 (50 ⁇ m), Tabulose (Microcel)®103 (50 ⁇ m);
• microcrystalline cellulose products available from Asahi Kasei Corporation, such as Ceolus® PH-F20JP (20 ⁇ m), Ceolus® PH-101 (50 ⁇ m), Ceolus® PH-301 (50 ⁇ m), Ceolus® KG-802 (50 ⁇ m).
• a particularly preferred microcrystalline cellulose is Ceolus® KG-802, average particle size (50 ⁇ m). Additional characteristics of Ceolus® KG-802 are a bulk density of about 0.2 (g/cm 3 ) and an angle of repose of about 49°.
• the average particle size of the Microcrystalline cellulose may be in the range of from 5 ⁇ m to 60 ⁇ m, in particular from 10 ⁇ m to 50 ⁇ m, e.g. about 20 ⁇ m.
• the tablet formulation according to the invention contains a lubricant. This provides a formulation which avoids manufacturing problems such as tablet sticking when the drug product blend is compressed into tablets.
• the lubricant is preferably magnesium stearate and is generally present in an amount of 0.4 to 0.6% w/w, particularly about 0.5% w/w.
• the tablet formulation also contains a disintegrant to aid disintegration and dissolution of the formulation upon administration to the patients.
• the preferred disintegrant is crospovidone, namely a synthetic homopolymer of cross-linked N-vinyl-2-pyrrolidone available commercially as Polyplasdone XL-10 and is preferably present in an amount of 1 to 4% w/w, especially about 3% w/w.
• Other disintegrants which may be used include croscarmellose sodium (sodium salt of cross-linked carboxymethylcellulose), available commercially as Acdisol.
• the above tablet formulations can be used to make tablet cores in conventional manner for example by initially dry blending the ingredients, that preferably having been sieved. Subsequently, the lubricant is added to the dry-blended mixture for final dry-blending of the total tablet core blend, which is then compressed into tablets having the desired size and weight.
• the tablet cores according to the invention are generally provided with a film coating for example an Opadry film-coating, which is generally used in an amount of about 4% w/w based on the tablet core.
• a film coating for example an Opadry film-coating, which is generally used in an amount of about 4% w/w based on the tablet core.
• Different coloring agents may be used in the film coating in order to differentiate between tablet strengths.
• the coating can be applied to the core in coating suspension for example in purified water, followed by drying of the coated cores.
• a dosage form in accordance with the present invention may suffice to treat HIV infection although it may be recommendable to co-administer other HIV inhibitors.
• the latter preferably include HIV inhibitors of other classes, in particular an NRTI, or NNRTI, but also a fusion inhibitor can be added. HIV inhibitors that may be co-administered by preference are those used in HAART combinations.
• the treatment of HIV infection may be limited to only the dosage form of the invention, without co-administration of further HIV inhibitors.
• This option may be recommended, for example, where the viral load is relatively low, e.g. where the viral load (represented as the number of copies of viral RNA in a specified volume of serum) is below about 200 copies/ml, in particular below about 100 copies/ml, more in particular below 50 copies/ml, specifically below the detection limit of the virus.
• This type of monotherapy may be applied after initial treatment with a combination of HIV drugs, such as any of the HAART combinations during a certain period of time until the viral load in blood plasma reaches the afore mentioned low viral level.
• the present invention relates to the use of a dosage form in accordance with the invention, for the manufacture of a medicament for maintenance therapy of a subject infected with HIV.
• the present invention also relates to the use of a dosage form in accordance with the invention, for the manufacture of a medicament for treating a subject infected with HIV, wherein the dosage form is combined with two different NRTIs or NNRTIs.
• treatment of HIV infection relates to a situation of the treatment of a subject being infected with HIV.
• subject in particular relates to a human being.
• the doses of darunavir and GS-9350 in the dosage forms of the invention are selected so as to keep the blood plasma concentration of darunavir above the minimum blood plasma level between two administrations.
• minimum blood plasma level in this context refers to the lowest efficacious blood plasma level, the latter being that blood plasma level of active that provides effective treatment of HIV.
• the plasma levels of anti-HIV compounds should be kept above these threshold blood plasma levels because at lower levels the drugs may no longer be effective thereby increasing the risk of mutations.
• the dosage forms of the present invention provide effective treatment of HIV infection in that the viral load is reduced while keeping viral replication suppressed.
• the limited number of drug administrations adds to the patients' compliance with the prescribed therapy.
• the word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.
• the term “about” in connection with a numerical value is meant to have its usual meaning in the context of the numerical value. Where necessary the word “about” may be replaced by the numerical value ⁇ 10%, or ⁇ 5%, or ⁇ 2%, or ⁇ 1%. All documents cited herein are incorporated by reference in their entirety.
• the film coating combined with debossing and differences in tablet size, aids in the differentiation of the tablet strengths.
• a secondary function of the film coating is taste masking.
• a high dose formulation e.g. 800-mg darunavir formulation, dose-proportionally derived from the currently marketed 600-mg tablet, was not perceived as suitable for use by patients because of its large size. Furthermore, direct compression of an 800 mg formulation proved not possible due to severely limited gliding and flowing capacity.
• the formulations studied are shown in Table 3.
• magnesium stearate All ingredients, except magnesium stearate, were sieved over a stainless steel screen of 0.95 mm and blended for 10 minutes using a lab-scale planetary mixer. In a second blending step, the magnesium stearate was sieved and mixed for 5 minutes. The blend was not compressed, because of the bad flowability (angle of repose).
• the powders of the internal phase were sieved over a stainless steel screen with 0.95 mm sieve openings and transferred into the granulation insert of the fluid bed granulator GPCG1.
• the purified water (without binder) was sprayed on the powder mixture.
• the process conditions for the granulation are reported in the table below.
• the dried granules and the excipients of the external phase were sieved (0.95 mm) and blended for 10 min.
• the magnesium stearate was sieved, added and blended for 5 min.
• the granulate after sieving was tested for granulometrics and LOD.
• This final mixture was compressed at different compression forces (750 ⁇ 2000 kg), using a single punch tablet press.
• the obtained tablets (nom. weight 1200 mg, punch AC27/42: 20 mm ⁇ 9.5 mm, radius 3 mm, oblong shape) were analyzed for hardness, disintegration time and dissolution.
• the API was sieved over a stainless steel screen with 0.95 mm sieve openings and transferred into the granulation insert of the fluid bed granulator GPCG1.
• the binder solution (HPMC 15 cps 4% solution in water) was sprayed on the powder mixture.
• the process conditions for the granulation are reported in the table below.
• the dried granules and the excipients of the external phase were sieved (0.95 mm) and blended for 10 min.
• the magnesium stearate was sieved, added and blended for 5 min.
• Tablet characteristics of the compression mixtures (B and C are shown in Table 6.
• the Direct Compression concept A was not compressed, because of insufficient flowability (high angle of repose) of the blend. Tablet hardness was measured according to industry standard.
• a representative oral dosage form comprising 800 mg free from equivalent of darunavir was formulated.
• the qualitative and quantitative composition of such a representative oral dosage form is provided in Table 7.
• b Purified Water does not appear in the final product.
• c A commercially available (‘Prosolv HD90’), spray-dried mixture consisting of 98% (w/w) microcrystalline cellulose and 2% (w/w) colloidal silicon dioxide, individually meeting compendial requirements.
• the dried granules were sieved through a hand sieve size with 0.95 mm openings and subsequently blended with external phase excipients (sieved through to 0.95 mm hand sieve) in a Gallay bin blender for 10 min at 9 rpm.
• the magnesium stearate was sieved, added and blended for 5 min.
• the final blend of the batches was compressed at nominal weight (1100 mg) at different compression forces and speeds on a Courtoy module S high-speed rotary tablet press (10-16 punches) using a demo punch (oval shape) set with dimension 19 ⁇ 9.5 mm.
• the obtained tablets were analyzed for weight, hardness, thickness, aspect, disintegration time and friability.
• incl. ejection force were monitored.
• the tablet cores compressed at target compression force (13N) were also coated on a lab-scale coater according to the final formulation composition (with Opadry II red at 4% level).
• Blend flowability improves with the addition of aerosil [(37° 40′ vs 43° 20′ for batches E (with aerosil) and batches D (without aerosil), respectively], confirming the functionality of the aerosil glidant material.
• the addition of the external phase excipients has a beneficial effect on material flowability.
• Drying of the granulate until an outlet-air temperature of 37° C. is reached results in a narrow LOD result range within 5.2 to 6.0% for the granulate and within 5.6 to 6.1% for the final blend, confirming the reproducibility of the drying process regardless of the granulation (thermodynamic) condition used.
• a binder solution was prepared analogous to wet granulation form C.
• the tablet cores were transferred into a suitable coating apparatus where the tablet cores were warmed up by supplying warm air. Subsequently the spraying of a coating suspension on the tablets was started and the coated tabled were dried in the coating apparatus.
• Microcrystalline cellulose (Keolus KG802) even further reduces the oral dosage form weight.

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