CA2172506C - Mycophenolate mofetil and mycophenolic acid high dose oral suspensions - Google Patents
Mycophenolate mofetil and mycophenolic acid high dose oral suspensions Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- 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
- A61K9/1611—Inorganic compounds
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- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- 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
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- 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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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Abstract
High dose, dry granulations and aqueous oral suspensions of mycophenolate mo fetil or mycophenolic acid, contain: active compound (7.5-30 %), suspending/viscosity agent, sweetener, flavor, buffer (to a pH o f 5-7), and optionally contain flavor enhancer, wetting agent, antimicrobial agent and color.
Description
. WO 95/09626 2 17 25 06 FCT/US94/10926 MYCOPHENOLATE MOFETIL HIGH DOSE ORAL SUSPENSIONS
Field of the Invention The present invention relates to mycaphenolate mofetil and mycophenolic acid, particularly to improved formulations thereof, and specifically to high dose oral suspension formulations. The invention is also directed to methods of manufacturing the formulations.
Background Information Mycophenolic acid ("MPA") was initially described as a weakly-active antibiotic found in the fermentation broth of Penicillium brevicompactum, having the following structure:.
1s D OH CH3 H
Mycophenolic Acid EPA and certain related compounds, such as mycophenolate mofetil (the morpholinoethyl ester of NPA), having the following structure:
ol OH CH3 ~, ''/'''N~\0 Mycophenolate Mofetil have more recently been described as having particularly advantageous therapeutic properties, e.g., as immunosuppressant drugs. See, for example, U.S. Patents Nos. 3,880,995; 4,727,069; 4,753,935; and 4,786,637, MPA and mycophenolate mofetil, notwithstanding the improved oral bioavailability characteristics of the latter, require daily doses on the order of 2.0 to as much as 3.5 or 4.0 grams per day (or even 5.0 grams per day in the case of MPA, for example as described in U.S. Patent No.
3,880,995) depending upon the patient and the disease state being treated.
Using a conventional dosage formulation containing 250 mg in a standard size 1 (0.48 cc volume) capsule, a patient receiving a 3.0 gram daily dose is required to take twelve capsules each day, giving rise to patient convenience and compliance concerns.
Coarse dispersions, such as oral suspensions, contain a finely divided insoluble material suspended in a liquid medium. These are described, for example, in Remington's Pharmaceutical Sciences (Fifteenth 2 -11 ~ 5 ~ 0 -2-Edition, Chapters 22 and 83, 1975) and for specific products in the Physicians' Desk Reference (46th Edition, Medical Economics Date, 1992).
Oral suspensions are known for ease of administration, for example, to children or elderly adults, and are not typically employed for the purpose of attaining high dose formulations. Certain "ready to use" suspension =
vehicles, such as Ora-Plus' combined with Ora-SweetTm (both available from Paddock Laboratories, Inc. of Minneapolis, MN) are available for extemporaneous compounding needs, but their suitability for any particular active agent must be determined on a case by case basis. Moreover, such vehicles are contraindicated for long term stability and, therefore, intended only for short term use.
Oral suspensions of mycophenolate mofetil have been described, for example, in U.S. Patent No.4,753,935 (see, Example 7), but at a relatively low dose incorporating 1 gram of active compound in 100 mL. While such suspensions are functional, they are subject to the same patient convenience and compliance concerns as prior low dose capsule formulations.
It has remained desired to provide high dose oral formulations for MPA and mycophenolate mofetil, particularly in view of the relatively high daily doses required for administration.
The present invention concerns high dose oral suspensions of mycophenolate mofetil or mycophenolic acid, and methods of manufacture therefor.
In one aspect, the invention relates to high dose oral suspensions having a composition as follows:
inaredient wt/vol mycophenolate mofetil or mycophenolic acid 7.5 - 30.0 suspending/viscosity agent 0.1 - 3.0 wetting agent 0 - 0.5 sweeteners 30.0 - 70.0 flavor 0.1 - 2.0 flavor enhancer/bitter maskant 0 - 1.0 buffer to pH 5.0 - 7.0 0.5 - 1.5 antimicrobial agent 0 - 10.0 color 0 - 0.01 purified water q.s. to 100 In a presently preferred aspect, the invention relates to a high dose oral suspension of mycophenolate mofetil having a composition as follows:
Field of the Invention The present invention relates to mycaphenolate mofetil and mycophenolic acid, particularly to improved formulations thereof, and specifically to high dose oral suspension formulations. The invention is also directed to methods of manufacturing the formulations.
Background Information Mycophenolic acid ("MPA") was initially described as a weakly-active antibiotic found in the fermentation broth of Penicillium brevicompactum, having the following structure:.
1s D OH CH3 H
Mycophenolic Acid EPA and certain related compounds, such as mycophenolate mofetil (the morpholinoethyl ester of NPA), having the following structure:
ol OH CH3 ~, ''/'''N~\0 Mycophenolate Mofetil have more recently been described as having particularly advantageous therapeutic properties, e.g., as immunosuppressant drugs. See, for example, U.S. Patents Nos. 3,880,995; 4,727,069; 4,753,935; and 4,786,637, MPA and mycophenolate mofetil, notwithstanding the improved oral bioavailability characteristics of the latter, require daily doses on the order of 2.0 to as much as 3.5 or 4.0 grams per day (or even 5.0 grams per day in the case of MPA, for example as described in U.S. Patent No.
3,880,995) depending upon the patient and the disease state being treated.
Using a conventional dosage formulation containing 250 mg in a standard size 1 (0.48 cc volume) capsule, a patient receiving a 3.0 gram daily dose is required to take twelve capsules each day, giving rise to patient convenience and compliance concerns.
Coarse dispersions, such as oral suspensions, contain a finely divided insoluble material suspended in a liquid medium. These are described, for example, in Remington's Pharmaceutical Sciences (Fifteenth 2 -11 ~ 5 ~ 0 -2-Edition, Chapters 22 and 83, 1975) and for specific products in the Physicians' Desk Reference (46th Edition, Medical Economics Date, 1992).
Oral suspensions are known for ease of administration, for example, to children or elderly adults, and are not typically employed for the purpose of attaining high dose formulations. Certain "ready to use" suspension =
vehicles, such as Ora-Plus' combined with Ora-SweetTm (both available from Paddock Laboratories, Inc. of Minneapolis, MN) are available for extemporaneous compounding needs, but their suitability for any particular active agent must be determined on a case by case basis. Moreover, such vehicles are contraindicated for long term stability and, therefore, intended only for short term use.
Oral suspensions of mycophenolate mofetil have been described, for example, in U.S. Patent No.4,753,935 (see, Example 7), but at a relatively low dose incorporating 1 gram of active compound in 100 mL. While such suspensions are functional, they are subject to the same patient convenience and compliance concerns as prior low dose capsule formulations.
It has remained desired to provide high dose oral formulations for MPA and mycophenolate mofetil, particularly in view of the relatively high daily doses required for administration.
The present invention concerns high dose oral suspensions of mycophenolate mofetil or mycophenolic acid, and methods of manufacture therefor.
In one aspect, the invention relates to high dose oral suspensions having a composition as follows:
inaredient wt/vol mycophenolate mofetil or mycophenolic acid 7.5 - 30.0 suspending/viscosity agent 0.1 - 3.0 wetting agent 0 - 0.5 sweeteners 30.0 - 70.0 flavor 0.1 - 2.0 flavor enhancer/bitter maskant 0 - 1.0 buffer to pH 5.0 - 7.0 0.5 - 1.5 antimicrobial agent 0 - 10.0 color 0 - 0.01 purified water q.s. to 100 In a presently preferred aspect, the invention relates to a high dose oral suspension of mycophenolate mofetil having a composition as follows:
Inaredient ~ wt/vol mycophenolate mofetil 20 hydroxypropylmethylcellulose 0.25 microcrystalline cellulose 0.25 ' 5 xanthan gum 0.1 sorbitol, 70W solution 30 - 50 Lycasiri (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.1 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.67 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor (selected from grape, (opt. w/anise), 0.3 - 1.0 cherry, strawberry, or mint) Magnasweet* 0 - 1 color(s) (selected from red 28, red 40, 0.005 blue 1, blue 2, or green 3) purified water q.s. to 100 In another presently preferred aspect, the invention relates to a high dose oral suspension of mycophenolate mofetil having a composition as follows:
Ingredient W wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol, 70%- solution 30 - 50 Lycasirri (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.5 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.8 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor (selected from grape (opt. w/anise), 0.1 - 3.0 cherry, strawberry, mint, orange, berry, or mixed fruit) Magnasweet' 0 - 1 color(s) (selected from red 28, red 40, 0.005 red #3, yellow #6, blue 1, blue 2, or green 3) purified water q.s. to 100 In another aspect, the invention relates to a dry granulation formulation of mycophenolate mofetil for constitution with water to give a high dose oral suspension, having a composition as follows:
Ingredient ma/mL*
mycophenolate mofetil or mycophenolic acid 75 - 300 suspending/viscosity agent 1 - 30 wetting agent 0 - 10 sweeteners 1 - 1200 flavor 0.1 - 100 flavor enhancer/bitter maskant 0 - 50 antimicrobial agent 0 - 10 color 0 - 2 (*concentration after constitution with water).
In a presently preferable aspect, the invention relates to a dry granulation formulation of mycophenolate mofetil for constitution with water to give a high dose oral suspension, having a composition as follows:
Inaredient mQ/mL*
mycophenolate mofetil 200 xanthan gum 1 - 1.5 collodial silicon dioxide 5 - 10 sorbitol 0 - 550 aspartame 0 - 3 soy lecithin 1 - 2 sodium methyl paraben 0 - 10 flavor ((selected from grape (opt. w/anise), 0.1 - 3.0 cherry, strawberry, mint, orange, berry, or mixed fruit) color (red, blue, and/or yellow to complement 0.01 - 0.1 the flavor) (*concentration after constitution with water).
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Parameters The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
Reference to the active agent employed in the formulations of the present invention, "mycophenolate mofetil," is intended to include the pharmaceutically acceptable salts thereof.
The term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.
The term "%, wt/vol" or "percent weight/volume" refers to the amount of excipient and/or drug substance, measured by weight (grams), that is contained in the final volume (milliliters) of a suspension. The amount of excipient and/or drug substance is expressed as a percent of the total, final volume of the liquid product.
Manufacturing Parameters The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100k) .
Unless specified to the contrary, the procedures described herein take place at atmospheric pressure within a temperature range from 5 C to.
100 C (preferably from 10 C to 50 C; most preferably at "rooa:" or "ambient"
temperature, e.g., 20 C).
Unless otherwise specified, the ceanposition percentages, times and conditions are intended to be approxima.te, e.g., add about 10ir wt/vol at about atmospheric pressure within a temperature range of about 5 C to about 100 C (preferably from about 10 C to about 50 C; most preferably about C) over a period of about 1 to about 10 hours (preferably about 5 hours). Parameters given in the Examples are intended to be specific, not approximate.
Materials 20 Mycophenolate mofetil can be made as described in U.S. Patent No.
Ingredient W wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol, 70%- solution 30 - 50 Lycasirri (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.5 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.8 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor (selected from grape (opt. w/anise), 0.1 - 3.0 cherry, strawberry, mint, orange, berry, or mixed fruit) Magnasweet' 0 - 1 color(s) (selected from red 28, red 40, 0.005 red #3, yellow #6, blue 1, blue 2, or green 3) purified water q.s. to 100 In another aspect, the invention relates to a dry granulation formulation of mycophenolate mofetil for constitution with water to give a high dose oral suspension, having a composition as follows:
Ingredient ma/mL*
mycophenolate mofetil or mycophenolic acid 75 - 300 suspending/viscosity agent 1 - 30 wetting agent 0 - 10 sweeteners 1 - 1200 flavor 0.1 - 100 flavor enhancer/bitter maskant 0 - 50 antimicrobial agent 0 - 10 color 0 - 2 (*concentration after constitution with water).
In a presently preferable aspect, the invention relates to a dry granulation formulation of mycophenolate mofetil for constitution with water to give a high dose oral suspension, having a composition as follows:
Inaredient mQ/mL*
mycophenolate mofetil 200 xanthan gum 1 - 1.5 collodial silicon dioxide 5 - 10 sorbitol 0 - 550 aspartame 0 - 3 soy lecithin 1 - 2 sodium methyl paraben 0 - 10 flavor ((selected from grape (opt. w/anise), 0.1 - 3.0 cherry, strawberry, mint, orange, berry, or mixed fruit) color (red, blue, and/or yellow to complement 0.01 - 0.1 the flavor) (*concentration after constitution with water).
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Parameters The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
Reference to the active agent employed in the formulations of the present invention, "mycophenolate mofetil," is intended to include the pharmaceutically acceptable salts thereof.
The term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.
The term "%, wt/vol" or "percent weight/volume" refers to the amount of excipient and/or drug substance, measured by weight (grams), that is contained in the final volume (milliliters) of a suspension. The amount of excipient and/or drug substance is expressed as a percent of the total, final volume of the liquid product.
Manufacturing Parameters The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100k) .
Unless specified to the contrary, the procedures described herein take place at atmospheric pressure within a temperature range from 5 C to.
100 C (preferably from 10 C to 50 C; most preferably at "rooa:" or "ambient"
temperature, e.g., 20 C).
Unless otherwise specified, the ceanposition percentages, times and conditions are intended to be approxima.te, e.g., add about 10ir wt/vol at about atmospheric pressure within a temperature range of about 5 C to about 100 C (preferably from about 10 C to about 50 C; most preferably about C) over a period of about 1 to about 10 hours (preferably about 5 hours). Parameters given in the Examples are intended to be specific, not approximate.
Materials 20 Mycophenolate mofetil can be made as described in U.S. Patent No.
4,753,935,, I.t is presently preferred to make mycoghenolate mofetil as described in Q.S. Patent No. 5,247,083, Mycophenolic acid is commercially available, e.g., from Sigma Chemical Company, St. Louis, rlD. The sources of various excipients are diselosed below, e.g., where the material is not commonly available or when the product of a particular source is preferred.
Suspending and/or viscosity increasing agents useful in the foimulations of the invention include, for example: hydroxypropyl methylcellulose (preferably USP: hydroxypropyl methylcellulose 2910);
xanthan gum _(preferably NF: xanthan gum, and most preferably Keltrol= CR, available from Kelco, San Diego, CA); microcrystalline cellulose (which is a colloidal suspending agent, preferably NF: microcrystalline cellulose, and most preferably Avicel= RC-591, available fraa FMC Corporation, Philadelphia, PA); sodium carboxymethylcellulose (preferably USP:
carboxymethylcellulose sodium, or BP: carmellose sodium or sodium carboxymethylcellulose); and colloidal silicon dioxide (preferable NF:
colloidal silicon dioxide, and more preferably Cab-o-sile M-5, available from Cabot Corporation, Tuscola, IL).
Wetting agents useful in the formulations of the invention include, for example: lecithin (compendial or non-cempeadial soy lecithin) and poloxamer (available as pluronic F68 from SASS Wyandotte Corporation, Parsippany, NJ).
Sweeteners useful in the formulations of the invention include, for example: sorbitol, 70t solution (preferably USP: sorbitol solution);
maltitol syrup (preferably USP or NF, most preferably Lycasine, available from Roquette Corporation, Gurnee, IL); sucrose (preferably NF or BP/EP);
fructose (preferably USP); aspartame (preferably NF); xylitol (preferably compendial grade); mannitol (preferably USP or BP); sorbitol, powder (preferably NF or BP); maltitol, crystalline (non-compendial, or preferably Ma.ltisorb SF, available from Roquette Corporation, Gurnee, IL). In cases where there is a choice of physical form, the liquid sweeteners are preferably used for the suspension formulations, and the dry sweeteners are preferably used for the dry granulation. The sweeteners (except aspartame) can also function as viscosity-increasing agents and/or as antimicrobial preservatives).
Flavors useful in the formulations of the invention include, for example: mint, strawberry, cherry, orange, berry, mixed fruit, and grape (optionally mixed with anise). They are available from Tastemaker, Cincinnatti, OH; Crompton & Knowles Corporation, Mahwah, NJ; and International Flavors & Fragrances Inc., Camden, NJ.
Flavor enhancers (or bitter maskants) useful in the formulation of the invention include, for example Magnasweet (available from MacAndrews &
Forbes Company, Camden, N.J.).
Buffers useful in the formulations of the invention include as components, for example, citric acid (preferably USP) and sodium phosphate dibasic (preferably USP).
Antimicrobial agents useful in the formulations of the invention include, for example: sodium benzoate; sodium methyl paraben (preferably NF: sodium methyl paraben); methyl paraben (preferably NF: methyl paraben, or BP: methyl hydroxybenzoate, or EP: methylis parahydroxybenzoas);
propylparaben (preferably NF: propylparaben, or BP/EP: propyl hydroxybenzoate); and potassium sorbate (preferably NF or BP).
Dyes (or colors) useful in the formulations of the invention include, for example: FD&C red 28, FD&C red 40, FD&C red 3, FD&C blue 1, FD&C blue 2, FD&C yellow 6, and FD&C green 3.
HIGH DOSE ORAL SUSPENSION
Composition The high dose oral suspensions of the present invention have the following general composition:
Ingredient W wt/vol mycophenolate mofetil or mycophenolic acid 7.5 - 30.0 suspending/viscosity agent 0.1 - 3.0 wetting agent 0 - 0.5 sweeteners 30.0 - 70.0 flavor 0.1 - 2.0 flavor enhancer/bitter maskant 0 - 1.0 buffer 0.5 - 1.5 antimicrobial agent 0 - 10.0 ~ WO 95/09626 06 - 7- PCTIUS94/10926 color 0 - 0.01 purified water q.s. to 100 Particularly when the active agent is MPA, pH must be kept below 7.0 to avoid dissolution.
Presently preferred oral suspensions of the invention have the following composition:
Ingredient W wt/vol mycophenolate mofetil 20 hydroxypropylmethylcellulose 0.25 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol, 70W solution 30 - 50 Lycasirn (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.1 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.67 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor 0.3 - 1.0 Magnasweet* 0 - i color 0.005 purified water q.s. to 100 Presently more preferred oral suspension of the invention have the following composition:
incrredient %- wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70t solution 30 - 50 Lycasin (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.5 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.8 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor 0.1 - 1.0 Magnasweet' 0 - 1 color 0.005 %I ,~~~
-$-purified water q.s. to 100 Manufacturing Method 1. To heated water (about 70 C), the antimicrobial agent was added and dispersed, followed by the suspending and/or viscosity agents (preferably microcrystalline cellulose, followed by xanthan gum). =
2. With mixing, the buffer(s) (preferably citric acid, followed by sodium phosphate dibasic) were dissolved, followed by sweetener(s), wetting agent (s) , dye (s) , flavor enhancer (s) , and flavor (s) .
3. The active compound (mycophenolate mofetil or mycophenolic acid) was added to the mixture from step 2; the liquid was mixed well to form a suspension.
DRY GRANLUATION FORMULATION
Composition The dry granulation formulations of the present invention have the following general composition:
Ingredient mQ/mL*
mycophenolate mofetil or mycophenolic acid 75 - 300 suspending/viscosity agent 10 - 30 wetting agent 3 - 10 sweeteners 200 - 1200 flavor 3 - 100 flavor enhancer/bitter maskant 0 - 50 antimicrobial agent 0 - 10 color 0 - 2 (*concentration after constitution with water) A presently preferred dry granulation formulation has the following composition:
Ingredient mca/mL*
mycophenolate mofetil 200 sodium carboxymethylcellulose 20 sucrose 0 - 700 fructose 0 - 700 xylitol 0 - 700 mannitol 0 - 1200 =
sorbitol 0 - 1080 maltitol 0 - 740 pluronic F68 4 - 8 flavor 10 potassium sorbate 0 - 1 color 0 - 1 (*concentration after constitution with water) A presently more preferred dry granulation formulation has the following composition:
Ingredient mcr/mL*
mycophenolate mofetil 200 xanthan gum i - 1.5 colloidal silicon dioxide 5 - 10 sucrose 0 - 700 fructose 0 - 700 xylitol 0 - 700 mannitol 0 - 1200 sorbitol 0 - 1080 maltitol 0 - 740 soy lecithin 1 - 2 flavor 1 - 10 sodium methyl paraben 0 - 10 color 0 - 1 (*concentration after constitution with water) Manufacturing Method 1. Mycophenolate mofetil, sweetener(s), wetting agent(s), and suspending and/or viscosity increasing agent(s) were weighed and combined in a mixer.
2. The dye(s) and buffer(s) were dissolved in water.
3. The solution of step (2) was added to the mixer bowl of step (1), until a desired granulation size was obtained.
4. The granulation was dried then milled to reduce particle size.
Suspending and/or viscosity increasing agents useful in the foimulations of the invention include, for example: hydroxypropyl methylcellulose (preferably USP: hydroxypropyl methylcellulose 2910);
xanthan gum _(preferably NF: xanthan gum, and most preferably Keltrol= CR, available from Kelco, San Diego, CA); microcrystalline cellulose (which is a colloidal suspending agent, preferably NF: microcrystalline cellulose, and most preferably Avicel= RC-591, available fraa FMC Corporation, Philadelphia, PA); sodium carboxymethylcellulose (preferably USP:
carboxymethylcellulose sodium, or BP: carmellose sodium or sodium carboxymethylcellulose); and colloidal silicon dioxide (preferable NF:
colloidal silicon dioxide, and more preferably Cab-o-sile M-5, available from Cabot Corporation, Tuscola, IL).
Wetting agents useful in the formulations of the invention include, for example: lecithin (compendial or non-cempeadial soy lecithin) and poloxamer (available as pluronic F68 from SASS Wyandotte Corporation, Parsippany, NJ).
Sweeteners useful in the formulations of the invention include, for example: sorbitol, 70t solution (preferably USP: sorbitol solution);
maltitol syrup (preferably USP or NF, most preferably Lycasine, available from Roquette Corporation, Gurnee, IL); sucrose (preferably NF or BP/EP);
fructose (preferably USP); aspartame (preferably NF); xylitol (preferably compendial grade); mannitol (preferably USP or BP); sorbitol, powder (preferably NF or BP); maltitol, crystalline (non-compendial, or preferably Ma.ltisorb SF, available from Roquette Corporation, Gurnee, IL). In cases where there is a choice of physical form, the liquid sweeteners are preferably used for the suspension formulations, and the dry sweeteners are preferably used for the dry granulation. The sweeteners (except aspartame) can also function as viscosity-increasing agents and/or as antimicrobial preservatives).
Flavors useful in the formulations of the invention include, for example: mint, strawberry, cherry, orange, berry, mixed fruit, and grape (optionally mixed with anise). They are available from Tastemaker, Cincinnatti, OH; Crompton & Knowles Corporation, Mahwah, NJ; and International Flavors & Fragrances Inc., Camden, NJ.
Flavor enhancers (or bitter maskants) useful in the formulation of the invention include, for example Magnasweet (available from MacAndrews &
Forbes Company, Camden, N.J.).
Buffers useful in the formulations of the invention include as components, for example, citric acid (preferably USP) and sodium phosphate dibasic (preferably USP).
Antimicrobial agents useful in the formulations of the invention include, for example: sodium benzoate; sodium methyl paraben (preferably NF: sodium methyl paraben); methyl paraben (preferably NF: methyl paraben, or BP: methyl hydroxybenzoate, or EP: methylis parahydroxybenzoas);
propylparaben (preferably NF: propylparaben, or BP/EP: propyl hydroxybenzoate); and potassium sorbate (preferably NF or BP).
Dyes (or colors) useful in the formulations of the invention include, for example: FD&C red 28, FD&C red 40, FD&C red 3, FD&C blue 1, FD&C blue 2, FD&C yellow 6, and FD&C green 3.
HIGH DOSE ORAL SUSPENSION
Composition The high dose oral suspensions of the present invention have the following general composition:
Ingredient W wt/vol mycophenolate mofetil or mycophenolic acid 7.5 - 30.0 suspending/viscosity agent 0.1 - 3.0 wetting agent 0 - 0.5 sweeteners 30.0 - 70.0 flavor 0.1 - 2.0 flavor enhancer/bitter maskant 0 - 1.0 buffer 0.5 - 1.5 antimicrobial agent 0 - 10.0 ~ WO 95/09626 06 - 7- PCTIUS94/10926 color 0 - 0.01 purified water q.s. to 100 Particularly when the active agent is MPA, pH must be kept below 7.0 to avoid dissolution.
Presently preferred oral suspensions of the invention have the following composition:
Ingredient W wt/vol mycophenolate mofetil 20 hydroxypropylmethylcellulose 0.25 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol, 70W solution 30 - 50 Lycasirn (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.1 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.67 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor 0.3 - 1.0 Magnasweet* 0 - i color 0.005 purified water q.s. to 100 Presently more preferred oral suspension of the invention have the following composition:
incrredient %- wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70t solution 30 - 50 Lycasin (maltitol syrup) 10 - 30 sucrose 0 - 10 fructose 0 - 10 aspartame 0 - 0.5 lecithin 0 - 0.5 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.8 methyl paraben 0 - 0.18 propyl paraben 0 - 0.02 flavor 0.1 - 1.0 Magnasweet' 0 - 1 color 0.005 %I ,~~~
-$-purified water q.s. to 100 Manufacturing Method 1. To heated water (about 70 C), the antimicrobial agent was added and dispersed, followed by the suspending and/or viscosity agents (preferably microcrystalline cellulose, followed by xanthan gum). =
2. With mixing, the buffer(s) (preferably citric acid, followed by sodium phosphate dibasic) were dissolved, followed by sweetener(s), wetting agent (s) , dye (s) , flavor enhancer (s) , and flavor (s) .
3. The active compound (mycophenolate mofetil or mycophenolic acid) was added to the mixture from step 2; the liquid was mixed well to form a suspension.
DRY GRANLUATION FORMULATION
Composition The dry granulation formulations of the present invention have the following general composition:
Ingredient mQ/mL*
mycophenolate mofetil or mycophenolic acid 75 - 300 suspending/viscosity agent 10 - 30 wetting agent 3 - 10 sweeteners 200 - 1200 flavor 3 - 100 flavor enhancer/bitter maskant 0 - 50 antimicrobial agent 0 - 10 color 0 - 2 (*concentration after constitution with water) A presently preferred dry granulation formulation has the following composition:
Ingredient mca/mL*
mycophenolate mofetil 200 sodium carboxymethylcellulose 20 sucrose 0 - 700 fructose 0 - 700 xylitol 0 - 700 mannitol 0 - 1200 =
sorbitol 0 - 1080 maltitol 0 - 740 pluronic F68 4 - 8 flavor 10 potassium sorbate 0 - 1 color 0 - 1 (*concentration after constitution with water) A presently more preferred dry granulation formulation has the following composition:
Ingredient mcr/mL*
mycophenolate mofetil 200 xanthan gum i - 1.5 colloidal silicon dioxide 5 - 10 sucrose 0 - 700 fructose 0 - 700 xylitol 0 - 700 mannitol 0 - 1200 sorbitol 0 - 1080 maltitol 0 - 740 soy lecithin 1 - 2 flavor 1 - 10 sodium methyl paraben 0 - 10 color 0 - 1 (*concentration after constitution with water) Manufacturing Method 1. Mycophenolate mofetil, sweetener(s), wetting agent(s), and suspending and/or viscosity increasing agent(s) were weighed and combined in a mixer.
2. The dye(s) and buffer(s) were dissolved in water.
3. The solution of step (2) was added to the mixer bowl of step (1), until a desired granulation size was obtained.
4. The granulation was dried then milled to reduce particle size.
5. Using a blender, the suspending and/or viscosity increasing agent(s), flavor(s) and antimicrobial agent(s) were added.
When used as a pharmaceutical formulation to administer mycophenolate mofetil or mycophenolic acid, for example, the dry granulation formulation is added to water in an appropriate container. The container is then sealed, shaken to give a suspension, and administered orally.
Alternatively, the granulation is provided in a container, such that when constituted with an appropriate volume of water a supply of drug in suspension is provided for an extended period of time (e.g., 90 grams of mycophenolate mofetil provided in a bottle marked to be filled with purified water to a final volume of 450 mL, provides a 30 day supply).
Preferred Formulations Presently preferred are the following formulations.
Incrredient g wt/vol mycophenolate mofetil 20 hydroxypropyl methylcellulose 0.25 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol solution 50 sucrose 10 Lycasin 10 lecithin 0.1 methyl paraben 0.036 propylparaben 0.004 =
grape 1.0 anise 0.01 color (red 28: blue 1, 90:10) 0.005 citric acid 0.0542 sodium phosphate dibasic 0.673 purified water q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
Inaredient ls wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol solution 50 sucrose 10 Lycasiri (maltitol syrup) 10 soy lecithin 0.1 methyl paraben 0.04 - .1 mixed fruit <0.3 color (to complement the flavor) 0.005 citric acid 0.06 sodium phosphate dibasic 0.7 purified water q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
Ingredient ma mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 mannitol 180,000 aspartame 1,575 pluronic F68 1,800 potassium sorbate 225 cherry 4,500 color (red 40:blue 1, 90:10) 4.5 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient ma mycophenolate mofetil 90,000 xanthan gum 450 ~ WO 95/09626 ~ PCT/US94/10926 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 sodium methyl paraben 900 berry flavor 1,350 . color (FD&C red #3 13.5 FD&C blue #1 2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient mg mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 135,000 aspartame 450 citric acid 225 sodium citrate 4,500 sodium methyl paraben 900 berry flavor 1,350 color (FD&C red #3 13.5 FD&C blue #1 2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient mg mycophenolate mofetil 90,000 xanthan gum 675 colloidal silicon dioxide 4,500 soy lecithin 900 aspartame 900 sodium methyl paraben 1,035 mixed fruit flavor 900 color (FD&C red #3 3.6 FD&C yellow #6) 0.9 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Inaredient mg mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 citric acid 225 sodium citrate 4,500 sodium methyl paraben 1,035 mixed fruit flavor 900 color (FD&C red #3 2.79 FD&C yellow #6) 0.675 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Inaredient mcT
mycophenolate mofetil 90,000 xarnthan gum 675 colloidal silicon dioxide 4,500 soy lecithin 900 aspartame 900 citric acid 225 sodium citrate 4,500 sodium methyl paraben 450 orange flavor 450 color (FD&C yellow #6) 45 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Testing, Administration and Utility Testing The following tests are performed to evaluate the suitability of formulation combinations made in accordance with the present invention.
The testing procedures are known by those skilled in the art.
1. Time to constitute (for a dry granulation).
2. Ease of resuspendability of solid(s).
3. Appearance.
4. Amount of drug dissolved in continuous aqueous phase.
5. Chemical stability (percent label strength of drug substance).
6. %- Degradant(s) formed (e.g. mycophenolic acid from a suspension of mycophenolate mofetil).
When used as a pharmaceutical formulation to administer mycophenolate mofetil or mycophenolic acid, for example, the dry granulation formulation is added to water in an appropriate container. The container is then sealed, shaken to give a suspension, and administered orally.
Alternatively, the granulation is provided in a container, such that when constituted with an appropriate volume of water a supply of drug in suspension is provided for an extended period of time (e.g., 90 grams of mycophenolate mofetil provided in a bottle marked to be filled with purified water to a final volume of 450 mL, provides a 30 day supply).
Preferred Formulations Presently preferred are the following formulations.
Incrredient g wt/vol mycophenolate mofetil 20 hydroxypropyl methylcellulose 0.25 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol solution 50 sucrose 10 Lycasin 10 lecithin 0.1 methyl paraben 0.036 propylparaben 0.004 =
grape 1.0 anise 0.01 color (red 28: blue 1, 90:10) 0.005 citric acid 0.0542 sodium phosphate dibasic 0.673 purified water q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
Inaredient ls wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol solution 50 sucrose 10 Lycasiri (maltitol syrup) 10 soy lecithin 0.1 methyl paraben 0.04 - .1 mixed fruit <0.3 color (to complement the flavor) 0.005 citric acid 0.06 sodium phosphate dibasic 0.7 purified water q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
Ingredient ma mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 mannitol 180,000 aspartame 1,575 pluronic F68 1,800 potassium sorbate 225 cherry 4,500 color (red 40:blue 1, 90:10) 4.5 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient ma mycophenolate mofetil 90,000 xanthan gum 450 ~ WO 95/09626 ~ PCT/US94/10926 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 sodium methyl paraben 900 berry flavor 1,350 . color (FD&C red #3 13.5 FD&C blue #1 2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient mg mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 135,000 aspartame 450 citric acid 225 sodium citrate 4,500 sodium methyl paraben 900 berry flavor 1,350 color (FD&C red #3 13.5 FD&C blue #1 2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient mg mycophenolate mofetil 90,000 xanthan gum 675 colloidal silicon dioxide 4,500 soy lecithin 900 aspartame 900 sodium methyl paraben 1,035 mixed fruit flavor 900 color (FD&C red #3 3.6 FD&C yellow #6) 0.9 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Inaredient mg mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 citric acid 225 sodium citrate 4,500 sodium methyl paraben 1,035 mixed fruit flavor 900 color (FD&C red #3 2.79 FD&C yellow #6) 0.675 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Inaredient mcT
mycophenolate mofetil 90,000 xarnthan gum 675 colloidal silicon dioxide 4,500 soy lecithin 900 aspartame 900 citric acid 225 sodium citrate 4,500 sodium methyl paraben 450 orange flavor 450 color (FD&C yellow #6) 45 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Testing, Administration and Utility Testing The following tests are performed to evaluate the suitability of formulation combinations made in accordance with the present invention.
The testing procedures are known by those skilled in the art.
1. Time to constitute (for a dry granulation).
2. Ease of resuspendability of solid(s).
3. Appearance.
4. Amount of drug dissolved in continuous aqueous phase.
5. Chemical stability (percent label strength of drug substance).
6. %- Degradant(s) formed (e.g. mycophenolic acid from a suspension of mycophenolate mofetil).
7. Viscosity.
8. Density.
9. Freeze/thaw (aggregate formation).
10. Sedimentation rate.
11. Sedimentation volume.
12. Homogeneity of drug substance.
13. Particle size.
14. Antimicrobial efficacy (USP/BP test).
15. Gravitational and vibrational stresses (simulated shipping).
The following tests are performed to evaluate the acceptability of formulations made in accordance with the present invention. The testing Zi V2506 procedures are known by those skilled in the art.
1. Ease of resuspendability of solid(s).
2. Appearance.
3. Chemical stability (percent label strength of drug substance).
4. %- Degradant(s) formed over time.
5. Viscosity.
6. Density.
7. Homogeneity of drug substance.
8. Particle size.
9. Antimicrobial efficacy (USP/BP test).
Criteria for acceptability include those set forth below.
Ease of resuspendability -- The suspension sediment should be loosely packed such that after minimal shaking the sediment redisperses and reforms the original suspension. From a practical standpoint, any sediment should redisperse within 10 seconds of minimal hand shaking.
Appearance -- In a freshly prepared suspension, all solids should be evenly and homogeneously dispersed in the liquid phase. Over time, sedimentation will occur; and ideally, the volume of sediment should encompass the volume of suspension. If the sediment volume is less than the volume of suspension, the supernatant which forms should be clear (indicating a flocculated system).
Chemical Stability -- The amount of drug substance must remain within 90 - 110%- of the intended labelled concentration.
%- Degradant(s) formed over time -- The formation of no more than 5%-degradant(s) over a period of 2 years is considered acceptable.
Viscosity -- The viscosity should be sufficiently high to hinder rapid sedimentation. However, too high a viscosity is not acceptable from a user's standpoint. An acceptable range is about 200 - 1000 centipoise, with a preferred range of 250 - 500 centipoise.
Density -- Ideally, the density of the vehicle will equal the density of the dispersed solids (drug substance); matching vehicle and drug densities will hinder sedimentation. An acceptable range for the formulations of the present invention is 1.10 - 1.25 g/mL.
Homogeneity -- After minimal hand shaking of the package containing suspension, the amount of drug substance present at the top, middle, and bottom of the packaged suspension, will be equivalent within 10t.
Particle Size -- Over time the mean particle size of the suspension will remain within 20* of the mean particle size of freshly prepared suspension.
Antimicrobial Efficacy -- The suspension will be tested for antimicrobial efficacy via the methods provided in the USP and BP. To be acceptable, the suspension must pass these tests according to the respective specifications.
The formulations of the invention are satisfactory when subjected to the foregoing tests. As will be apparent from the present specification to those skilled in the art, the selection of particular ingredients and their relative concentrations will modify the characteristics balances of the resulting formulations. For example, a 200 mg/mL of mycophenolate mofetil , can be suspended in Ora-Plus1m combined with Ora-SweetT"', but, the characteristics balance of the resulting formulation is unacceptably viscous and expected to have too much drug dissolved in the continuous aqueous phase giving rise to increased degradant formation and loss of chemical stability (given the pH of the vehicles, i.e., below 5.0, the lowest acceptable pH for mycophenolate mofetil in the present formulations).
Administration The formulations of the present invention are useful for oral administration in any oral treatment regimen for mycophenolate mofetil or mycophenolic acid. While human dosage levels have yet to be finalized, generally, a daily dose of mycophenolate mofetil or mycophenolic acid is from about 2.0 to 5.0 grams, preferably about 2.0 to 3.5 grams. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, a treatment regimen for administering 3.0 grams of mycophenolate mofetil per day, which previously entailed taking 12 capsules (250 mg) (e.g., six, twice daily), when administered with a formulation of the present invention entails taking one 7.5 mL dose (e.g., a spoonfull) twice daily. The formulations of the present invention are also particularly well suited to administration via gastric lavage.
Utility The formulations of the present invention are useful for the administration of mycophenolate mofetil or mycophenolic acid (the "compounds") as immunosuppressive agents, anti-inflammatory agents, anti-tumor agents, anti-proliferative agents, anti-viral agents and anti-psoriatic agents (as discussed in greater detail below) in mammals, whether domestic (cattle, pigs, sheep, goats, horses), pets (cats, dogs), or preferably humans. The compounds are inhibitors of inosine monophosphate dehydrogenase (IMPDH) and thus inhibit de novo purine synthesis; they have anti-proliferative effects (e.g., against smooth muscle cells and both B
and T lymphocytes) and inhibit antibody formation and the glycosylation of cell adhesion molecules in lymphocytes and endothelial cells.
As immunosuppressive agents, the compounds are useful in treating auto-immune related disorders, for example: Type I Diabetes Mellitus;
Inflammatory Bowel Disease (e.g., Crohn's Disease and Ulcerative Colitis);
Systemic Lupus Erythematosus; Chronic Active Hepatitis; Multiple Sclerosis;
Grave's Disease; Hashimoto's Thyroiditis; Behcet's Syndrome; Myasthenia Gravis; Sjogren's Syndrome; Pernicious Anemia; Idiopathic Adrenal ~ WO 95/09626 PCT/US94/10926 insufficiency; and Polyglandular Autoimmune Syndromes Type I and II.
The compounds are also useful as therapeutic immunosuppressive agents in the treatment of Asthma, Immunohemolytic Anemia, Glomerulonephritis, and Hepatitis. Preventative uses of the compounds as immunosuppressive agents include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, skin and corneal allografts, and prevention of Graft vs. Host Disease.
The compounds are useful for inhibiting proliferative responses to vascular injury, for example, stenosis following an insult to a blood vessel wall in post-angioplasty restenosis, and post-cardiac by-pass surgery restenosis.
The compounds are useful as anti-inflammatory agents, for example, in treating Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis and Uveitis.
As anti-tumor agents, the compounds are useful in treating solid tumors and malignancies of lymphoreticular origin. For example, the compounds' utility for treatment of solid tumors includes: cancers of the head and neck, including squamous cell carcinoma; lung cancer, including small cell and non-small cell lung carcinoma; mediastinal tumors;
esophageal cancer, including squamous cell carcinoma and adenocarcinoma;
pancreatic cancer; cancer of the hepatobiliary system, including hepatocellular carcinoma, cholangiocarcinoma, gall bladder carcinoma and biliary tract carcinoma; small intestinal carcinoma, including adenocarcinoma, sarcoma, lymphoma and carcinoids; colorectal cancer, including colon carcinoma and rectal carcinoma; metastatic carcinoma;
cancers of the genitourinary system, including ovarian cancer, uterine sarcoma, and renal cell, ureteral, bladder, prostate, urethral, penile, testicular, vulvar, vaginal, cervical, endometrial, and fallopian tube carcinoma; breast cancer; endocrine system cancer; soft tissue sarcomas;
malignant mesotheliomas; skin cancer, including squamous cell carcinoma, basal cell carcinoma and melanoma; cancer of the central nervous system;
malignant bone tumors; and plasma cell neoplasms.
As anti-tumor agents for the treatment of malignancies of lymphoreticular origin, the compounds are useful in treating, for example:
Lymphomas and Leukemias, including B, T and promonocyte cell line malignancies, Mycoses Fungoides, Non-Hodgkins Lymphoma, Malignancies of Burkitt Lymphoma Cells and other EBV-transformed B-lymphocytes, Lymphomas resulting from Epstein-Barr viral infections in allograft recipients, Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and Hairy Cell Leukemia.
As anti-viral agents, the compounds are useful in treating, for example: retroviruses, including Human T-leukemia Viruses, Types I and II
(HTLV-1 and HTLV-2), Human immuno Deficiency Viruses, Types I and II
(HIV-1, HIV-2) and, Human Nasopharyngeal Carcinoma Virus (NPCV) and in treating Herpes Viruses, including EBV infected B-lymphocytes, CMV
infection, Herpes Virus Type 6, Herpes Simplex, Types 1 and 2, (HSV-1, ~=~~ ~~ ~~ -HSV-2) and Herpes Zoster.
As anti-psoriatic agents, the compounds are useful in treating, for example, psoriasis and psoriatic arthritis.
EXAMPLES
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
These examples illustrate the preparation of high dose oral suspension formulations. In each Example, the formulation was manufactured by one of the following alternative methods:
A. 1. To heated water, hydroxypropylmethylcellulose was added and dispersed.
2. Microcrystalline cellulose was added to the dispersion of #1 and dispersed.
3. Xanthan gum was added to the mixture of #2 and dispersed.
4. The sweeteners, flavors, color dyes and lecithin were added individually to the mixture of #3 with mixing.
5. In a small separate aliquot of water, citric acid and sodium phosphate dibasic were dissolved, then added to the mixture of step 4, adjusting pH as indicated.
6. In a small separate aliquot of water (heated to 80 C), methyl paraben and propylparaben were dissolved, then added to the mixture of step 5.
7. Mycophenolate mofetil was added to the mixture of step 6 and mixed well to form a suspension suitable for oral administration.
B. 1. To heated water (70 - 75 C), sodium methyl paraben was dissolved with mixing.
2. Microcrystalline cellulose was added to the dispersion of #1 and dispersed.
3. The sorbitol solution was added and mixed to the dispersion of #2.
Xanthan gum was added to the mixture and dispersed. This was followed by addition of the maltitol solution with mixing.
4. In a separate vessel containing purified water, citric acid was added and dissolved, followed by the addition and dissolution of sodium phosphate dibasic, anhydrous. This was followed by the dissolution of sucrose and the addition and dispersion of soy lecithin. Mycophenolate mofetil was added and dispersed.
5. The dispersions of steps 3 and 4 were combined and mixed.
6. A stock solution of the dye was prepared. The dye and flavor were added to the dispersion of step 5, with mixing.
7. The dispersion of step 6 was brought to volume with purified water, as necessary.
Inaredient wt/vol !k Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 = Microcrystalline cellulose 0.25 Xarzthan gum 0.1 Sorbitol, 70%- solution 50 Sucrose 10 Lycasirn (maltitol syrup) 10 Lecithin 0.1 Methyl paraben 0.036 Propyl paraben 0.004 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.241 Sodium phosphate dibasic 0.547 pH 6 Purified water q.s. to 100 Inaredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70%- solution 50 Sucrose 10 Lycasin (maltitol syrup) 10 Lecithin 0.1 Methyl paraben 0.036 Propyl paraben 0.004 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0542 Sodium phosphate dibasic 0.673 pH 7 Purified water q.s. to 100 Incrredient wt/vol ~
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70W solution 50 Sucrose 10 Lycasin (maltitol syrup) 10 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0542 Sodium phosphate dibasic 0.673 pH 7 Purified water q.s. to 100 Inaredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.2 Microcrystalline cellulose 0.2 Xanthan gum 0.075 Sorbitol, 70t solution 50 Sucrose 10 Lycasin (maltitol syrup) 10 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0962 Sodium phosphate dibasic 0.219 pH 6 Purified water q.s. to 100 Ingredient wt/vol k Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70V solution 50 Sucrose 10 Lycasiri (maltitol syrup) 10 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.269 pH 7 Purified water q.s. to 100 inaredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.35 .15 Microcrystalline cellulose 0.3 Xanthan gum 0.125 Sorbitol, 70W solution 30 Sucrose 10 Lycasin (maltitol syrup) 30 Grape flavor 0.75 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.269 pH 7 Purified water q.s. to 100 Inaredient wt/vol W
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70%- solution 30 Sucrose 10 Lycasin (maltitol syrup) 30 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Magnasweet* 0.2 Color (red 28:blue 1, 90:10) 0.005 Buf f er Citric acid 0.142 Sodium phosphate dibasic 0.438 -pH 6 Purified water q.s. to 100 Incrredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70t solution 30 Lycasiri (maltitol syrup) 10 Aspartame 0.5 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.269 pH 7 Purified water q.s. to 100 Inaredient wt/vol V
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 7015 solution 30 Sucrose 10 Lycasiri (maltitol syrup) 30 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.136 Sodium phosphate dibasic 0.192 pH 5 Purified water q.s. to 100 inaredient wt/vol ~
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 1 (,.e,5tJ6 -21-Microczystalline cellulose 0.25 Sorbitol, 70%~ solution 50 Sucrose 10 Lycasiri (maltitol syrup) 10 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Magnasweet' 1 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.192 pH 7 Purified water q.s. to 100 Inaredient wt/vol ~
Mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 Sorbitol, 70%- solution 50 Sucrose 10 Lycasiri (maltitol syrup) 10 soy Lecithin 0.1 citric acid 0.06 sodium phosphate dibasic (pH 7) 0.7 methyl paraben 0.04 - 0.1 flavor <0.3 Color (to complement the flavor) 0.005 Purified water q.s. to 100 This example illustrates the preparation of a dry granulation of the invention.
Ingredient mg mycophenolate mofetil 3,000 sodium carboxymethylcellulose 300 sorbitol, powder 3,000 xylitol 2,000 maltitol 2,000 pluronic F68 60 mint 150 FD&C green 3 0.1 The above ingredients are combined and blended to a homogeneous mixture, with the addition of adequate purified water to give a desired granule size. The mixture is granulated and then dried to give a dry granulation suitable for use as a pharmaceutical formulation by the addition of 15mL purified water followed by shaking to form a suspension having 3.0 grams of mycophenolate mofetil in 15 mL.
This example illustrates a dry granulation of the invention.
Ingredient mQ
mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 mannitol 4,000 aspartame 35 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention.
Ingredient mQ
mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 sorbitol, powder 10,000 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention.
Inaredient mcr mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 mannitol 4,000 aspartame 35 potassium sorbate 5 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention.
-Ingredient mg mycophenolate mofetil 3,000 xanthan gum 15 colloidal silicon dioxide 75 soy lecithin 15 sorbitol 8,250 aspartame 7.5 sodium methyl paraben 30 berry flavor 45 color (FD&C red #3 0.45 FD&C blue #1 0.09 in a container marked to be filled with purified water to a final predetermined volume of 15 mL.
Ingredient ma mycophenolate mofetil 3,000 xanthan gum 15 colloidal silicon dioxide 75 soy lecithin 15 sorbitol 4,500 aspartame 15 citric acid 67.5 sodium citrate 150 sodium methyl paraben 30 berry flavor 45 color (FD&C red #3 0.45 FD&C blue #1 0.09 in a container marked to be filled with purified water to a final predetermined volume of 15 mL.
Ingredient mg mycophenolate mofetil 3,000 xanthan gum 15 colloidal silicon dioxide 75 soy lecithin 15 sorbitol 8,250 aspartame 7.5 citric acid 7.5 sodium citrate 150 sodium methyl paraben 34.5 mixed fruit flavor 30 color (FD&C red #3 0.093 FD&C yellow #6) 0.0225 in a container marked to be filled with purified water to a final predetermined volume of 15 mL.
Ingredient mQ
mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 =
mannitol 4,000 aspartame 35 potassium sorbate 5 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention, provided as in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Incrredient mQ
mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 mannitol 180,000 aspartame 1,575 pluronic F68 1,800 potassium sorbate 225 cherry 4,500 color (red 40:blue 1, 90:10) 4.5 This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient m ml*
mycophenolate mofetil 200.0 xanthan gum 1.0 colloidal silicon dioxide 5.0 soy lecithin 1.0 sorbitol 300.0 aspartame 1.0 citric acid 0.5 sodium citrate 10.0 sodium methyl paraben 2.0 berry flavor 3.0 color (FD&C red #3 0.034 FD&C blue #1) 0.006 (*concentration after constitution with water) To prepare the dry granulation mycophenolate mofetil, sorbitol, aspartame, soy lecithin, and xanthan gum were combined in a mixer for 5 minutes. The dye was dissolved with sodium citrate, and citric acid in purified water at approximately 45-55 C. The solution was then cooled to room temperature. This dye/buffer solution was added to the mycophenolate mofetil mixture in a cooled mixer bowl at a rate of approximately 60 mi/min with mixing. In the granulation temperature exceeds 30 C, mixing was stopped and the granulation allowed to cool to 20-24 C. Once the granulation temperature reached 20-24 C, it was mixed for an additional 2 to 8 minutes and then dried. If necessary the granulation was milled to reduce particle size. Colloidal silicon dioxide, flavor and sodium methyl paraben were then added using a blender.
This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient m ml*
mycophenolate mofetil 200.0 xanthan gum 1.5 colloidal silicon dioxide 10.0 soy lecithin 2.0 aspartame 2.0 citric acid 0.5 sodium citrate 10.0 sodium methyl paraben 1.0 orange flavor 1.0 color (FD&C yellow #6) 0.1 (*concentration after constitution with water) This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient mcr/ml*
mycophenolate mofetil 200.0 xanthan gum 1.0 colloidal silicon dioxide 5.0 soy lecithin 1.0 sorbitol 550.0 aspartame 0.5 sodium methyl paraben 2.0 berry flavor 3.0 color (FD&C red #3 0.034 FD&C blue #1) 0.006 (*concentration after constitution with water) This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient mcr/ml*
mycophenolate mofetil 200.0 xanthan gum 1.5 colloidal silicon dioxide 10.0 soy lecithin 2.0 aspartame 2,0 sodium methyl paraben 2.3 mixed fruit flavor 2.0 color (FD&C red #3 0.008 FD&C yellow #6) 0.002 (*concentration after constitution with water) This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient m ml*
mycophenolate mofetil 200.0 xanthan gum 1.0 colloidal silicon dioxide 5.0 soy lecithin 1.0 sorbitol 550.0 aspartame 0.5 citric acid 0.5 sodium citrate 10.0 sodium methyl paraben 2.3 mixed fruit flavor 2.0 color (FD&C red #3 0.0062 FD&C yellow #6) 0.0015 (*concentration after constitution with water) By following the procedures of Examples 1-25 and substituting mycophenolate mofetil with mycophenolic acid, there are obtained the corresponding respective suspensions and dry granulations.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such WO 95/09626 211c~C~06 -27- PCT/US9~3/10926 ~+
modifications are intended to be within the scope of the claims appended hereto. All patents and publications cited above are hereby incorporated by reference.
The following tests are performed to evaluate the acceptability of formulations made in accordance with the present invention. The testing Zi V2506 procedures are known by those skilled in the art.
1. Ease of resuspendability of solid(s).
2. Appearance.
3. Chemical stability (percent label strength of drug substance).
4. %- Degradant(s) formed over time.
5. Viscosity.
6. Density.
7. Homogeneity of drug substance.
8. Particle size.
9. Antimicrobial efficacy (USP/BP test).
Criteria for acceptability include those set forth below.
Ease of resuspendability -- The suspension sediment should be loosely packed such that after minimal shaking the sediment redisperses and reforms the original suspension. From a practical standpoint, any sediment should redisperse within 10 seconds of minimal hand shaking.
Appearance -- In a freshly prepared suspension, all solids should be evenly and homogeneously dispersed in the liquid phase. Over time, sedimentation will occur; and ideally, the volume of sediment should encompass the volume of suspension. If the sediment volume is less than the volume of suspension, the supernatant which forms should be clear (indicating a flocculated system).
Chemical Stability -- The amount of drug substance must remain within 90 - 110%- of the intended labelled concentration.
%- Degradant(s) formed over time -- The formation of no more than 5%-degradant(s) over a period of 2 years is considered acceptable.
Viscosity -- The viscosity should be sufficiently high to hinder rapid sedimentation. However, too high a viscosity is not acceptable from a user's standpoint. An acceptable range is about 200 - 1000 centipoise, with a preferred range of 250 - 500 centipoise.
Density -- Ideally, the density of the vehicle will equal the density of the dispersed solids (drug substance); matching vehicle and drug densities will hinder sedimentation. An acceptable range for the formulations of the present invention is 1.10 - 1.25 g/mL.
Homogeneity -- After minimal hand shaking of the package containing suspension, the amount of drug substance present at the top, middle, and bottom of the packaged suspension, will be equivalent within 10t.
Particle Size -- Over time the mean particle size of the suspension will remain within 20* of the mean particle size of freshly prepared suspension.
Antimicrobial Efficacy -- The suspension will be tested for antimicrobial efficacy via the methods provided in the USP and BP. To be acceptable, the suspension must pass these tests according to the respective specifications.
The formulations of the invention are satisfactory when subjected to the foregoing tests. As will be apparent from the present specification to those skilled in the art, the selection of particular ingredients and their relative concentrations will modify the characteristics balances of the resulting formulations. For example, a 200 mg/mL of mycophenolate mofetil , can be suspended in Ora-Plus1m combined with Ora-SweetT"', but, the characteristics balance of the resulting formulation is unacceptably viscous and expected to have too much drug dissolved in the continuous aqueous phase giving rise to increased degradant formation and loss of chemical stability (given the pH of the vehicles, i.e., below 5.0, the lowest acceptable pH for mycophenolate mofetil in the present formulations).
Administration The formulations of the present invention are useful for oral administration in any oral treatment regimen for mycophenolate mofetil or mycophenolic acid. While human dosage levels have yet to be finalized, generally, a daily dose of mycophenolate mofetil or mycophenolic acid is from about 2.0 to 5.0 grams, preferably about 2.0 to 3.5 grams. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, a treatment regimen for administering 3.0 grams of mycophenolate mofetil per day, which previously entailed taking 12 capsules (250 mg) (e.g., six, twice daily), when administered with a formulation of the present invention entails taking one 7.5 mL dose (e.g., a spoonfull) twice daily. The formulations of the present invention are also particularly well suited to administration via gastric lavage.
Utility The formulations of the present invention are useful for the administration of mycophenolate mofetil or mycophenolic acid (the "compounds") as immunosuppressive agents, anti-inflammatory agents, anti-tumor agents, anti-proliferative agents, anti-viral agents and anti-psoriatic agents (as discussed in greater detail below) in mammals, whether domestic (cattle, pigs, sheep, goats, horses), pets (cats, dogs), or preferably humans. The compounds are inhibitors of inosine monophosphate dehydrogenase (IMPDH) and thus inhibit de novo purine synthesis; they have anti-proliferative effects (e.g., against smooth muscle cells and both B
and T lymphocytes) and inhibit antibody formation and the glycosylation of cell adhesion molecules in lymphocytes and endothelial cells.
As immunosuppressive agents, the compounds are useful in treating auto-immune related disorders, for example: Type I Diabetes Mellitus;
Inflammatory Bowel Disease (e.g., Crohn's Disease and Ulcerative Colitis);
Systemic Lupus Erythematosus; Chronic Active Hepatitis; Multiple Sclerosis;
Grave's Disease; Hashimoto's Thyroiditis; Behcet's Syndrome; Myasthenia Gravis; Sjogren's Syndrome; Pernicious Anemia; Idiopathic Adrenal ~ WO 95/09626 PCT/US94/10926 insufficiency; and Polyglandular Autoimmune Syndromes Type I and II.
The compounds are also useful as therapeutic immunosuppressive agents in the treatment of Asthma, Immunohemolytic Anemia, Glomerulonephritis, and Hepatitis. Preventative uses of the compounds as immunosuppressive agents include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, skin and corneal allografts, and prevention of Graft vs. Host Disease.
The compounds are useful for inhibiting proliferative responses to vascular injury, for example, stenosis following an insult to a blood vessel wall in post-angioplasty restenosis, and post-cardiac by-pass surgery restenosis.
The compounds are useful as anti-inflammatory agents, for example, in treating Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis and Uveitis.
As anti-tumor agents, the compounds are useful in treating solid tumors and malignancies of lymphoreticular origin. For example, the compounds' utility for treatment of solid tumors includes: cancers of the head and neck, including squamous cell carcinoma; lung cancer, including small cell and non-small cell lung carcinoma; mediastinal tumors;
esophageal cancer, including squamous cell carcinoma and adenocarcinoma;
pancreatic cancer; cancer of the hepatobiliary system, including hepatocellular carcinoma, cholangiocarcinoma, gall bladder carcinoma and biliary tract carcinoma; small intestinal carcinoma, including adenocarcinoma, sarcoma, lymphoma and carcinoids; colorectal cancer, including colon carcinoma and rectal carcinoma; metastatic carcinoma;
cancers of the genitourinary system, including ovarian cancer, uterine sarcoma, and renal cell, ureteral, bladder, prostate, urethral, penile, testicular, vulvar, vaginal, cervical, endometrial, and fallopian tube carcinoma; breast cancer; endocrine system cancer; soft tissue sarcomas;
malignant mesotheliomas; skin cancer, including squamous cell carcinoma, basal cell carcinoma and melanoma; cancer of the central nervous system;
malignant bone tumors; and plasma cell neoplasms.
As anti-tumor agents for the treatment of malignancies of lymphoreticular origin, the compounds are useful in treating, for example:
Lymphomas and Leukemias, including B, T and promonocyte cell line malignancies, Mycoses Fungoides, Non-Hodgkins Lymphoma, Malignancies of Burkitt Lymphoma Cells and other EBV-transformed B-lymphocytes, Lymphomas resulting from Epstein-Barr viral infections in allograft recipients, Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and Hairy Cell Leukemia.
As anti-viral agents, the compounds are useful in treating, for example: retroviruses, including Human T-leukemia Viruses, Types I and II
(HTLV-1 and HTLV-2), Human immuno Deficiency Viruses, Types I and II
(HIV-1, HIV-2) and, Human Nasopharyngeal Carcinoma Virus (NPCV) and in treating Herpes Viruses, including EBV infected B-lymphocytes, CMV
infection, Herpes Virus Type 6, Herpes Simplex, Types 1 and 2, (HSV-1, ~=~~ ~~ ~~ -HSV-2) and Herpes Zoster.
As anti-psoriatic agents, the compounds are useful in treating, for example, psoriasis and psoriatic arthritis.
EXAMPLES
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
These examples illustrate the preparation of high dose oral suspension formulations. In each Example, the formulation was manufactured by one of the following alternative methods:
A. 1. To heated water, hydroxypropylmethylcellulose was added and dispersed.
2. Microcrystalline cellulose was added to the dispersion of #1 and dispersed.
3. Xanthan gum was added to the mixture of #2 and dispersed.
4. The sweeteners, flavors, color dyes and lecithin were added individually to the mixture of #3 with mixing.
5. In a small separate aliquot of water, citric acid and sodium phosphate dibasic were dissolved, then added to the mixture of step 4, adjusting pH as indicated.
6. In a small separate aliquot of water (heated to 80 C), methyl paraben and propylparaben were dissolved, then added to the mixture of step 5.
7. Mycophenolate mofetil was added to the mixture of step 6 and mixed well to form a suspension suitable for oral administration.
B. 1. To heated water (70 - 75 C), sodium methyl paraben was dissolved with mixing.
2. Microcrystalline cellulose was added to the dispersion of #1 and dispersed.
3. The sorbitol solution was added and mixed to the dispersion of #2.
Xanthan gum was added to the mixture and dispersed. This was followed by addition of the maltitol solution with mixing.
4. In a separate vessel containing purified water, citric acid was added and dissolved, followed by the addition and dissolution of sodium phosphate dibasic, anhydrous. This was followed by the dissolution of sucrose and the addition and dispersion of soy lecithin. Mycophenolate mofetil was added and dispersed.
5. The dispersions of steps 3 and 4 were combined and mixed.
6. A stock solution of the dye was prepared. The dye and flavor were added to the dispersion of step 5, with mixing.
7. The dispersion of step 6 was brought to volume with purified water, as necessary.
Inaredient wt/vol !k Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 = Microcrystalline cellulose 0.25 Xarzthan gum 0.1 Sorbitol, 70%- solution 50 Sucrose 10 Lycasirn (maltitol syrup) 10 Lecithin 0.1 Methyl paraben 0.036 Propyl paraben 0.004 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.241 Sodium phosphate dibasic 0.547 pH 6 Purified water q.s. to 100 Inaredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70%- solution 50 Sucrose 10 Lycasin (maltitol syrup) 10 Lecithin 0.1 Methyl paraben 0.036 Propyl paraben 0.004 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0542 Sodium phosphate dibasic 0.673 pH 7 Purified water q.s. to 100 Incrredient wt/vol ~
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70W solution 50 Sucrose 10 Lycasin (maltitol syrup) 10 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0542 Sodium phosphate dibasic 0.673 pH 7 Purified water q.s. to 100 Inaredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.2 Microcrystalline cellulose 0.2 Xanthan gum 0.075 Sorbitol, 70t solution 50 Sucrose 10 Lycasin (maltitol syrup) 10 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0962 Sodium phosphate dibasic 0.219 pH 6 Purified water q.s. to 100 Ingredient wt/vol k Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70V solution 50 Sucrose 10 Lycasiri (maltitol syrup) 10 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.269 pH 7 Purified water q.s. to 100 inaredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.35 .15 Microcrystalline cellulose 0.3 Xanthan gum 0.125 Sorbitol, 70W solution 30 Sucrose 10 Lycasin (maltitol syrup) 30 Grape flavor 0.75 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.269 pH 7 Purified water q.s. to 100 Inaredient wt/vol W
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70%- solution 30 Sucrose 10 Lycasin (maltitol syrup) 30 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Magnasweet* 0.2 Color (red 28:blue 1, 90:10) 0.005 Buf f er Citric acid 0.142 Sodium phosphate dibasic 0.438 -pH 6 Purified water q.s. to 100 Incrredient wt/vol t Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 70t solution 30 Lycasiri (maltitol syrup) 10 Aspartame 0.5 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.269 pH 7 Purified water q.s. to 100 Inaredient wt/vol V
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 0.25 Microcrystalline cellulose 0.25 Xanthan gum 0.1 Sorbitol, 7015 solution 30 Sucrose 10 Lycasiri (maltitol syrup) 30 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.136 Sodium phosphate dibasic 0.192 pH 5 Purified water q.s. to 100 inaredient wt/vol ~
Mycophenolate mofetil 20 Hydroxypropylmethylcellulose 1 (,.e,5tJ6 -21-Microczystalline cellulose 0.25 Sorbitol, 70%~ solution 50 Sucrose 10 Lycasiri (maltitol syrup) 10 Lecithin 0.1 Grape flavor 1.0 Anise flavor 0.01 Magnasweet' 1 Color (red 28:blue 1, 90:10) 0.005 Buffer Citric acid 0.0217 Sodium phosphate dibasic 0.192 pH 7 Purified water q.s. to 100 Inaredient wt/vol ~
Mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 Sorbitol, 70%- solution 50 Sucrose 10 Lycasiri (maltitol syrup) 10 soy Lecithin 0.1 citric acid 0.06 sodium phosphate dibasic (pH 7) 0.7 methyl paraben 0.04 - 0.1 flavor <0.3 Color (to complement the flavor) 0.005 Purified water q.s. to 100 This example illustrates the preparation of a dry granulation of the invention.
Ingredient mg mycophenolate mofetil 3,000 sodium carboxymethylcellulose 300 sorbitol, powder 3,000 xylitol 2,000 maltitol 2,000 pluronic F68 60 mint 150 FD&C green 3 0.1 The above ingredients are combined and blended to a homogeneous mixture, with the addition of adequate purified water to give a desired granule size. The mixture is granulated and then dried to give a dry granulation suitable for use as a pharmaceutical formulation by the addition of 15mL purified water followed by shaking to form a suspension having 3.0 grams of mycophenolate mofetil in 15 mL.
This example illustrates a dry granulation of the invention.
Ingredient mQ
mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 mannitol 4,000 aspartame 35 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention.
Ingredient mQ
mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 sorbitol, powder 10,000 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention.
Inaredient mcr mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 mannitol 4,000 aspartame 35 potassium sorbate 5 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention.
-Ingredient mg mycophenolate mofetil 3,000 xanthan gum 15 colloidal silicon dioxide 75 soy lecithin 15 sorbitol 8,250 aspartame 7.5 sodium methyl paraben 30 berry flavor 45 color (FD&C red #3 0.45 FD&C blue #1 0.09 in a container marked to be filled with purified water to a final predetermined volume of 15 mL.
Ingredient ma mycophenolate mofetil 3,000 xanthan gum 15 colloidal silicon dioxide 75 soy lecithin 15 sorbitol 4,500 aspartame 15 citric acid 67.5 sodium citrate 150 sodium methyl paraben 30 berry flavor 45 color (FD&C red #3 0.45 FD&C blue #1 0.09 in a container marked to be filled with purified water to a final predetermined volume of 15 mL.
Ingredient mg mycophenolate mofetil 3,000 xanthan gum 15 colloidal silicon dioxide 75 soy lecithin 15 sorbitol 8,250 aspartame 7.5 citric acid 7.5 sodium citrate 150 sodium methyl paraben 34.5 mixed fruit flavor 30 color (FD&C red #3 0.093 FD&C yellow #6) 0.0225 in a container marked to be filled with purified water to a final predetermined volume of 15 mL.
Ingredient mQ
mycophenolate mofetil 2,000 sodium carboxymethylcellulose 200 =
mannitol 4,000 aspartame 35 potassium sorbate 5 pluronic F68 40 cherry 100 FD&C red 40 0.1 FD&C blue 1 0.01 This example illustrates a dry granulation of the invention, provided as in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Incrredient mQ
mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 mannitol 180,000 aspartame 1,575 pluronic F68 1,800 potassium sorbate 225 cherry 4,500 color (red 40:blue 1, 90:10) 4.5 This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient m ml*
mycophenolate mofetil 200.0 xanthan gum 1.0 colloidal silicon dioxide 5.0 soy lecithin 1.0 sorbitol 300.0 aspartame 1.0 citric acid 0.5 sodium citrate 10.0 sodium methyl paraben 2.0 berry flavor 3.0 color (FD&C red #3 0.034 FD&C blue #1) 0.006 (*concentration after constitution with water) To prepare the dry granulation mycophenolate mofetil, sorbitol, aspartame, soy lecithin, and xanthan gum were combined in a mixer for 5 minutes. The dye was dissolved with sodium citrate, and citric acid in purified water at approximately 45-55 C. The solution was then cooled to room temperature. This dye/buffer solution was added to the mycophenolate mofetil mixture in a cooled mixer bowl at a rate of approximately 60 mi/min with mixing. In the granulation temperature exceeds 30 C, mixing was stopped and the granulation allowed to cool to 20-24 C. Once the granulation temperature reached 20-24 C, it was mixed for an additional 2 to 8 minutes and then dried. If necessary the granulation was milled to reduce particle size. Colloidal silicon dioxide, flavor and sodium methyl paraben were then added using a blender.
This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient m ml*
mycophenolate mofetil 200.0 xanthan gum 1.5 colloidal silicon dioxide 10.0 soy lecithin 2.0 aspartame 2.0 citric acid 0.5 sodium citrate 10.0 sodium methyl paraben 1.0 orange flavor 1.0 color (FD&C yellow #6) 0.1 (*concentration after constitution with water) This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient mcr/ml*
mycophenolate mofetil 200.0 xanthan gum 1.0 colloidal silicon dioxide 5.0 soy lecithin 1.0 sorbitol 550.0 aspartame 0.5 sodium methyl paraben 2.0 berry flavor 3.0 color (FD&C red #3 0.034 FD&C blue #1) 0.006 (*concentration after constitution with water) This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient mcr/ml*
mycophenolate mofetil 200.0 xanthan gum 1.5 colloidal silicon dioxide 10.0 soy lecithin 2.0 aspartame 2,0 sodium methyl paraben 2.3 mixed fruit flavor 2.0 color (FD&C red #3 0.008 FD&C yellow #6) 0.002 (*concentration after constitution with water) This example illustrates the preparation of a dry granulation formulation of the invention.
Ingredient m ml*
mycophenolate mofetil 200.0 xanthan gum 1.0 colloidal silicon dioxide 5.0 soy lecithin 1.0 sorbitol 550.0 aspartame 0.5 citric acid 0.5 sodium citrate 10.0 sodium methyl paraben 2.3 mixed fruit flavor 2.0 color (FD&C red #3 0.0062 FD&C yellow #6) 0.0015 (*concentration after constitution with water) By following the procedures of Examples 1-25 and substituting mycophenolate mofetil with mycophenolic acid, there are obtained the corresponding respective suspensions and dry granulations.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such WO 95/09626 211c~C~06 -27- PCT/US9~3/10926 ~+
modifications are intended to be within the scope of the claims appended hereto. All patents and publications cited above are hereby incorporated by reference.
Claims (24)
1. A pharmaceutical formulation comprising:
Ingredient ~~~~% wt/vol mycophenolate mofetil or mycophenolic acid ~~~7.5 - 30.0 suspending/viscosity agent ~0.1 - 3.0 wetting agent ~~~~0 - 0.5 sweeteners ~~~~30.0 - 70.0 flavor ~~~~~0.1 - 2.0 flavor enhancer/bitter maskant 0 -1.0 buffer to pH 5.0 - 7.0 ~~0.5-1.5 antimicrobial agent ~~0 - 1.0 color ~~~~~0 - 0.01 purified water ~~~q.s. to 100 as a liquid suspension suitable for oral administration.
Ingredient ~~~~% wt/vol mycophenolate mofetil or mycophenolic acid ~~~7.5 - 30.0 suspending/viscosity agent ~0.1 - 3.0 wetting agent ~~~~0 - 0.5 sweeteners ~~~~30.0 - 70.0 flavor ~~~~~0.1 - 2.0 flavor enhancer/bitter maskant 0 -1.0 buffer to pH 5.0 - 7.0 ~~0.5-1.5 antimicrobial agent ~~0 - 1.0 color ~~~~~0 - 0.01 purified water ~~~q.s. to 100 as a liquid suspension suitable for oral administration.
2. The pharmaceutical formulation of Claim 1 having:
Ingredient ~~~~% wt/vol mycophenolate mofetil ~~20 hydroxypropylmethylcellulose ~0.25 microcrystalline cellulose ~0.25 xanthan gum ~~~~0.1 sorbitol, 70% solution ~~30 - 50 Lycasin (maltitol syrup) ~10 - 30 sucrose ~~~~~0 - 10 fructose ~~~~~0 - 10 aspartame ~~~~0 - 0.5 lecithin ~~~~~0 - 0.1 citric acid ~~~~0.02 - 0.25 sodium phosphate dibasic ~0.19 - 0.67 methyl paraben ~~~0 - 0.18 propyl paraben ~~~0 - 0.02 flavor ~~~~~0.3 -1.0 Magnasweet ~~~~0 - 1 color ~~~~~0.005 purified water ~~~q.s. to 100 as a liquid suspension suitable for oral administration.
Ingredient ~~~~% wt/vol mycophenolate mofetil ~~20 hydroxypropylmethylcellulose ~0.25 microcrystalline cellulose ~0.25 xanthan gum ~~~~0.1 sorbitol, 70% solution ~~30 - 50 Lycasin (maltitol syrup) ~10 - 30 sucrose ~~~~~0 - 10 fructose ~~~~~0 - 10 aspartame ~~~~0 - 0.5 lecithin ~~~~~0 - 0.1 citric acid ~~~~0.02 - 0.25 sodium phosphate dibasic ~0.19 - 0.67 methyl paraben ~~~0 - 0.18 propyl paraben ~~~0 - 0.02 flavor ~~~~~0.3 -1.0 Magnasweet ~~~~0 - 1 color ~~~~~0.005 purified water ~~~q.s. to 100 as a liquid suspension suitable for oral administration.
3. A pharmaceutical formulation of Claim 1 having 20 % wt/vol mycophenolate mofetil.
4. The pharmaceutical formulation of Claim 1 having:
Ingredient % wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70% solution 30 - 50 Lycasin (maltitol syrup) 10 - 30 sucrose 0 -10 fructose 0 -10 aspartame 0 - 0.5 lecithin 0 - 0 5 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.8 sodium methyl paraben 0- 0.18 propyl paraben 0 - 0.02 flavor 0.1 - 1.0 Magnasweet 0-1 color 0.005 purified water q.s. to 100 as a liquid suspension suitable for oral administration.
Ingredient % wt/vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70% solution 30 - 50 Lycasin (maltitol syrup) 10 - 30 sucrose 0 -10 fructose 0 -10 aspartame 0 - 0.5 lecithin 0 - 0 5 citric acid 0.02 - 0.25 sodium phosphate dibasic 0.19 - 0.8 sodium methyl paraben 0- 0.18 propyl paraben 0 - 0.02 flavor 0.1 - 1.0 Magnasweet 0-1 color 0.005 purified water q.s. to 100 as a liquid suspension suitable for oral administration.
5. The pharmaceutical formulation of Claim 4 having:
Ingredient % wt vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70% solution 50 Lycasin (maltitol syrup) 10 sucrose 10 soy lecithin 0.1 citric acid 0.06 sodium phosphate dibasic 0.7 sodium methyl paraben 0.04 flavor <0.3 color 0.005 purified water q.s. to 100 as a liquid suspension suitable for oral administration.
Ingredient % wt vol mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70% solution 50 Lycasin (maltitol syrup) 10 sucrose 10 soy lecithin 0.1 citric acid 0.06 sodium phosphate dibasic 0.7 sodium methyl paraben 0.04 flavor <0.3 color 0.005 purified water q.s. to 100 as a liquid suspension suitable for oral administration.
6. A pharmaceutical formulation comprising:
Ingredient mg/mL
mycophenolate mofetil or mycophenolic acid 75 - 300 suspending/viscosity agent 1 - 30 wetting agent 0 - 10 sweeteners 1- 1200 flavor 0.1-100 flavor enhancer/bitter maskant 0 - 50 antimicrobial agent 0 -10 color 0-2 as a dry granulation suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water.
Ingredient mg/mL
mycophenolate mofetil or mycophenolic acid 75 - 300 suspending/viscosity agent 1 - 30 wetting agent 0 - 10 sweeteners 1- 1200 flavor 0.1-100 flavor enhancer/bitter maskant 0 - 50 antimicrobial agent 0 -10 color 0-2 as a dry granulation suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water.
7. A pharmaceutical formulation of Claim 6 having 200 mg/mL mycophenolate mofetil.
8. A pharmaceutical formulation of Claim 6, having:
Ingredient mg/ mL
mycophenolate mofetil 200 sodium carboxymethylcellulose 20 mannitol 400 aspartame 3.5 pluronic F68 4 potassium sorbate 0.5 cherry 10 color (red 40:blue 1, 90:10) 0.01 as a dry granulation suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water.
Ingredient mg/ mL
mycophenolate mofetil 200 sodium carboxymethylcellulose 20 mannitol 400 aspartame 3.5 pluronic F68 4 potassium sorbate 0.5 cherry 10 color (red 40:blue 1, 90:10) 0.01 as a dry granulation suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water.
9. A pharmaceutical formulation of Claim 6, having:
Ingredient mg/mL
mycophenolate mofetil 200 xanthan gum 1-1.5 colloidal silicon dioxide 5 -10 sorbitol 0 - 550 aspartame 0 - 3.0 soy lecithin 1-2 sodium methyl paraben 0.5 - 2.5 flavor 1-3 color (to complement the flavor) 1-3 as a dry granulation suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water.
Ingredient mg/mL
mycophenolate mofetil 200 xanthan gum 1-1.5 colloidal silicon dioxide 5 -10 sorbitol 0 - 550 aspartame 0 - 3.0 soy lecithin 1-2 sodium methyl paraben 0.5 - 2.5 flavor 1-3 color (to complement the flavor) 1-3 as a dry granulation suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water.
10. A pharmaceutical formulation of Claim 6, comprising:
Ingredient mg mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 mannitol 180,000 aspartame 1,575 pluronic F68 1,800 potassium sorbate 225 cherry 4,500 color (red 28:blue 1, 90:10) 4.5 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient mg mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 mannitol 180,000 aspartame 1,575 pluronic F68 1,800 potassium sorbate 225 cherry 4,500 color (red 28:blue 1, 90:10) 4.5 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
11. A pharmaceutical formulation of Claim 6, comprising:
Ingredient mg mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 sodium methyl paraben 900 berry flavor 1,350 color (FD&C red #3 13.5 FD&C blue -1) ~~~2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient mg mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 sodium methyl paraben 900 berry flavor 1,350 color (FD&C red #3 13.5 FD&C blue -1) ~~~2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
12. A pharmaceutical formulation of Claim 6, comprising:
Ingredient~~~~mg mycophenolate mofetil ~~90,000 xanthan gum ~~~450 colloidal silicon dioxide ~~2,250 soy lecithin ~~~~450 sorbitol ~~~~135,000 aspartame ~~~~450 citric acid ~~~~225 sodium citrate ~~~4,500 sodium methyl paraben ~~900 berry flavor ~~~~1,350 color (FD&C red #3 ~~~13.5 FD&C blue #1) ~~~2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient~~~~mg mycophenolate mofetil ~~90,000 xanthan gum ~~~450 colloidal silicon dioxide ~~2,250 soy lecithin ~~~~450 sorbitol ~~~~135,000 aspartame ~~~~450 citric acid ~~~~225 sodium citrate ~~~4,500 sodium methyl paraben ~~900 berry flavor ~~~~1,350 color (FD&C red #3 ~~~13.5 FD&C blue #1) ~~~2.7 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
13. A pharmaceutical formulation of Claim 6, comprising:
Ingredient ~~~~mg mycophenolate mofetil ~~90,000 xanthan gum ~~~675 colloidal silicon dioxide ~~4,500 soy lecithin ~~~~900 aspartame ~~~~900 sodium methyl paraben ~~1,035 mixed fruit flavor ~~~900 color (FD&C red #3 ~~~3.6 FD&C yellow #6) ~~~0.9 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient ~~~~mg mycophenolate mofetil ~~90,000 xanthan gum ~~~675 colloidal silicon dioxide ~~4,500 soy lecithin ~~~~900 aspartame ~~~~900 sodium methyl paraben ~~1,035 mixed fruit flavor ~~~900 color (FD&C red #3 ~~~3.6 FD&C yellow #6) ~~~0.9 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
14. A pharmaceutical formulation of Claim 6, comprising:
Ingredient ~~~~mg mycopholate mofetil ~~90,000 xanthan gum ~~~~~450 colloidal silicon dioxide ~~2,250 soy lecithin ~~~~~450 sorbitol ~~~~~~247,500 aspartame ~~~~~225 citric acid ~~~~~225 sodium citrate ~~~~4,500 sodium methyl paraben ~~~1,035 mixed fruit flavor ~~~~900 color (FD&C red #3 ~~~~2.79 FD&C yellow #6) ~~~~0.675 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient ~~~~mg mycopholate mofetil ~~90,000 xanthan gum ~~~~~450 colloidal silicon dioxide ~~2,250 soy lecithin ~~~~~450 sorbitol ~~~~~~247,500 aspartame ~~~~~225 citric acid ~~~~~225 sodium citrate ~~~~4,500 sodium methyl paraben ~~~1,035 mixed fruit flavor ~~~~900 color (FD&C red #3 ~~~~2.79 FD&C yellow #6) ~~~~0.675 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
15. A pharmaceutical formulation of Claim 6, comprising:
Ingredient ~~~~~mg mycophenolate mofetil ~~~90,000 xanthan gum ~~~~~675 colloidal silicon dioxide ~~4,500 soy lecithin~~~~~900 aspartame~~~~~~900 citric acid~~~~~225 sodium citrate ~~~~4,500 sodium methylparaben ~~~450 orange flavor ~~~~~450 color (FD&C yellow #6) ~~~45 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
Ingredient ~~~~~mg mycophenolate mofetil ~~~90,000 xanthan gum ~~~~~675 colloidal silicon dioxide ~~4,500 soy lecithin~~~~~900 aspartame~~~~~~900 citric acid~~~~~225 sodium citrate ~~~~4,500 sodium methylparaben ~~~450 orange flavor ~~~~~450 color (FD&C yellow #6) ~~~45 in a container marked to be filled with purified water to a final predetermined volume of 450 mL.
16. The pharmaceutical formulation of Claim 6 provided in a container marked to be filled with purified water to a final predetermined volume.
17. A pharmaceutical formulation consisting essentially of:
Ingredient ~~~~~% wt/vol mycophenolate mofetil ~~~20 hydroxypropyl methylcellulose ~0.25 microcrystalline cellulose ~~0.25 xanthan gum ~~~~~0.1 sorbitol solution ~~~50 sucrose ~~~~~10 Lycasin ~~~~~10 lecithin ~~~~0.1 methyl paraben ~~~0.036 propyl paraben ~~~0.004 grape ~~~~~1.0 anise ~~~~~0.01 color (red 28: blue 1, 90:10) 0.005 citric acid ~~~~0.0542 sodium phosphate dibasic ~0.673 purified water ~~~q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
Ingredient ~~~~~% wt/vol mycophenolate mofetil ~~~20 hydroxypropyl methylcellulose ~0.25 microcrystalline cellulose ~~0.25 xanthan gum ~~~~~0.1 sorbitol solution ~~~50 sucrose ~~~~~10 Lycasin ~~~~~10 lecithin ~~~~0.1 methyl paraben ~~~0.036 propyl paraben ~~~0.004 grape ~~~~~1.0 anise ~~~~~0.01 color (red 28: blue 1, 90:10) 0.005 citric acid ~~~~0.0542 sodium phosphate dibasic ~0.673 purified water ~~~q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
18. A pharmaceutical formulation consisting essentially of:
Ingredient ~~~~% wt/vol mycophenolate mofetil ~~20 microcrystalline cellulose ~0.2 xanthan gum ~~~~0.1 sorbitol solution ~~~50 Lycasin ~~~~~10 sucrose ~~~~~10 lecithin ~~~~~0.1 citric acid ~~~~0.06 sodium phosphate dibasic ~0.7 sodium methyl paraben ~~0.04 flavor ~~~~~<0.3 color (to complement the flavor) 0.005 purified water ~~~q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
Ingredient ~~~~% wt/vol mycophenolate mofetil ~~20 microcrystalline cellulose ~0.2 xanthan gum ~~~~0.1 sorbitol solution ~~~50 Lycasin ~~~~~10 sucrose ~~~~~10 lecithin ~~~~~0.1 citric acid ~~~~0.06 sodium phosphate dibasic ~0.7 sodium methyl paraben ~~0.04 flavor ~~~~~<0.3 color (to complement the flavor) 0.005 purified water ~~~q.s. to 100 adjusted to a pH of 7, as a liquid suspension suitable for oral administration.
19. A process for the preparation of a pharmaceutical formulation of Claim 1 comprising:
a. adding and dispersing the antimicrobial agent to heated water at about 70°C, followed by adding the suspending and/or viscosity agents microcrystalline cellulose, followed by xanthan gum;
b. dissolving, with mixing, the buffer(s) citric acid, followed by sodium phosphate dibasic, followed by adding the sweetener(s), wetting agent(s), dye(s), flavor enhancer(s), and flavor(s); and c. a dding the acti.ve compound (mycophenolate mofetil or mycophenolic acid) to the mixtLn o from step b; followed by mixing the liquid well to form a suspension.
a. adding and dispersing the antimicrobial agent to heated water at about 70°C, followed by adding the suspending and/or viscosity agents microcrystalline cellulose, followed by xanthan gum;
b. dissolving, with mixing, the buffer(s) citric acid, followed by sodium phosphate dibasic, followed by adding the sweetener(s), wetting agent(s), dye(s), flavor enhancer(s), and flavor(s); and c. a dding the acti.ve compound (mycophenolate mofetil or mycophenolic acid) to the mixtLn o from step b; followed by mixing the liquid well to form a suspension.
20. A process according to claim 19 wherein the suspending and/or viscosity agents are added in the order of microcrystalline cellulose, followed by xanthan gum.
21. A process according to claim 19 wherein the buffer(s) are citric acid, followed by sodium phosphate dibasic.
22. A proccss for the preparation of a dry granulation of Claim 6 comprising:
a. coni!iining mycophenolate mofetil, sweetener(s), wetting agent (6), and suspending and/or viscosity increasing agent (6) in a mixer;
b. dissolving the dye(s) and buffer (8) in water;
c. combining the solution of step (b) to the mixer bowl of step (a) and mixing until a desirvd granulation size is obtained;
d. drving the granulation then milling to reduce particle size; e. adding the suspending; and/or viscosity increasing agent(s), flavor(s) and antimicrobial agent(s) to the granwiation of step (d) using a blender.
a. coni!iining mycophenolate mofetil, sweetener(s), wetting agent (6), and suspending and/or viscosity increasing agent (6) in a mixer;
b. dissolving the dye(s) and buffer (8) in water;
c. combining the solution of step (b) to the mixer bowl of step (a) and mixing until a desirvd granulation size is obtained;
d. drving the granulation then milling to reduce particle size; e. adding the suspending; and/or viscosity increasing agent(s), flavor(s) and antimicrobial agent(s) to the granwiation of step (d) using a blender.
23. Use of formulation of Claim 1 for the treatment of immunosuppressive diseases, inflammatory diseases, tumors, proliferative diseases, viral diseases and psoriatic diseases.
24. Use of a dry granulation of Claim 6 for the preparation of a pharmaceutical formulation for the treatment of immunosuppressive diseases, inflammatory diseases, tumors, proliferative diseases, viral diseases and psoriatic diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13034393A | 1993-10-01 | 1993-10-01 | |
| US08/130,343 | 1993-10-01 | ||
| PCT/US1994/010926 WO1995009626A1 (en) | 1993-10-01 | 1994-09-27 | Mycophenolate mofetil high dose oral suspensions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2172506A1 CA2172506A1 (en) | 1995-04-13 |
| CA2172506C true CA2172506C (en) | 2007-07-17 |
Family
ID=36809071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002172506A Expired - Lifetime CA2172506C (en) | 1993-10-01 | 1994-09-27 | Mycophenolate mofetil and mycophenolic acid high dose oral suspensions |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2172506C (en) |
| SI (1) | SI9420057B (en) |
-
1994
- 1994-09-27 SI SI9420057A patent/SI9420057B/en active Search and Examination
- 1994-09-27 CA CA002172506A patent/CA2172506C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| SI9420057B (en) | 2006-04-30 |
| SI9420057A (en) | 1996-10-31 |
| CA2172506A1 (en) | 1995-04-13 |
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