AU2001229775A1 - Low dose entecavir formulation and use - Google Patents
Low dose entecavir formulation and useInfo
- Publication number
- AU2001229775A1 AU2001229775A1 AU2001229775A AU2977501A AU2001229775A1 AU 2001229775 A1 AU2001229775 A1 AU 2001229775A1 AU 2001229775 A AU2001229775 A AU 2001229775A AU 2977501 A AU2977501 A AU 2977501A AU 2001229775 A1 AU2001229775 A1 AU 2001229775A1
- Authority
- AU
- Australia
- Prior art keywords
- entecavir
- composition
- weight
- carrier substrate
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
Description
Low Dose Entecavir Formulation And Use
Entecavir, [IS- (lα, 3α, 4β) }-2-amino-l, 9-dihydro-9- [4- hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] -6H- purin-6-one
is an antiviral agent currently undergoing clinical evaluation for the treatment of hepatitis B virus infection .
Entecavir and its use in treating hepatitis B are disclosed by Zahler et al. in U.S. Patent 5,206,244.
This patent discloses that an effective antiviral dose for oral or parenteral administration will likely be in the range of about 1.0 to 50 mg/kg of body weight and that the desired dose may be administered several times daily at appropriate intervals.
Improved methods for the synthesis of entecavir are disclosed by Bisacchi et al . in WO 98/09964.
This invention is directed to pharmaceutical compositions containing a low dose of entecavir and the use of such low dose composition to safely and effectively treat hepatitis B virus infection.
This invention is also directed to pharmaceutical compositions ■ for oral administration containing low doses of a pharmaceutically active substance. This result is achieved by adhering particles of the pharmaceutically active substance to the surface of a carrier substrate. The process of depositing the active substance on the carrier substrate is controlled to minimize the agglomeration of the active substance/carrier substrate particles .
This invention is directed to pharmaceutical compositions containing a low dose of from about 0.001 mg to about 25 mg of the active antiviral agent entecavir for once daily administration to treat hepatitis B virus infection in an adult human patient. Preferred pharmaceutical compositions contain from about 0.01 mg to about 10 mg of entecavir and most preferred pharmaceutical compositions contain from about 0.01 to about 5 mg of entecavir. Such preferred and most preferred pharmaceutical compositions are also administered once daily to treat hepatitis B virus infection in an adult patient.
The term adult human patient is defined as a patient of about 16 years or more of age and a weight equal to or greater than about 50 kilograms. Pharmaceutical compositions containing entecavir at the lower end of the above ranges are suitable for administration to pediatric
patients or adult patients weighing less than about 50 kilograms .
The low dose entecavir pharmaceutical compositions described above for daily administration may also be administered to certain patients less often. For example, patients who have been treated by daily administration of the low dose entecavir pharmaceutical compositions so that their hepatitis B virus infection is now under control may be placed on a maintenance regimen to protect against further infection. Such maintenance therapy may involve the administration of the low dose entecavir composition on a less than daily basis. For example, a single dose administered every three or four days or administered on a weekly basis may be sufficient. The low dose entecavir pharmaceutical compositions of this invention can be formulated for administration by any suitable means. For example, compositions for oral administration, which are preferred, can be in the form of tablets, capsules, granules or powders or in the form of elixirs, solutions or suspensions. The low dose entecavir pharmaceutical compositions may also be formulated for parenteral, rectal, transdermal or nasal administration according to methods well known m the art. Such formulations can include pharmaceutically acceptable excipients including bulking agents, lubricants, dismtegrants, binding agents, etc. as commonly employed in such compositions. Sustained release formulations are also within the scope of this invention . Surprisingly, it has been found that once daily administration of the low dose entecavir pharmaceutical compositions of this invention are effective in treating hepatitis B virus infection without undesirable side effects that can result from administration of the high dose regimen described in U.S. Patent 5,206,244.
This invention is also directed to the treatment of hepatitis B virus infection with low dose entecavir compositions as described above in combination with one or more other pharmaceutically active agents. Suitable pharmaceutically active agents for this purpose include one or more antiviral agents, for example, didanosine, lamivudine, abacavir, adefovir, adefovir dipivoxil, famciclovir, (2R, 4R) -4- (2, 6-diamino-9H-purin-9-yl ) -2- hydroxymethyl-1, 3-dioxolane (DAPD), hepatitis B immunomodulating proteins (EHT 899 from Enzo Biochem) , emtricitabine, 1- (2-deoxy-2-fluoro-β-D- arabinofuranosyl) thymine (FMAU) , GLQ-223 (Compound A, alpha-trichosanthin) , epavudine (L-dT) , epcitabine (L- dC) , ribavirin, tenofovir (PMPA), 2 ' , 3 ' -dideoxy-2 ' , 3 ' - didehydro-beta-L (-) -5-fluorocytidine [L
(-)Fd4C], as well as other fluoro L- and D- nucleosides. Suitable pharmaceutically active agents for this purpose also include one or more immunomodulators, for example, alpha interferon, beta interferon, pegylated interferon, thymosin alpha, and hepatitis B vaccines such as HBV/MF59, Hepagene and Theradigm-HBV.
When the other pharmaceutically active agent or agents are suitable for oral administration, they can be combined with the low dose of entecavir into a single tablet or capsule. If the other pharmaceutically active agent or agents are not compatable with entecavir for co- administration from a single dosage form, for example, if the mode of administration is different or if the frequency of administration is different, then the otner pharmaceutically active agent or agents will be administered separately. The amount of the other agent or agents administered is that conventionally employed in mono therapy or a reduced amount as determined by the treating physician. The separate dose forms can be
administered at the same time or sequentially according to a prescribed schedule.
This invention also includes the treatment of co- mfected patients with the low dose entecavir compositions described above. A co-infected patient is one infected with other viral or non-viral diseases in addition to hepatitis B. In particular, such treatment is possible for hepatitis B patients co-infected with hepatitis C or HIV. Such co-mfected patients are preferably treated with the low dose entecavir compositions as described above m combination with one or more other pharmaceutically active agents as described above. For example, a patient co-mfected with hepatitis B and hepatitis C can be treated with the low dose entecavir composition in addition to being treated with a regimen of ribavinn and an interferon.
Another aspect of this invention is the preparation of pharmaceutical compositions, particularly tablets and capsules, containing entecavir in an amount of less than or equal to about 10 mg . Such compositions cannot be prepared with good content uniformity by simply mixing the active substance and the excipients. The traditional methods of granulation are also not suitable for products active at such low doses. Tablet and capsule formulations containing from about 0.001 mg to about 10 mg of entecavir are prepared according to the following procedures that ensure high potency and good uniformity of the product. The compositions are prepared by first carefully depositing the entecavir on the surface of carrier substrate particles. This step is accomplished by forming a solution of the entecavir in a solvent along with an adhesive substance at temperatures ranging from about 25°C to about 80°C and applying the solution as a spray or a stream while the carrier substrate particles are in
motion. The conditions are controlled to minimize particle agglomeration. Subsequently, the solvent is removed from the carrier surface leaving the entecavir particles adhered to the surface of the carrier substrate. This prevents the separation of the entecavir from the substrate and minimizes the loss of entecavir during subsequent processing.
Following drying, the entecavir coated carrier substrate particles are mixed with any other ingredients to be included in the composition such as a disintegrant and/or lubricant. The resulting powder is then compressed into tablets or filled into capsules.
The carrier substrate particles are kept in motion during the spraying step by means of mechanical or air stream agitation. In the mechanical agitation procedure, the carrier substrate is placed in a mechanical (high shear) mixer and agitated. A solution containing the entecavir and adhesive substance maintained at a temperature of from about 25°C to about 80°C is sprayed onto the carrier substrate particles at a controlled rate and atomizing pressure (0 to 2 bar) . To maximize the amount of entecavir deposited on the carrier, the position of the spray assembly is adjusted to make certain that the spray pattern only encompasses the carrier. The rate of deposition and the spray pattern are controlled to minimize particle agglomeration. Once the entecavir containing solution is deposited, the wet entecavir/carrier substrate particles are transferred to a drier, either a tray drier or fluidbed drier is suitable. The solvent is removed at an elevated temperature. When the solvent is water or pH adjusted water, a temperature of from about 50° to about 80°C is suitable .
In the air stream agitation procedure, tne carrier substrate is placed in a bowl with a fine mesh screen at the bottom. The incoming air stream is adjusted so that the substrate particle motion is constant and fluid. The carrier material is equilibrated to a temperature of from about 25°C to about 80°C. A solution containing the entecavir and adhesive substance maintained at a temperature of from about 25°C to about 80°C is sprayed onto the carrier substrate particles at a controlled rate and atomizing pressure as described above. Again, the position of the spray assembly is adjusted to make certain that the spray pattern only encompasses the carrier and the rate of deposition is controlled to minimize particle agglomeration. Once the entecavir solution is deposited, the temperature is elevated to remove the solvent. When the solvent is water or pH adjusted water, a temperature of from about 50°C to about 80°C is suitable. In the air stream agitation procedure, both the deposition of the entecavir onto the carrier substrate and the removal of the solvent are carried out in a single unit whereas the mechanical agitation procedure requires a two-unit operation.
The above procedures have the additional advantage of reducing exposure of the manufacturing personnel to entecavir in the atmosphere of the facility.
While the above procedures are described for preparing pharmaceutical compositions containing from about 0.005 mg to about 10 mg of entecavir, they can also be employed to prepare pharmaceutical compositions containing low doses of any soluble pharmaceutically active substance.
Preferred solvents in the above procedures are water and pH adjusted water. The solubility of entecavir in water can be increased by lowering the pH of water by the
addition of an acid such as hydrochloric acid or by raising the pH of water by the addition of a base such as ammonium hydroxide.
The adhesive substance is preferably a polymeric material possessing a high degree of tackiness. Suitable materials include povidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, and xanthan gum and mixtures thereof with povidone being preferred. The adhesive substance is preferably present in the final composition at from about 0.01% to about 10% by weight of the total composition.
The carrier substrate is a pharmaceutically acceptable substance that can be readily spray coated and yet will not easily agglomerate. Suitable materials include lactose, microcrystalline cellulose, calcium phosphate, dextrin, dextrose, dextrates, mannitol, sorbitol, and sucrose and mixtures thereof with lactose and microcrystalline cellulose and mixtures thereof being preferred. The carrier substrate is preferably present in the final composition at from about 80% to about 95% by weight of the total composition.
A disintegrant is preferably included in the final composition at from about 1% to about 7% by weight of the total composition. Suitable disintegrants include crospovidone, croscarmellose, sodium starch glycolate, pregelatinized starch, and corn starch and mixtures thereof with crospovidone being preferred.
A lubricant is preferably included in the final composition at from about 0.1% to about 5% by weight of the total composition. Suitable lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium lauryl sulfate with magnesium stearate being preferred.
The resulting tablet or capsule can be film coated for ease of administration. Suitable materials for use in the film coating are polymeric coating agents, pigments, plasticizers , solubilizing agents, etc. Suitable coating agents include hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc. Polyethylene glycol can be included in the film coating composition as a plasticizer. Additional plasticizers such as diethyl citrate and trietyl citrate may also be included in the film coating composition. Suitable solubilizing agents include polyoxyethylene sorbitan fatty acid esters particularly polysorbate 80. Suitable pigments include titanium dioxide and various iron oxides.
The ingredients of the coating compositions are dispersed in a suitable solvent, preferably water. The coating composition can be applied to the tablets or capsules using conventional pan coating or spray coating techniques.
The following examples describe low dose entecavir compositions within the scope of this invention.
Example 1
Employing the above procedures a tablet of 0.5 milligram strength entecavir was prepared.
removed by drying
Example 2
Employing the above procedures a tablet of 0.1 milligram strength entecavir was prepared.
'removed by drying
Example 3
Employing the above procedures a tablet of 0.01 milligram strength entecavir was prepared.
removed by drying
Example 4
Employing the above procedures a 10 milligram strength entecavir capsule was prepared.
Capsule shell
*removed by drying
Example 5
Employing the above procedures a 0.05 milligram strength entecavir capsule was prepared.
Capsule shell
*removed by drying
Example 6
Employing the above procedures a tablet of 1 milligram strength entecavir was prepared.
*removed by drying
Example 7
The 100 mg tablet of Example 1 containing 0.5 mg of entecavir, the 100 mg tablet of Example 2 containing 0.1 mg of entecavir, the 100 mg tablet of Example 3 containing 0.01 mg of entecavir and the 100 mg tablet of Example 6 containing 1.0 mg of -entecavir can be film coated with the composition set forth below using conventional pan coating or spray coating techniques.
*removed by drying
Opadry® is commercially available and contains hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, polysorbate 80, synthetic yellow iron oxide and synthetic red iron oxide.
λ The calculations are done assuming a tablet weight of 100 mg.
2 Suitable plasticizers are diethyl citrate and triethyl citrate.
Example 8
The safety and .nviral activity of entecavir given for 28 days to human subjects with chronic hepatitis B virus infection was studied in a randomized, double- blind, placebo-controlled, dose-escalating trial. Entecavir demonstrated potent antiviral activity at all doses tested. The mean log reduction in hepatitis B virus DNA viral levels m the blood at day 28 were 2.21, 2.25, 2.81, and 2.42 for the 0.05, 0.1, 0.5 and 1.0 mg once daily doses of entecavir, respectively. Entecavir was well tolerated.
Example 9
The safety and antiviral activity of three doses of entecavir (0.01 mg, 0.1 mg and 0.5 mg) given once daily for 24 weeks were studies m adults with chronic hepatitis B in a randomized, double-blind, lamivudme (100 mg QD) controlled trial. All three doses of entecavir demonstrated potent antiviral activity. The two higher doses of entecavir produced significantly greater reductions in hepatitis B virus DNA viral levels m blood compared to lamivudme. Entecavir at all doses was well tolerated.
Claims (23)
1. A pharmaceutical composition for once a day administration to treat hepatitis B virus infection comprising a pharmaceutically acceptable carrier and from about 0.001 mg to about 25 mg of entecavir.
2. A composition of Claim 1 wherein: said entecavir is present at from about 0.01 mg to about 10 mg.
3. A composition of Claim 1 wherein: said entecavir is present at from about 0.01 mg to about 5 mg .
4. A composition of Claim 3 wherein said entecavir is present at about 0.01 mg .
5. A composition of Claim 3 wherein said entecavir is present at about 0.05 mg.
6. A composition of Claim 3 wherein said entecavir is present at about 0.1 mg .
7. A composition of Claim 3 wherein said entecavir is present at about 0.5 mg .
8. A composition of Claim 3 wherein said entecavir is present at about 1.0 mg.
9. A composition of Claim 1 in the form of a tablet or capsule.
10. A composition of Claim 1 containing one or more other pharmaceutically active substances.
11. A pharmaceutical composition for oral administration of a low dose of entecavir comprising: from about 0.001 mg to about 10 mg of entecavir adhered to a carrier substrate.
12. A composition of Claim 11 wherein: said carrier substrate is selected from lactose, microcrystalline cellulose, calcium phosphate, dextrin, dextrose, dextrates, mannitol, sorbitol and sucrose, and mixture thereof, and said entecavir is adhered to said substrate by an adhesive substance which is a polymeric material possessing sufficient tack.
13. A composition of Claim 12 wherein: said adhesive substance is selected from povidone, methylcellulose, hydroxymethylcellulose, hydroxypropyl- methylcellulose, hydroxypropylcellulose, hydroxyethyl- cellulose, gelatin, guar gum, and xanthan gum and mixtures thereof.
14. A composition of Claim 11 including a lubricant and a disintegrant wherein: said lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium lauryl sulfate, and mixtures thereof and said disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, and corn starch and mixtures thereof.
15. A pharmaceutical composition for oral administration of a low dose of entecavir comprising entecavir coated by means of an adhesive substance to a carrier substrate, a lubricant, and a disintegrant wherein: said entecavir is present at from about 0.001 to about 10% by weight of said composition, said adhesive substance is present at from about 0.01 to about 10% by weight of said composition, said carrier substrate is present at from about 80 to about 95% by weight of said composition, said disintegrant is present at from about 1 to about 7% by weight of said composition, and said lubricant is present at from about 0.1 to about 5% by weight of said composition.
16. A composition of Claim 15 wherein: said adhesive substance is selected from povidone, methylcellulose, hydroxymethylcellulose, hydroxypropyl- methylcellulose, hydroxypropylcellulose, hydroxyethyl- cellulose, gelatin, guar gum, and xanthan gum and mixtures thereof, said carrier substrate is selected from lactose, microcrystalline cellulose, calc__.-_.n_i phosphate, dextrin, dextrose, dextrates, mannitol, sorbitol, and sucrose and mixtures thereof, said disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatmized starch, and corn starch, and mixtures thereof, and said lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium lauryl sulfate, and mixtures thereof.
17. A composition of Claim 16 wherein: said aαnesive substance is povidone; said carrier substrate is microcrystalline cellulose or lactose or mixtures thereof; said disintegrant is crospovidone; and said luoπcant is magnesium stearate.
18. The low dose entecavir tablet composition comprisin : about 0.01% entecavir, about 93.24% microcrystalline cellulose, about 4.0% crospovidone, about 2.50% povidone, and about 0.25% magnesium stearate, said percentages being on a weight/weight basis; or about 1.0% entecavir, about 90.0% mannitol, about 4.0% croscarmellose sodium, about 2.50% methyl cellulose, and about 2.50% stearic acid, said percentages being on a weight/weight basis; or about 0.5% entecavir, about 60.00% lactose monohydrate, about 32.50% microcrystalline cellulose, about 4.0% crospovidone, about 2.50% povidone, and about 0.50% magnesium stearate, said percentages being on a weight/weight basis; or about 0.1% entecavir, about 60.00% lactose monohydrate, about 35.39% microcrystalline cellulose, about 4.0% crospovidone, about 0.01% povidone, and about 0.5% magnesium stearate, said percentage being on a weight/weight basis.
19. The low dose entecavir tablet composition of Claim 18 having an outer film coating.
20. The low dose entecavir capsule composition comprising: about 10.0% entecavir, about 82.03% microcrystalline cellulose, about 4.00% crospovidone, about 2.50% povidone, about 0.25% magnesium stearate, and about 1.22% hydrochloric acid, said percentages being on a weight/weight basis; or about 0.05% entecavir, about 93.20% dicalcium phosphate, about 4.00% crospovidone, about 2.50% hydroxypropyl cellulose, and' about 0.25% magnesium stearate, said percentages being on a weight/weight basis.
21. The method of preparing a pharmaceutical composition for oral administration containing a low dose of a soluble pharmaceutically active agent comprising: (a) dissolving said pharmaceutically active agent and an adhesive substance in a solvent, (b) spraying said solution from step (a) onto a carrier substrate while said carrier substrate is in motion,
(c) drying said coated carrier substrate from step
(b) to remove said solvent, and (d) combining said dried coated carrier substrate from step (c) with other desired ingredients to form said pharmaceutical composition.
22. The method of Claim 21 wherein: said pharmaceutically active substance is entecavir which is present at from about 0.001 to about 10% on a weight/weight basis of said composition, and said solvent is water or water having an acidic or basic pH.
23. The method of Claim 21 wherein: said carrier substrate is kept in motion during spraying step (b) by mechanical agitation, and said coated carrier substrate is dried in step (c) in a tray drier or fluidbed drier; or said carrier substrate is kept in motion during spraying step (b) by air stream agitation, and said coated carrier substrate is dried in step (c) also by means of air stream agitation.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18567200P | 2000-02-29 | 2000-02-29 | |
| US60/185,672 | 2000-02-29 | ||
| US22131300P | 2000-07-28 | 2000-07-28 | |
| US60/221,313 | 2000-07-28 | ||
| PCT/US2001/002630 WO2001064221A1 (en) | 2000-02-29 | 2001-01-26 | Low dose entecavir formulation and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2001229775A1 true AU2001229775A1 (en) | 2001-09-12 |
Family
ID=26881354
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001229775A Abandoned AU2001229775A1 (en) | 2000-02-29 | 2001-01-26 | Low dose entecavir formulation and use |
Country Status (35)
| Country | Link |
|---|---|
| US (1) | US6627224B2 (en) |
| EP (2) | EP1267880B2 (en) |
| JP (3) | JP5140222B2 (en) |
| KR (1) | KR100757155B1 (en) |
| AR (1) | AR027965A1 (en) |
| AT (1) | ATE312613T1 (en) |
| AU (1) | AU2001229775A1 (en) |
| BG (1) | BG65815B1 (en) |
| BR (1) | BRPI0108435B8 (en) |
| CA (1) | CA2401569C (en) |
| CO (1) | CO5261593A1 (en) |
| CZ (1) | CZ303395B6 (en) |
| DE (1) | DE60115870T3 (en) |
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Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0108435B8 (en) * | 2000-02-29 | 2021-05-25 | Bristol Myers Squibb Co | formulation and use of low-dose entecavir |
| TWI275392B (en) * | 2002-04-08 | 2007-03-11 | Bristol Myers Squibb Co | Low dose liquid entecavir formulations and use |
| AR040588A1 (en) | 2002-07-26 | 2005-04-13 | Schering Corp | PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE |
| DK1644384T3 (en) | 2002-12-11 | 2013-02-11 | Bristol Myers Squibb Co | Process and intermediates for the synthesis of entecavir |
| EP1923063A3 (en) | 2003-01-14 | 2009-04-08 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
| EP1708690B1 (en) | 2003-11-17 | 2016-07-20 | BioMarin Pharmaceutical Inc. | Treatment of phenylketonuria with bh4 |
| NZ547880A (en) * | 2003-11-18 | 2010-02-26 | Boehringer Ingelheim Int | Solid pharmaceutical preparation form |
| US7511139B2 (en) * | 2004-06-04 | 2009-03-31 | Bristol-Myers Squibb Company | Process for the preparation of entecavir and novel intermediates thereof via carbon-silicon oxidation |
| JP4756153B2 (en) * | 2004-08-27 | 2011-08-24 | 富士製薬工業株式会社 | Method for producing tablets with low content |
| JP2008513584A (en) * | 2004-09-23 | 2008-05-01 | エフ エム シー コーポレーション | Coating composition |
| TWI375560B (en) | 2005-06-13 | 2012-11-01 | Gilead Sciences Inc | Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same |
| TWI471145B (en) | 2005-06-13 | 2015-02-01 | Bristol Myers Squibb & Gilead Sciences Llc | Unitary pharmaceutical dosage form |
| CN101245068A (en) * | 2007-02-14 | 2008-08-20 | 浙江医药股份有限公司新昌制药厂 | Crystallization type entecavir, method of producing the same, pharmaceutical composition and uses thereof |
| PE20090185A1 (en) * | 2007-03-22 | 2009-02-28 | Bristol Myers Squibb Co | PHARMACEUTICAL FORMULATIONS CONTAINING AN SGLT2 INHIBITOR |
| CN102596183B (en) | 2009-10-28 | 2014-09-17 | 麦克内尔-Ppc股份有限公司 | Fast dissolving/disintegrating coating compositions |
| WO2011076412A1 (en) | 2009-12-23 | 2011-06-30 | Ratiopharm Gmbh | Oral form of administration comprising entecavir |
| DE102009060194A1 (en) | 2009-12-23 | 2011-06-30 | ratiopharm GmbH, 89079 | Intermediate, useful for treating chronic hepatitis B virus infections, comprises entecavir and an auxiliary material |
| EP2536411A4 (en) * | 2010-02-18 | 2013-08-07 | Univ Princeton | Inhibitors of long and very long chain fatty acid metabolism as broad spectrum anti-virals |
| CN102892291A (en) | 2010-03-31 | 2013-01-23 | 米伦纽姆医药公司 | Derivatives of 1-amino-2-cyclopropylethylboronic acid |
| EP2606895A4 (en) * | 2010-10-12 | 2014-04-02 | Univ Wuhan | Transdermal absorption patch of antiviral drug and its preparation method |
| EP2508172A1 (en) | 2011-04-06 | 2012-10-10 | Zentiva, a.s. | Stable and uniform formulations of entecavir and preparation method thereof |
| KR101594820B1 (en) * | 2011-06-16 | 2016-02-17 | 건일제약 주식회사 | Entecavir-containing microspheres and process for preparing the same |
| WO2013066028A1 (en) | 2011-11-01 | 2013-05-10 | 대원제약주식회사 | Improved-safety entecavir-containing pharmaceutical composition and production method therefor |
| CA2881119A1 (en) * | 2011-11-14 | 2013-05-23 | Hetero Research Foundation | Fast release solid oral compositions of entecavir |
| EP2644196B1 (en) * | 2012-03-26 | 2019-09-18 | Arven Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions of Entecavir |
| EP2644197A1 (en) * | 2012-03-26 | 2013-10-02 | Sanovel Ilac Sanayi ve Ticaret A.S. | Novel Pharmaceutical Compositions of Entecavir |
| KR101285008B1 (en) * | 2012-04-18 | 2013-07-10 | 제일약품주식회사 | A method for preparing oral formulation of low dose entecavir |
| CA2779052A1 (en) * | 2012-05-31 | 2013-11-30 | Pharmascience Inc. | Pharmaceutical composition of entecavir and process of manufacturing |
| CN103908436B (en) * | 2012-12-29 | 2016-02-10 | 安徽贝克生物制药有限公司 | A kind of quick-releasing type entecavir composite |
| KR101512895B1 (en) | 2013-08-09 | 2015-04-16 | 대화제약 주식회사 | A preparation method of pharmaceutical composition comprising entecavir |
| US10045993B2 (en) * | 2014-06-20 | 2018-08-14 | Ctc Bio, Inc. | Pharmaceutical preparation containing entecavir as active ingredient, and preparation method therefor |
| JP6998210B2 (en) * | 2015-09-30 | 2022-01-18 | 株式会社ダイセル | Particle composition for easy-to-take solid preparation and easy-to-take solid preparation containing the particle composition |
| KR20230112817A (en) | 2022-01-21 | 2023-07-28 | 한림대학교 산학협력단 | Composition for preventing or treating brain disease comprising pyruvate and a PDK inhibitor |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3836618A (en) * | 1971-12-23 | 1974-09-17 | American Home Prod | Process for the uniform distribution of a drug on a granulated base |
| US4513008A (en) * | 1982-07-30 | 1985-04-23 | The Vinoxen Company, Inc. | Virucidal compositions and therapy |
| US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
| US4631284A (en) * | 1984-11-19 | 1986-12-23 | Mallinckrodt, Inc. | Acetaminophen compositions containing low doses of chlorpheniramine maleate, method for preparing same and tablets formed therefrom |
| US5206244A (en) | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| JPH08208478A (en) * | 1994-10-14 | 1996-08-13 | Japan Energy Corp | Anti-aids agent preparation and its production |
| DK0929294T3 (en) * | 1996-04-04 | 2003-09-29 | Felix Specht | Process for the preparation of low-dose free-flowing and / or directly compressible powder systems |
| AU4090697A (en) | 1996-09-03 | 1998-03-26 | Bristol-Myers Squibb Company | Improved process for preparing the antiviral agent {1s-(1alpha, 3alpha, 4beta)}-2-amino-1,9-dihydro-9-{4-hydroxy-3-(hydroxymethyl)-2 -methylenecyclopentyl}-6h-purin-6-one |
| WO2000009531A2 (en) * | 1998-08-10 | 2000-02-24 | Novirio Pharmaceuticals Limited | β-L-2'-DEOXY-NUCLEOSIDES FOR THE TREATMENT OF HEPATITIS B |
| US5997905A (en) * | 1998-09-04 | 1999-12-07 | Mcneil-Ppc | Preparation of pharmaceutically active particles |
| GB9820417D0 (en) | 1998-09-18 | 1998-11-11 | Glaxo Group Ltd | Antiviral combinations |
| GB9820420D0 (en) | 1998-09-18 | 1998-11-11 | Glaxo Group Ltd | Antiviral combinations |
| GB9820416D0 (en) | 1998-09-18 | 1998-11-11 | Glaxo Group Ltd | Antiviral combinations |
| US6432966B2 (en) * | 1999-10-29 | 2002-08-13 | Smithkline Beecham Corporation | Antiviral combinations |
| BRPI0108435B8 (en) * | 2000-02-29 | 2021-05-25 | Bristol Myers Squibb Co | formulation and use of low-dose entecavir |
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