EP3052086A1 - Pharmaceutical composition comprising low dose active pharmaceutical ingredient and preparation thereof - Google Patents

Pharmaceutical composition comprising low dose active pharmaceutical ingredient and preparation thereof

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Publication number
EP3052086A1
EP3052086A1 EP14781121.0A EP14781121A EP3052086A1 EP 3052086 A1 EP3052086 A1 EP 3052086A1 EP 14781121 A EP14781121 A EP 14781121A EP 3052086 A1 EP3052086 A1 EP 3052086A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
mixture
acceptable excipient
mixing
active ingredient
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP14781121.0A
Other languages
German (de)
French (fr)
Inventor
Andreas Krekeler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
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 Sandoz AG filed Critical Sandoz AG
Priority to EP14781121.0A priority Critical patent/EP3052086A1/en
Publication of EP3052086A1 publication Critical patent/EP3052086A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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

Definitions

  • the present invention relates to a process for preparation of a pharmaceutical composition that is suitable for preparation of low dose solid formulations having a homogenous distribution of the active ingredient and good content uniformity.
  • the present invention relates to a pharmaceutical composition comprising a low dose of active ingredient and the use of said the pharmaceutical composition as a medicament.
  • compositions comprising low dose of active pharmaceutical ingredient require sufficient homogeneity of the active ingredient in the composition.
  • An inhomogeneous distribution of the active ingredient during production of the composition can result both in too high and/or too low content of the active ingredient in the dosage form, which may sequentially lead to an under- dose or over-dose in the patient. Therefore, producing pharmaceutical compositions comprising low dose of active ingredient that have sufficient content uniformity is of high importance.
  • the test for determining content uniformity is defined in Ph. Eur. section 2.9.40 and/or USP ⁇ 905>. According to the method described the values of content uniformity below 15 are considered as passing the test.
  • WO 2001/64221 discloses pharmaceutical compositions containing a low dose of from about
  • WO 2001/64221 discloses a method for producing said pharmaceutical compositions comprising dissolving entecavir and an adhesive substance,
  • EP 2508172 discloses a process suitable for producing low dose pharmaceutical formulations comprising entecavir and pharmaceutically acceptable excipients comprising dispersing the entecavir or a pharmaceutically acceptable salt thereof in a granulation liquid comprising purified water to form an entecavir solution, preparing a mixture of excipients, wet granulating of the excipients with the entecavir solution, and then drying the wet blend of the excipients and entecavir solution to form the pharmaceutical composition.
  • WO 201 1076412 discloses intermediates comprising entecavir and excipients, in which the d(50) value for the particle size distribution of the intermediate is less than 50 pm.
  • WO 2011076412 further discloses a process for preparation of said intermediate comprising the steps of (i) mixing entecavir and excipients, and (ii) grinding the mixture to produce an intermediate in which the d(50) value for the particle size distribution of the intermediate is less than 50 pm.
  • the object of the present invention is to provide a new process for producing an oral pharmaceutical composition exhibiting a homogenous distribution of the active ingredient and good content uniformity.
  • the aim of the present invention is to provide said pharmaceutical composition and its use as a medicament.
  • the present invention relates to a process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprising the steps of
  • step b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient to form a first pre-mixture having the weight ratio of active ingredient to at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture
  • step d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture
  • the process according to the present invention resulted in a pharmaceutical composition having a homogenous distribution of the active ingredient and good content uniformity.
  • One of the observed advantages of the process of the present invention is that it is simple and robust and does not require the use of a carrier substance and or additional process steps to prevent the loss of the active ingredient.
  • the process according to the present invention is found to be in particularly advantageous for the active ingredients that are sensitive to hydrolysis as it does not require a granulating step in the presence of a solvent. It was also surprisingly found that the process of the present invention is suitable to be carried out in low number of reaction containers which minimize the loss of entecavir during the process for preparation.
  • the present invention relates to the process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprising the steps of
  • step b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step b) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture
  • step d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
  • the present invention relates to a process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprising the steps of
  • step a) providing the active ingredient having particle size distribution of d(90) of less than 50 b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step b) consisting of a binder, a filler and a combination thereof, to the first pre-mixture of step b) and mixing to form a second pre-mixture,
  • step d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
  • step b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable
  • excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step b) consisting of a binder, a filler and a combination thereof, to the first pre-mixture of step b) and mixing to form a second pre-mixture,
  • step d) adding at least one pharmaceutically acceptable excipient selected from the group of consisting of a binder, a filler, and a disintegrant to the second pre-mixture of step c) and mixing the obtained pre-mixture to form a third pre-mixture.
  • the present invention relates to the process wherein the oral pharmaceutical composition comprises from 0.05 wt % to 5.0 wt % of active ingredient. In a preferred embodiment the oral pharmaceutical composition comprises from 0.15 wt % to 0.35 wt % of active ingredient.
  • active pharmaceutical ingredient refers to a substance in a pharmaceutical composition that is biologically active. According to one embodiment the present invention relates to the process wherein the active ingredient has particle size distribution of d(90) of less than 25 ⁇ .
  • Pore size distribution is to be understood in the context of this invention as meaning the statistical distribution of the volume portions based on all the particle sizes of the particles.
  • Volume portion according to the invention means the volume-based proportion in percent of all particles with a defined particle size. Accordingly, the “d(90)” is defined as the particle size at which 90% by volume of the particles have a smaller particle size than the particle size corresponding to the d(90) value.
  • the present invention relates to the process wherein the active ingredient is selected from the group of loratadine, entecavir, anastrazole, pitavastatine, ropinirole, tolterodine, vortioxetine, acenocoumarol, cabergoline, everolimus, glimeperid, lorazepame, pramipexole, rasagiline, trandolapril, and the pharmaceutically acceptable salts thereof.
  • the active ingredient is entecavir.
  • the present invention relates to the process wherein the oral pharmaceutical composition comprises from 0.5 mg to 1 mg of active ingredient.
  • the present invention relates to the process according to claim 1 , wherein the weight ratio of the active ingredient to at least one pharmaceutically acceptable excipient in the first pre-mixture is from 1 : 1 to 1 : 10.
  • the weight ratio of the active ingredient to the at least one pharmaceutically acceptable excipient in the first pre- mixture is 1 : 1 to 1 : 8.
  • the present invention relates to the process wherein the at least one pharmaceutically acceptable excipient in step b) and c) is selected from the group consisting of a binder, a filler and a combination thereof.
  • suitable binders include celluloses (e.g. microcrystalline cellulose) and cellulose derivatives (e.g. methylcellulose and sodium carboxymethylcellulose), calcium phosphates (e.g. dicalcium phosphate dihydrate), mono- and polysaccharides (e.g. maltodextrin), sugar alcohols (e.g. mannitol), gelatin, glucose, lactose (e.g.
  • the binder may be present in the form of a single compound or in the form of a mixture of compounds.
  • the binder is selected from dry binders. Dry binders are preferably selected from celluloses (e.g. microcrystalline cellulose) and cellulose derivatives, lactose (e.g. lactose monohydrate), modified starches (e.g. Starch 1500), calcium phosphates (e.g. dicalcium phosphate dihydrate)
  • Mono- and polysaccharides e.g. maltodextrin
  • sugar alcohols e.g. mannitol
  • the binder is selected from the group of celluloses, lactose, modified starches, calcium phosphates, mono-saccharides, polysaccharides and sugar alcohols, preferably the binder is microcrystalline cellulose. In most preferred embodiment the dry binder is microcrystalline cellulose.
  • Further excipients include at least one filler selected a group of celluloses (e.g. microcrystalline cellulose), lactoses (e.g. lactose monohydrate), starches (e.g. corn starch), calcium phosphate, calcium hydrogenphosphate, glucose, saccharose, sucrose, sugar alcohols (e.g. mannitol), polyethylene glycols, composed fillers of microcrystalline cellulose and lactose monohydrate, composed fillers of powdered cellulose and lactose monohydrate, composed fillers of corn starch and lactose monohydrate.
  • celluloses e.g. microcrystalline cellulose
  • lactoses e.g. lactose monohydrate
  • starches e.g. corn starch
  • calcium phosphate calcium hydrogenphosphate
  • glucose saccharose
  • sucrose sucrose
  • sugar alcohols e.g. mannitol
  • polyethylene glycols composed fillers of microcrystalline cellulose and lactose monohydrate, composed fillers of powdered cellulose and
  • the filler is selected from the group of starches, celluloses, lactoses, glucose, saccharose, sugar alcohols, polyethylene glycols, preferably the filler is lactose monohydrate. Most preferably, lactose monohydrate is used as the filler.
  • the present invention relates to the process wherein the at least one pharmaceutically acceptable excipient in step d) is selected from the group of a binder, a filler, a disintegrant and a combination thereof.
  • binder and filler are described above.
  • disintegrant as used herein is an agent accelerating the disintegration of the composition when in contact with a liquid.
  • Preferred disintegrants are polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl glycolate and sodium bicarbonate.
  • disintegrant is crosslinked polyvinylpyrrolidone (crospovidone).
  • the present invention relates to the process wherein the mixing time in step b), c) and d) is 5 to 30 min. In a preferred embodiment the mixing time in step b), c) and d) is 10 to 20 min.
  • the present invention relates to the process further comprising a step e) adding a lubricant to the third pre-mixture of step d) and mixing to form the final blend.
  • step b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable
  • excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step b) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture
  • step d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture
  • step e) adding lubricant to the third pre-mixture of step c) and mixing to form the final blend.
  • lubricant as used herein is defined as an agent able to decrease adhesion of a powder to punches and friction between particles.
  • the lubricant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds.
  • suitable lubricants include but are not limited to stearic acid, talc, hydrogenated vegetable oil (e.g. hydrogenated castor oil), sodium lauryl sulphate, glyceryl behenate, polyethylene glycol, magnesium stearate and sodium stearyl fumarate.
  • lubricant is selected from the group consisting of hydrogenated castor oil, polyethylene glycol, glyceryl behenate, magnesium stearate and sodium stearyl fumarate, more preferably lubricant glyceryl behenate, sodium stearyl fumarate, magnesium stearate, calcium stearate or stearic acid.
  • the lubricant is selected from the group of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol, preferably the lubricant is magnesium stearate. Most preferably the lubricant is magnesium stearate.
  • the present invention relates to the process wherein further comprises compressing the final blend to form tablets.
  • step b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable
  • excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step b) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture
  • step d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture
  • the present invention relates to the process wherein further comprises the coating of the tablets.
  • coating refers to a layer which completely covers an object and is applied by film coating. The coating is sprayed on the tablet cores as a suspension, the suspension being prepared either by mixing of single excipients or by using ready-made mixtures (e.g. Opadry).
  • the coating dispersion may comprise a polymer selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose and polymethacrylates (such as for example low viscosity HPMC, HPC, PVA and the like), plastificators (e.g. PEG), colorants and may optionally include other excipients such as antitacking agents.
  • a polymer selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose and polymethacrylates (such as for example low viscosity HPMC, HPC, PVA and the like), plastificators (e.g. PEG), colorants and may optionally include other excipients such as antitacking agents.
  • Any method for film coating known in the field of the pharmaceutical technology, may be used.
  • step a) providing the active ingredient having particle size distribution of d(90) of less than 50 pm, b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • step b) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture
  • step d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture
  • step e) adding lubricant to the third pre-mixture of step c) and mixing to form the final blend, f) compressing the final blend to form tablets,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process comprising the steps of
  • the pharmaceutical composition according to the present invention has homogenous distribution of the active ingredient and good content uniformity.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient having particle size distribution of d(90) of less than 50 pm, wherein having a content uniformity of less or equal 15.
  • a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process comprising the steps of a) mixing the active ingredient having particle size distribution of d(90) of less than 50 ⁇ with at least one pharmaceutically acceptable excipient selected from a group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process comprising the steps of
  • composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process according to claim 1 .
  • the present invention relates to a pharmaceutical composition and to a process for preparing an oral composition as described above, wherein the active ingredient is entecavir.
  • entecavir used in the first pre-mixing step a) has a particle size distribution of d(90) of less than 50 ⁇ , preferably less than 25 ⁇ .
  • compositions and the process are particularly advantageously applied to entecavir, as the obtained pharmaceutical composition has an excellent entecavir content uniformity.
  • Its content uniformity, with respect to a compartment of the composition comprising a desired amount of 0.1 mg to 1 mg entecavir, is defined by an acceptance value of ⁇ 15.0, preferably ⁇ 10.0, particularly ⁇ 5.0.
  • acceptance value can be determined according to Ph. Eur. 2.9.40 / USP ⁇ 905>.
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising from 20 wt % to 95 wt % of at least one pharmaceutically acceptable excipient selected from a group consisting of a binder, a filler and a combination thereof.
  • the pharmaceutical composition comprises from about 40 wt % to 95 wt % of said excipient.
  • the pharmaceutical composition comprises from about 60 wt % to 95 wt % of said excipient.
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising from about 1 wt % to about 7 wt % of disintegrant.
  • the composition comprised about 2 wt % to 5 wt % of disintegrant.
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising from about 0.1 wt % to about 5 wt % of lubricant.
  • the composition comprised about 0.5 wt % to about 2 wt % of lubricant.
  • the pharmaceutical composition further may comprise glidants.
  • glidants as used herein is defined as an agent improving the fluidity of the powder and thus the filling of the compression chamber of the tablet press.
  • the gliding agent may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds.
  • the glidant is selected from starches, colloidal silicon dioxide and talc. In a preferred embodiment glidant is talc.
  • a pharmaceutical composition according to the present invention is preferably in solid form, including tablets, capsules, caplets, lozenges and sachets. Tablets may be suitably coated (film coated tablets, pills). Capsule formulations may cover both soft and hard capsules, preferably the capsule formulations are hard capsules.
  • a pharmaceutical composition according to the present invention is preferably in the form of tablet, more preferably coated tablet with appropriate film coating material.
  • the pharmaceutical composition can be used as a medicament.
  • the API was mixed with part 1 of microcrystalline cellulose in a 10 liter container for 10min at 25 rpm to obtain the pre-mixture 1.
  • Microcrystalline cellulose part 2 was added to pre-mixture 1 and further mixed for 10 min at 25 rpm in a 10 liter container to obtain the pre-mixture 2.
  • microcrystalline cellulose part 3 was added and mixed again in a 100 liter container for 30 min at 5 rpm to obtain the pre-mixture 3.
  • lactose monohydrate and polyvinylpyrrolidone Kollidon CL
  • magnesium stearate was added and the blend was mixed for 10 min at 5 rpm.
  • the blend was compressed to tablets with a target weight of 200 mg. Two vessels were used for carrying out the process.
  • Particle size was determined using a Mastersizer 2000 instrument; supplier: Malvern Instruments GmbH, Berlinberg, Germany, parameters: Eisenhofer diffraction method; general purpose (irregular) / normal sensitivity analysis model; 1.33 refractive index dispersant; 2000 RPM pump stir speed.
  • the API was mixed with part 1 of microcrystalline cellulose in a 25 liter cubus container to obtain the pre-mixture 1.
  • Microcrystalline cellulose part 2 was added to pre-mixture 1 and further mixed for 10 min at 9 rpm in 25 liter cubus container to obtain the pre-mixture 2.
  • microcrystalline cellulose part 3 was added and mixed again for 20 min at 9 rpm in a 150 liter cubus container to obtain the pre-mixture 3.
  • lactose monohydrate and polyvinylpyrrolidone Kollidon CL
  • magnesium stearate was added and the blend was mixed for 5 min at 9 rpm.
  • the blend was compressed to tablets with a target weight of 200 mg. Two vessels were used for carrying out the process.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

The present invention relates to a process for preparation of a pharmaceutical composition comprising an active ingredient that is suitable for preparation of low dose solid formulations having a homogenous distribution of the active ingredient and good content uniformity. In addition, the present invention relates to a pharmaceutical composition comprising a low dose of active ingredient and the use of said the pharmaceutical composition as a medicament.

Description

Pharmaceutical com position comprising low dose active pharmaceutical ing redient and preparation thereof
Field of the invention
The present invention relates to a process for preparation of a pharmaceutical composition that is suitable for preparation of low dose solid formulations having a homogenous distribution of the active ingredient and good content uniformity. In addition, the present invention relates to a pharmaceutical composition comprising a low dose of active ingredient and the use of said the pharmaceutical composition as a medicament.
Description of the background art
Pharmaceutical compositions comprising low dose of active pharmaceutical ingredient require sufficient homogeneity of the active ingredient in the composition. An inhomogeneous distribution of the active ingredient during production of the composition can result both in too high and/or too low content of the active ingredient in the dosage form, which may sequentially lead to an under- dose or over-dose in the patient. Therefore, producing pharmaceutical compositions comprising low dose of active ingredient that have sufficient content uniformity is of high importance. The test for determining content uniformity is defined in Ph. Eur. section 2.9.40 and/or USP<905>. According to the method described the values of content uniformity below 15 are considered as passing the test.
WO 2001/64221 discloses pharmaceutical compositions containing a low dose of from about
0.001 mg to about 25 mg of the active antiviral agent entecavir for once daily administration to treat hepatitis B virus infection in an adult human patient. According to WO 2001/64221 , the necessary content uniformity cannot be ensured simply by mixing the ingredients or by employing conventional granulation methods. Therefore, WO 2001/64221 discloses a method for producing said pharmaceutical compositions comprising dissolving entecavir and an adhesive substance,
1. e. povidone, in a solvent to form a solution and then spraying said solution onto a carrier substrate, drying entecavir coated carrier particles, and finally combining said coated particles with desired ingredients to form said pharmaceutical composition.
EP 2508172 discloses a process suitable for producing low dose pharmaceutical formulations comprising entecavir and pharmaceutically acceptable excipients comprising dispersing the entecavir or a pharmaceutically acceptable salt thereof in a granulation liquid comprising purified water to form an entecavir solution, preparing a mixture of excipients, wet granulating of the excipients with the entecavir solution, and then drying the wet blend of the excipients and entecavir solution to form the pharmaceutical composition.
WO 201 1076412 discloses intermediates comprising entecavir and excipients, in which the d(50) value for the particle size distribution of the intermediate is less than 50 pm. WO 2011076412 further discloses a process for preparation of said intermediate comprising the steps of (i) mixing entecavir and excipients, and (ii) grinding the mixture to produce an intermediate in which the d(50) value for the particle size distribution of the intermediate is less than 50 pm.
Thus, the object of the present invention is to provide a new process for producing an oral pharmaceutical composition exhibiting a homogenous distribution of the active ingredient and good content uniformity. In addition, the aim of the present invention is to provide said pharmaceutical composition and its use as a medicament.
Detailed description of the invention According to one aspect the present invention relates to a process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprising the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 μιτι,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient to form a first pre-mixture having the weight ratio of active ingredient to at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture, d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
Unexpectedly, it was observed that the process according to the present invention resulted in a pharmaceutical composition having a homogenous distribution of the active ingredient and good content uniformity. One of the observed advantages of the process of the present invention is that it is simple and robust and does not require the use of a carrier substance and or additional process steps to prevent the loss of the active ingredient. In addition, the process according to the present invention is found to be in particularly advantageous for the active ingredients that are sensitive to hydrolysis as it does not require a granulating step in the presence of a solvent. It was also surprisingly found that the process of the present invention is suitable to be carried out in low number of reaction containers which minimize the loss of entecavir during the process for preparation.
According to one embodiment the present invention relates to the process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprising the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 Mm,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
According to another embodiment the present invention relates to a process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprising the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient selected from the group
consisting of a binder, a filler and a combination thereof, to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
According to another embodiment of the present invention the process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprises the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 um,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable
excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient selected from the group
consisting of a binder, a filler and a combination thereof, to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient selected from the group of consisting of a binder, a filler, and a disintegrant to the second pre-mixture of step c) and mixing the obtained pre-mixture to form a third pre-mixture.
According to another embodiment the present invention relates to the process wherein the oral pharmaceutical composition comprises from 0.05 wt % to 5.0 wt % of active ingredient. In a preferred embodiment the oral pharmaceutical composition comprises from 0.15 wt % to 0.35 wt % of active ingredient.
As used herein the term "active pharmaceutical ingredient" refers to a substance in a pharmaceutical composition that is biologically active. According to one embodiment the present invention relates to the process wherein the active ingredient has particle size distribution of d(90) of less than 25 μιτι.
"Particle size distribution" is to be understood in the context of this invention as meaning the statistical distribution of the volume portions based on all the particle sizes of the particles. "Volume portion" according to the invention means the volume-based proportion in percent of all particles with a defined particle size. Accordingly, the "d(90)" is defined as the particle size at which 90% by volume of the particles have a smaller particle size than the particle size corresponding to the d(90) value.
According to another embodiment the present invention relates to the process wherein the active ingredient is selected from the group of loratadine, entecavir, anastrazole, pitavastatine, ropinirole, tolterodine, vortioxetine, acenocoumarol, cabergoline, everolimus, glimeperid, lorazepame, pramipexole, rasagiline, trandolapril, and the pharmaceutically acceptable salts thereof. In a preferred embodiment the active ingredient is entecavir.
In another preferred embodiment the present invention relates to the process wherein the oral pharmaceutical composition comprises from 0.5 mg to 1 mg of active ingredient. According to one embodiment the present invention relates to the process according to claim 1 , wherein the weight ratio of the active ingredient to at least one pharmaceutically acceptable excipient in the first pre-mixture is from 1 : 1 to 1 : 10. In a preferred embodiment the weight ratio of the active ingredient to the at least one pharmaceutically acceptable excipient in the first pre- mixture is 1 : 1 to 1 : 8.
According to one embodiment the present invention relates to the process wherein the at least one pharmaceutically acceptable excipient in step b) and c) is selected from the group consisting of a binder, a filler and a combination thereof. The suitable binders include celluloses (e.g. microcrystalline cellulose) and cellulose derivatives (e.g. methylcellulose and sodium carboxymethylcellulose), calcium phosphates (e.g. dicalcium phosphate dihydrate), mono- and polysaccharides (e.g. maltodextrin), sugar alcohols (e.g. mannitol), gelatin, glucose, lactose (e.g. lactose monohydrate), sucrose, polyethylene glycol, polymethacrylates, hydroxypropylcellulose, sugar alcohols, modified starches (e.g. starch 1500), pregelatinized starch and sodium alginate. The binder may be present in the form of a single compound or in the form of a mixture of compounds. In the preferred embodiment the binder is selected from dry binders. Dry binders are preferably selected from celluloses (e.g. microcrystalline cellulose) and cellulose derivatives, lactose (e.g. lactose monohydrate), modified starches (e.g. Starch 1500), calcium phosphates (e.g. dicalcium phosphate dihydrate)
Mono- and polysaccharides (e.g. maltodextrin), and sugar alcohols (e.g. mannitol). In a preferred embodiment the binder is selected from the group of celluloses, lactose, modified starches, calcium phosphates, mono-saccharides, polysaccharides and sugar alcohols, preferably the binder is microcrystalline cellulose. In most preferred embodiment the dry binder is microcrystalline cellulose.
Further excipients include at least one filler selected a group of celluloses (e.g. microcrystalline cellulose), lactoses (e.g. lactose monohydrate), starches (e.g. corn starch), calcium phosphate, calcium hydrogenphosphate, glucose, saccharose, sucrose, sugar alcohols (e.g. mannitol), polyethylene glycols, composed fillers of microcrystalline cellulose and lactose monohydrate, composed fillers of powdered cellulose and lactose monohydrate, composed fillers of corn starch and lactose monohydrate. In a preferred embodiment the filler is selected from the group of starches, celluloses, lactoses, glucose, saccharose, sugar alcohols, polyethylene glycols, preferably the filler is lactose monohydrate. Most preferably, lactose monohydrate is used as the filler.
According to another embodiment the present invention relates to the process wherein the at least one pharmaceutically acceptable excipient in step d) is selected from the group of a binder, a filler, a disintegrant and a combination thereof.
The terms binder and filler are described above.
The term disintegrant as used herein is an agent accelerating the disintegration of the composition when in contact with a liquid. Preferred disintegrants are polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl glycolate and sodium bicarbonate. Preferably, disintegrant is crosslinked polyvinylpyrrolidone (crospovidone). According to one embodiment the present invention relates to the process wherein the mixing time in step b), c) and d) is 5 to 30 min. In a preferred embodiment the mixing time in step b), c) and d) is 10 to 20 min. According to yet another embodiment the present invention relates to the process further comprising a step e) adding a lubricant to the third pre-mixture of step d) and mixing to form the final blend.
According to one embodiment the process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprises the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 Mm,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable
excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture,
e) adding lubricant to the third pre-mixture of step c) and mixing to form the final blend.
The term "lubricant" as used herein is defined as an agent able to decrease adhesion of a powder to punches and friction between particles. The lubricant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Various suitable lubricants include but are not limited to stearic acid, talc, hydrogenated vegetable oil (e.g. hydrogenated castor oil), sodium lauryl sulphate, glyceryl behenate, polyethylene glycol, magnesium stearate and sodium stearyl fumarate. In one embodiment lubricant is selected from the group consisting of hydrogenated castor oil, polyethylene glycol, glyceryl behenate, magnesium stearate and sodium stearyl fumarate, more preferably lubricant glyceryl behenate, sodium stearyl fumarate, magnesium stearate, calcium stearate or stearic acid. In a preferred embodiment the lubricant is selected from the group of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol, preferably the lubricant is magnesium stearate. Most preferably the lubricant is magnesium stearate. According to another embodiment the present invention relates to the process wherein further comprises compressing the final blend to form tablets. According to yet another embodiment the process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprises the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 Mm,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable
excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture,
e) adding lubricant to the third pre-mixture of step c) and mixing to form the final blend, f) compressing the final blend to form tablets. According to one embodiment the present invention relates to the process wherein further comprises the coating of the tablets. The term "coating" as used herein refers to a layer which completely covers an object and is applied by film coating. The coating is sprayed on the tablet cores as a suspension, the suspension being prepared either by mixing of single excipients or by using ready-made mixtures (e.g. Opadry). The coating dispersion may comprise a polymer selected from the group consisting of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose and polymethacrylates (such as for example low viscosity HPMC, HPC, PVA and the like), plastificators (e.g. PEG), colorants and may optionally include other excipients such as antitacking agents.
Any method for film coating, known in the field of the pharmaceutical technology, may be used.
According to another embodiment the process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient comprises the steps of
a) providing the active ingredient having particle size distribution of d(90) of less than 50 pm, b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient selected from the group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture,
e) adding lubricant to the third pre-mixture of step c) and mixing to form the final blend, f) compressing the final blend to form tablets,
g) coating the tablets.
According to another aspect the present invention relates to a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process comprising the steps of
a) mixing the active ingredient having particle size distribution of d(90) of less than 50 μιτι with at least one pharmaceutically acceptable excipient to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
b) adding the at least one pharmaceutically acceptable excipient to the first pre-mixture and mixing, to form a second pre-mixture,
c) adding at least one pharmaceutically acceptable excipient to the second pre-mixture and mixing to form the third pre-mixture.
Surprisingly, it was found that the pharmaceutical composition according to the present invention has homogenous distribution of the active ingredient and good content uniformity.
In a preferred embodiment the present invention relates to a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient having particle size distribution of d(90) of less than 50 pm, wherein having a content uniformity of less or equal 15.
According to one embodiment of the present invention relates to a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process comprising the steps of a) mixing the active ingredient having particle size distribution of d(90) of less than 50 μηη with at least one pharmaceutically acceptable excipient selected from a group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
b) adding the at least one pharmaceutically acceptable excipient to the first pre-mixture and mixing, to form a second pre-mixture,
c) adding at least one pharmaceutically acceptable excipient to the second pre-mixture and mixing to form the third pre-mixture.
According to another embodiment the present invention relates to a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process comprising the steps of
a) mixing the active ingredient having particle size distribution of d(90) of less than 50 μηι with at least one pharmaceutically acceptable excipient selected from a group consisting of a binder, a filler and a combination thereof, to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
b) adding the at least one pharmaceutically acceptable excipient selected from a group consisting of a binder, a filler and a combination thereof, to the first pre-mixture and mixing, to form a second pre-mixture,
c) adding at least one pharmaceutically acceptable excipient to the second pre-mixture and mixing to form the third pre-mixture.
According to yet another embodiment of the present invention relates to a pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient obtained by the process according to claim 1 .
According to yet another embodiment, the present invention relates to a pharmaceutical composition and to a process for preparing an oral composition as described above, wherein the active ingredient is entecavir. According, entecavir used in the first pre-mixing step a) has a particle size distribution of d(90) of less than 50μιη, preferably less than 25μηι. The
pharmaceutical composition and the process are particularly advantageously applied to entecavir, as the obtained pharmaceutical composition has an excellent entecavir content uniformity. Its content uniformity, with respect to a compartment of the composition comprising a desired amount of 0.1 mg to 1 mg entecavir, is defined by an acceptance value of <15.0, preferably≤10.0, particularly <5.0. The term "acceptance value" can be determined according to Ph. Eur. 2.9.40 / USP<905>.
According to one embodiment of the present invention relates to the pharmaceutical composition comprising from 20 wt % to 95 wt % of at least one pharmaceutically acceptable excipient selected from a group consisting of a binder, a filler and a combination thereof. In a preferred embodiment the pharmaceutical composition comprises from about 40 wt % to 95 wt % of said excipient. In the most preferred embodiment the pharmaceutical composition comprises from about 60 wt % to 95 wt % of said excipient.
According to one embodiment of the present invention relates to the pharmaceutical composition comprising from about 1 wt % to about 7 wt % of disintegrant. In the most preferred embodiment the composition comprised about 2 wt % to 5 wt % of disintegrant.
The term "about" generally means within 10%, preferably 5% and more preferably within 1 % of a given value or range. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of the ordinary skill in the art.
According to one embodiment of the present invention relates to the pharmaceutical composition comprising from about 0.1 wt % to about 5 wt % of lubricant. In the most preferred embodiment the composition comprised about 0.5 wt % to about 2 wt % of lubricant. In a further aspect, the pharmaceutical composition further may comprise glidants. The term "glidants" as used herein is defined as an agent improving the fluidity of the powder and thus the filling of the compression chamber of the tablet press. The gliding agent may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. In one embodiment, the glidant is selected from starches, colloidal silicon dioxide and talc. In a preferred embodiment glidant is talc.
A pharmaceutical composition according to the present invention is preferably in solid form, including tablets, capsules, caplets, lozenges and sachets. Tablets may be suitably coated (film coated tablets, pills). Capsule formulations may cover both soft and hard capsules, preferably the capsule formulations are hard capsules. A pharmaceutical composition according to the present invention is preferably in the form of tablet, more preferably coated tablet with appropriate film coating material.
According to the third aspect of the present invention relates to the pharmaceutical composition can be used as a medicament.
Examples
Example 1
Entecavir was micronized using a jet mill to particle size of d(90) = 23 pm. Particle size was determined using a Mastersizer 2000 instrument; supplier: Malvern Instruments GmbH, Herrenberg, Germany, parameters: Frauenhofer diffraction method; general purpose (irregular) / normal sensitivity analysis model; 1.33 refractive index dispersant; 2000 RPM pump stir speed.
The API was mixed with part 1 of microcrystalline cellulose in a 10 liter container for 10min at 25 rpm to obtain the pre-mixture 1. Microcrystalline cellulose part 2 was added to pre-mixture 1 and further mixed for 10 min at 25 rpm in a 10 liter container to obtain the pre-mixture 2. To pre-mixture 2 microcrystalline cellulose part 3 was added and mixed again in a 100 liter container for 30 min at 5 rpm to obtain the pre-mixture 3. Afterwards, lactose monohydrate and polyvinylpyrrolidone (Kollidon CL) were added to the mixture which was further mixed for 40 min at 5 rpm to obtain the blend. Finally, magnesium stearate was added and the blend was mixed for 10 min at 5 rpm. The blend was compressed to tablets with a target weight of 200 mg. Two vessels were used for carrying out the process.
Content uniformity was assessed by drawing 10 samples equally distributed over the whole compression process.
Determination according to Ph. Eur. 2.9.40 / USP<905>. resulted in an acceptance value of 4.3 (requirement acc. Ph. Eur: Acceptance value <15,0)
Determination according to Ph. Eur. 2.9.6: Average content was 98.7%. All single values were very well within 85-1 15% limit of average content (95.4 - 101.0 %).
Example 2
Loratadine was micronized using a jet mill to particle size of d(90) = 7.5 μηη . Particle size was determined using a Mastersizer 2000 instrument; supplier: Malvern Instruments GmbH, Herrenberg, Germany, parameters: Frauenhofer diffraction method; general purpose (irregular) / normal sensitivity analysis model; 1.33 refractive index dispersant; 2000 RPM pump stir speed.
The API was mixed with part 1 of microcrystalline cellulose in a 25 liter cubus container to obtain the pre-mixture 1. Microcrystalline cellulose part 2 was added to pre-mixture 1 and further mixed for 10 min at 9 rpm in 25 liter cubus container to obtain the pre-mixture 2. To pre-mixture 2 microcrystalline cellulose part 3 was added and mixed again for 20 min at 9 rpm in a 150 liter cubus container to obtain the pre-mixture 3. Afterwards, lactose monohydrate and polyvinylpyrrolidone (Kollidon CL) were added to the mixture which was further mixed for 30 min at 9 rpm to obtain the blend. Finally, magnesium stearate was added and the blend was mixed for 5 min at 9 rpm. The blend was compressed to tablets with a target weight of 200 mg. Two vessels were used for carrying out the process.
Content uniformity was assessed by drawing 10 samples equally distributed over the whole compression process.
Determination according to Ph. Eur. 2.9.40 / USP<905> resulted in an acceptance value of 4.2 (requirement acc. Ph. Eur: Acceptance value≤15,0)
Determination according to Ph. Eur. 2.9.6: Average content was 96.5%. All single values were very well within 85-1 5% limit of average content (95.3 - 98.1 %).

Claims

Claims
1. A process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of entecavir or a pharmaceutically acceptable salt thereof, comprising the steps of a) providing entecavir, or a pharmaceutically acceptable salt thereof, having particle size distribution of d(90) of less than 50 pm,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient to form a first pre-mixture having the weight ratio of entecavir, or a
pharmaceutically acceptable salt thereof, to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
2. The process according to claim 1 , wherein the oral pharmaceutical composition comprises from 0.05 wt % to 5.0 wt % of entecavir or a pharmaceutically acceptable salt thereof, and/or wherein the oral pharmaceutical composition comprises from 0.5 mg to 1 mg of entecavir or a pharmaceutically acceptable salt thereof.
3. The process according to claim 1 or 2, wherein the entecavir or a pharmaceutically
acceptable salt thereof has particle size distribution of d(90) of less than 25 μιτι.
4. The process according to any of claims 1 to 3, wherein the weight ratio of entecavir, or a pharmaceutically acceptable salt thereof, to at least one pharmaceutically acceptable excipient in the first pre-mixture is 1 : 1 to 1 : 10.
5. The process according to any of claims 1 to 4, wherein the mixing in step b) and c) is
performed by dry mixing of dry flowable powder of said at least one pharmaceutically acceptable excipient used in step b) and c).
6. The process according to any of claims 1 to 5, wherein the at least one pharmaceutically acceptable excipient in step b) and c) is selected from the group consisting of a binder, a filler and a combination thereof.
7. The process according to claim 6, wherein the binder is selected from the group consisting of celluloses, lactose, modified starches, calcium phosphates, mono-saccharides, polysaccharides and sugar alcohols, preferably the binder is microcrystalline cellulose.
8. The process according to claim 6, wherein the filler is selected from the group of starches, celluloses, lactose, glucose, saccharose, sugar alcohols, polyethylene glycols, preferably the filler is lactose monohydrate.
9. The process according to any of claims 1 to 8, wherein the at least one pharmaceutically acceptable excipient in step d) is selected from the group consisting of a binder, a filler, a disintegrant and a combination thereof.
10. The process according to claim 9, wherein the disintegrant is selected from the group of polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl glycolate and sodium bicarbonate, preferably the disintegrant is crosslinked polyvinylpyrrolidone.
11. The process according any of claims 1 to 10, wherein comprising a further step e) adding a lubricant to the third pre-mixture of step d) and mixing to form the final blend.
12. The process according to claim 1 1 , wherein the lubricant is selected from the group of magnesium stearate, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol, preferably the lubricant is magnesium stearate.
13. A process for preparing an oral pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient, comprising the steps of
a) providing an the active ingredient being selected from the group consisting of loratadine, anastrazole, pitavastatine, ropinirole, tolterodine, vortioxetine, acenocoumarol, cabergoline, everolimus, glimeperid, lorazepame, pramipexole, rasagiline, trandolapril, and the pharmaceutically acceptable salts thereof, wherein said active ingredient has a particle size distribution of d(90) of less than 50 μηη,
b) mixing the active ingredient of step a) with at least one pharmaceutically acceptable excipient to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15, c) adding at least one pharmaceutically acceptable excipient to the first pre-mixture of step b) and mixing to form a second pre-mixture,
d) adding at least one pharmaceutically acceptable excipient to the second pre-mixture of step c) and mixing to form a third pre-mixture.
14. A pharmaceutical composition comprising from 0.1 mg to 1 mg of entecavir or a
pharmaceutically acceptable salt thereof as active ingredient and at least one
pharmaceutically acceptable excipient selected from the group consisting of a binder and a filler, wherein the entecavir has been incorporated into the pharmaceutical composition in pre-mixing steps including a) mixing entecavir having a particle size distribution of d(90) of less than 50 pm with at least one pharmaceutically acceptable excipient to form a first pre-mixture having a weight ratio of entecavir, or a pharmaceutically acceptable salt thereof, to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
b) adding at least one pharmaceutically acceptable excipient to the first pre-mixture and mixing, to form a second pre-mixture,
c) adding at least one pharmaceutically acceptable excipient to the second pre-mixture and mixing to form the third pre-mixture.
15. The pharmaceutical composition according to claim 14, wherein the pre-mixing steps are dry pre-mixing steps, and/or wherein the first pre-mixture is defined by a weight ratio of entecavir, or a pharmaceutically acceptable salt thereof, to the at least one
pharmaceutically acceptable excipient from 1 : 1 to 1 : 10, preferably 1 :8.
16. The pharmaceutical composition according to claim 14 or 15, wherein entecavir or a
pharmaceutically acceptable salt thereof used in the pre-mixing step a) has a particle size distribution of d(90) of less than 25pm.
17. The pharmaceutical composition according to any one of claims 14 to 16, wherein the pharmaceutical composition has an entecavir content uniformity, with respect to the compartment of the composition comprising said amount of 0.1 mg to 1 mg, defined by an acceptance value of <15.0, preferably <10.0, particularly <5.0 (acceptance value determined according to Ph. Eur. 2.9.40 / USP<905>).
18. The pharmaceutical composition according to any one of claims 14 to 17, wherein said binder is selected from the group consisting of celluloses, lactose, modified starch, calcium phosphates, mono-saccharides, and polysaccharides and sugar alcohols, preferably the binder is microcrystalline cellulose;
and/or said filler is selected from the group of starches, celluloses, lactose, glucose, saccharose, sugar alcohols, polyethylene glycols, preferably the filler is lactose
monohydrate.
19. A pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient
selected from the group consisting of loratadine, anastrazole, pitavastatine, ropinirole, tolterodine, vortioxetine, acenocoumarol, cabergoline, everolimus, glimeperid, lorazepame, pramipexole, rasagiline, trandolapril, and the pharmaceutically acceptable salts thereof, obtained by a process comprising the steps of
a) mixing the active ingredient having a particle size distribution of d(90) of less than 50 pm with at least one pharmaceutically acceptable excipient to form a first pre-mixture having the weight ratio of active ingredient to the at least one pharmaceutically acceptable excipient from 1 : 1 to 1 : 15,
b) adding the at least one pharmaceutically acceptable excipient to the first pre-mixture and mixing, to form a second pre-mixture,
c) adding at least one pharmaceutically acceptable excipient to the second pre-mixture and mixing to form the third pre-mixture.
20. A pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient
obtained by the process according to claim 1 , the active ingredient being entecavir or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising from 0.1 mg to 10 mg of active ingredient
obtained by the process according to claim 13, the active ingredient being selected from the group consisting of loratadine, anastrazole, pitavastatine, ropinirole, tolterodine, vortioxetine, acenocoumarol, cabergoline, everolimus, glimeperid, lorazepame, pramipexole, rasagiline, trandolapril, and the pharmaceutically acceptable salts thereof.
22. A pharmaceutical composition of any one of claims 14 to 21 for use as a medicament.
EP14781121.0A 2013-09-30 2014-09-26 Pharmaceutical composition comprising low dose active pharmaceutical ingredient and preparation thereof Withdrawn EP3052086A1 (en)

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