Orally administrable solid ribavirin dosage forms and process for making them (original) (raw)

Orally administrable solid ribavirin dosage forms and process for making them Download PDF

Info

Publication number

CA2287056C

CA2287056C CA002287056A CA2287056A CA2287056C CA 2287056 C CA2287056 C CA 2287056C CA 002287056 A CA002287056 A CA 002287056A CA 2287056 A CA2287056 A CA 2287056A CA 2287056 C CA2287056 C CA 2287056C

Authority

CA

Canada

Prior art keywords

ribavirin

composition

compacted

rapidly dissolving

tap density

Prior art date

1997-12-22

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.)

Expired - Fee Related

Application number

CA002287056A

Other languages

French (fr)

Other versions

CA2287056A1 (en

Inventor

Stephen M. Liebowitz

Elliot I. Stupak

Imtiaz A. Chaudry

Winston A. Vadino

Frank E. Bowen

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Merck Sharp and Dohme Corp

Original Assignee

Schering Corp

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1997-12-22

Filing date

1998-12-21

Publication date

2000-08-15

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27130673&utm\_source=google\_patent&utm\_medium=platform\_link&utm\_campaign=public\_patent\_search&patent=CA2287056(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1997-12-22 Priority claimed from US08/997,172 external-priority patent/US5914128A/en

1997-12-22 Priority claimed from US08/997,169 external-priority patent/US5916594A/en

1998-12-21 Application filed by Schering Corp filed Critical Schering Corp

1998-12-21 Priority to CA002300452A priority Critical patent/CA2300452C/en

1999-07-01 Publication of CA2287056A1 publication Critical patent/CA2287056A1/en

2000-08-15 Application granted granted Critical

2000-08-15 Publication of CA2287056C publication Critical patent/CA2287056C/en

2018-12-21 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • 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
  • 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
  • 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
  • A61K9/4833—Encapsulating processes; Filling of capsules

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Communicable Diseases (AREA)
• Virology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

An orally administrable solid dosage form containing a compacted ribavirin composition having an advantageously high tap density of at least 0.6 g/mL as well as surprisingly rapid disintegration and dissolution rates and wherein the ribavirin is substantially free of polymorphic forms of ribavirin and a process for making such solid dosage forms are disclosed

Description

V1'O 99:'3=I25 PCT,~L.'S98,'26='_:
ORALLY ADMINISTRABLE SOLID RIBAVIRIN DOSAGE FORMS
AND PROCESS FOR MAKING THEM
Background of the Invention This invention relate; to an orally administrable solid dosage form comprising a comp<~cted ribavirin composition and process for making such solid dosage forms. The compacted ribavirin composition of this invention has an advantageously high tap density as well as surprisingly fast disintegration and ~~issolution rates and contains a freely flowing ribavirin of uniform physical characters:>tics which is substantially free of other polymorphic forms.
Ribavirin is a.n antiviral agent which is currently being administered in association with intE~rferon alpha-2b to treat patients with chronic hepatitis C
infections.
Ribavirin 200 (ng capsules are manufactured and marketed by ICN
Pharmaceuticals in Canada. under the trade-mark VirazoleTM capsules. The ribavirin used to make the ribavirin~composition in the Virazole capsules is a non-freely flowing powder vrith low and variable tap densities in the range of 0.320 to 0.449 g/mL.. A ribawirin composition with a tap density of at least 0.6 g/mL is needed for iihe uniform filling of the 200 mg capsules. It would be desirable for the ribavirin composition to have a uniformly high tap density of at least 0.6 g/mL to fill any capsule and to avoid excessive weight variation and excessive packing in the capsule shell during the capsule filling operation especiali~r in the high speed capsule filling equipment which operate at a fill rate of over 20,000 capsules per hour.
Dry compacting of the ribavirin formulation would be an attractive solution to this problem so long as the heat produced during the compaction operation does not cause the formation of ribavirin polymorphic forms, which forms are unacceptable for obtaining health registration.
The Virazole capsules exhibited inconsistency in meeting the dissolution specifications which requires that 80% of the ribavirin be dissolved in water in 30 minutes. The disintegration times of the Virazole composition were typically around 20 minutes.
There is a need for a. ribavirin composition with a tap density of at least 0.6 g/mL and having improved dissolution rates and reduced disintegration times. There is also a need to compact the ribavirin composition to achieve such high tap densities while maintaining the ribavirin in the physical state substantially free of polymorphic forms.
Summarlr of the Invention The invention provides an orally administrable solid dosage form comprising a rapidly dissolving compacted ribavirin composition comprising ribavirin and a pharmaceutically acceptable disintegrant wherein said composition after dlry compaction has a tap density of at least about 0.6 g/mL
and wherein more than 80'% by weight of the ribavirin dissolves in water in about 30 minutes.
The invention also provides a rapidly dissolving compacted ribavirin composition comprising:
(a) an antivirally effective amount of ribavirin;
(b) an effective amount of at least one filler selected from the group consisting of lactose anhydrous, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, dibasic calcium phosphate dihydrate,calcium sulfate dihydrate and calcium sulfate trihydrate;
(c) an effective amount of a pharmaceutically acceptable disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starches, sodium cart~oxymethyl cellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium aluminium silicate, bentonite, alginic acid and alginates;
and;
(d) an elfective amount of a lubricant selected from the group consisting of magnESSium stearate, calcium stearate, zinc stearate, talc, propylEane glycol, PEG 4000, PEG 5000, PEG 6000, and stearic acid;
and, wherein the tap density of the compacted composition is at least about 0.6 g/mL.

In another aspect of the invention, there is provided a compacted ribavirin composition substantially free of other ribavirin polymorphic forms, and comprising a pharmaceutically acceptable carrier.
In an embodiment of the invention, there is provided an orally administrable sollid dosage form comprising a rapidly dissolving ribavirin compacted composition comprising ribavirin which is substantially free of other polymorphic forms ~of ribavirin, and a pharmaceutically acceptable carrier.
In another embodiment of the invention, there is provided an orally administrable solid dosage form comprising a rapidly dissolving ribavirin compacted composition comprising ribavirin and a pharma-ceutically acceptable disintegrant wherein said composition has a tap density of at least: about 0.6 g/mL and wherein more than about 80% by weight of the ribavirin dissolves in water in about 30, and wherein the ribavirin is substantially free of other polymorphic forms of ribavirin.
-2a-In a preferred embodiment, the invention further provides is a rapidly dissolving compacted ribavirin composition comprising of:
Ingredient mg Ribavirin USP 150.0 to 250.0 Lactose Monohydnate NF 30.0 to 50.0 Microcryst~~lline Cellulose NF 37.5 to 62.5 Croscarme~llose Sodium NF 4.5 to 7.5 Magnesiurn Stearate NF 2.25 to 5.0 and wherein the tap density of the compacted composition is at least about 0.6 g/mL.
In a preferred embodiment, the invention provides a rapidly dissolving compacted ribavirin composition comprising:
Ingredient mg Ribavirin USP 200.0 Lactose Monohydrate NF 40.0 Microcrystalline CE:Ilulose NF 50.0 CroscarmE~llose Sodium NF 6.0 Magnesium Stearate NF 4.0 wherein the tap density of thecompacted composition is at least about 0.6 g/mL;and wherein tile ribavirin is substantially free of polymorphic forms of ribavirin.
In another aspect, this invention provides a method of producing a rapidly dissolving compacted ribavirin composition which comprises the steps of:
(a) adrnixing an antivirally effective amount of ribavirin, an effective amount of a pharrnaceutically acceptable disintegrant, and an effective amount of at least one filler for a time sufficient to form a homogenESOUS mi;~ture;

b) comF~acting the homogeneous mixture of Step (a) at a compressinca force in the range of about 50 to about 75 kN for a time sufficient to produce an acceptable compact wherein the ribavirin is substantially free of polymorphic forms ; and c) admi;~cing the acceptable compact of Step (b) with an effective amount of a lubricant for a time sufficient to produce a rapidly dissolving compactESd ribavirin composition.
Detailed Description of the Invention We have suirprisingly discovered that we can consistently manufacture a uniform ribavirin composition which consistently meets and exceeds the dissolution specifications which requires that 80% of the ribavirin be dissolved in water in 30 minutes; about 90% of the ribavirin in the compacted rib~~virin compositions of this invention is consistently dissolved in water in 15 minutes and about 100% of the ribavirin from the compositions of this invention is dissolved in 30 minutes. The disintegration time of the ribavirin compositions of this invention was reduced to less than 10 minutes compared to the Virazole capsule composition which disintegrated in 2Ci minutes (see Table 1 ).
The ribavirin composition of this invention was blended and passed through a roller compactor at a compressing force in the range of about 50 to 75 kiloNewtons ("b;N") for a time sufficient to produce an acceptable compact.
An "acceptable compact" as used herein means a compact that is in the form of a ribbon which is homogeneous, and almost completely free, i.e., more than 95% free, of lamination and flaking, and sustantially free of polymorphic forms of ribavirin. A compressing force in the range of 50 to about 75 kN
consistently produced an ;acceptable compact. Typically suitable screw speeds and (on ti. a Fitzpatrick roller/compactor) roller speeds include ( 1 ) a screw speed of 40 revolutions per minute ("RPM") with a roller-speed of 10 RPM; (2) a screw speed of 30 RPM with a roller speed of 7 RPM; and (3) a screw speed of 2a' RPM with a roller speed of 5 RPM. No definitive range of screw speeds and roller speeds was able to be deduced from these results.However vve have discovered that an acceptable compact is consistently obtainable by maintaining the compressing force in the range of about 50 to about 75 kN. The compacted material is milled, combined with a lubricant and the resulting tap density of the resulting ribavirin composition is WO 99!32128 PCT/US98/26222 at least 0.6 g/mL amd preferably it is significantly higher, e.g., in the range of about 0.75 to about 0.85 g/mL. The compacted ribavirin compositions of this invention surprisingly havf~ substantially uniform physical and chemical characteristics and the ribavirin in the compacted ribavirin composition is substantially free of polym~rphic forms of ribavirin, i.e., there are no signs of polymorphic chanl~e in the compacted ribavirin as determined by differential scanning calorimetry. This result is particularly surprising in view of the large amount of heat generated during the compaction step which could normally produce polymorphic forms.
The rapidly dissolving ribavirin compositions of this invention are stable and have been subjected to three freeze-thaw cycles without any adverse impact upon the physical apperance, tap density, dissolution and disintegration rates.
Typically suitable disintegrants include pharmaceutically acceptable disintegrants which are chemically and physically compatible with ribavirin;
preferably those disintegrants are selected from the group consisting of croscarmellose sodium" sodium starch glycolate, corn starch, pregelatinized starches, sodium carboxymethyl cellulose, potato starch, microcrystalline cellulose, polyvirn~lpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium aluminium sillicate, bentonite, alginic acid and alginates.
The effective amount of a disintegrant found useful in the ribavirin compositions of this invention is in the range of about 1.0 to about 3.0 weight percent, preferably about 1.5 to about 2.5 weight percent, and most preferably about 2.0 weight percent of the ribavirin compositions of this invention. The pre;fered dl~sintegrants are croscarmellose sodium and polyvinyl pryrolidine or mixtures thereof. The most preferred disintegrant is croscarmellose sodium.
Typically suitable lubricants include any pharmaceutically acceptable solid or liquid lubricants which are used to enhance the flow and prevent sticking of the rik~avirin composition after compaction and whch are chemically and plhysically compatible with ribavirin.
Typically suitable lubricants include magnesium stearate, calcium stearate, zinc ste~arate, talc, propylene glycol, PEG 4000, PEG 5000, PEG
6000, and stearic: acid.
The effective amount of a lubricant found useful in the ribavirin compositions of this invention is in the range of about 0.75 to about 2.0 weight percent, p~referabl~~r about 1.0 to about 1.7 weight percent, and most _5_ preferably about 1.3 weight percent of the ribavirin compositions of this invention. The prefered lubricant is magnesium stearate.
Typically suitable fillers include any such pharmaceutically acceptable filler which gives the powder ribavirin composition bulk and which is physically and chESmically compatible with ribavirin; preferably those fillers are selected from the group consisting of lactose anhydrous, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches,~dibasic calcium phosphate dehydrate, calcium sulfate trihydrate and calcium sulfatE~ dehydrate.
Typically two fillers are used in the ribavirin compositions of this invention.The effective amount of the fillers found useful in the ribavirin compositions of this invention is in the range of about 20 to about 40 weight percent, preferably about 2'S to about 35 weight percent, and most preferably about 30 weight percent of the ribavirin compositions of this invention. One of the prefered fillers is lactose monohydrate which is typically present in the range of about 10 ~oo about 15 weight percent, more preferably about 13 to about 14 weight pE~rcent of the ribavirin compositions of this invention.The other prefered filler is microcrystaliine cellulose which is typically present in the range of about 10 to about 20 weight percent, more preferably about 12 to about 18 weight percent, and most preferably about 16 to about 17 weight percent of the rib~wirin compositions of this invention.
The term "tap density" as used herein means the measured mass of a powder attained at a limiting volume measured in a cylinder after being "tapped down", typically by a mechanical device; typically tap density is recorded as mass in grams divided by volume in milliliters("mL"). The tap density is measurE~d in accordance with the procedure described in USP 23, NF 18, Supplement 6,(19~i7), procedure <616> at page 3768. The tap density of the orally administrable ribavirin composition of this invention is at least 0.6 g/mL which is advantageous when a capsule containing 200 mg of ribavirin in the 300 mg preferred composition of this invention is used.
Typically the tap densities of the orally administrable ribavirin is in the range of about 0.75 g/mL to about 0.85 g/mL.
While the rapidly dissolving ribavirin compositions of this invention are described for ;?00 mg ribavirin strengths as capsules or tablets, other strengths e.g., 300 or 400 mg of ribavirin, may be used without deviating from this invention.
Ribavirin (1600-1200 mg in single or divided daily doses such as 600 mg QD or 600 mg BlD or 400mg T1D) is being used in clinical trials in combination with subcutaneous injections of interferon alfa-2b (3 million international units, three times a week (TIW)) to treat chronic hepatitis C
patients. Thus, the term antivirally effective amount of ribavirin as used herein means dosages of ribavirin, e.g.,200 mg, 300 mg or 400 mg as tablets or capsules, which would provide the 600-1200 mg/day, preferably 800-1200 mg/day or 1000-1200 mg/day of ribavirin used to treat chronic hepatitis C patients in combination with the interferon alfa-2b. The ribavirin compositions of this invention may be filled into capsules or compressed into tablets.
Manufacturing_ Procedure General Manufacturing Procedure (1 ) Change the ribavirin, one or more fillers and disintegrant into a suitable double cone blender.
(2) Blend the charge from step (1) for a time sufficient to form uiniform blend.
(3) Optionally pass the blend of step (2)-if the such blend should contain lumps- thr~~ugh a suitable comminutor mill set at medium speed to provide a lump-free blend, (4) Pass. the milled uniform blend from step 2 or 3 through a suitable roller/compactor equipped with an oscillator for screening and operated at a compressing force of about 50 to about 70 kN for a time sufficient to produce an acceptable compact;

(5) Combine the compacted screened blend from step (4) and charge said blend to the blender used in step (1).

(6) Charge the lubricant to the blend from step (5) and blend the mixture for a time sufficiernt to produce a uniform mixture;

(7) Fill tlhe uniform mixture from step (6) into capsules.
A large sc~ile batch of the capsule formulation was prepared using the formulations of Example 1 or 2.
_7_ *rB

Procedure:
1. Charge the ribavirin, microcrystalline cellulose, lactose monohydrai:e, and croscarmellose sodium into a suitable double cone blender of appropriate volume.
2. Glenn the charge in step (1 ) for 10 to 15 minutes, preferably about 15 minutes. Discharge the so-formed mixture into plastic lined containers.~~

3. Optionally pass the blended mixture in step (2) through a suitable comminutor mill set at medium speed, impact hammers forward fittE~d with a. No. 6 mesh screen. (This step is optional and may be elinninated i,f the blended mixture from step (2) is lump-free.) 4. Pas; the milled blend in step 2 or 3 through a suitable roller/compactor such as a Bepex or Fitzpatrick roller compactor machine equipped with an oscillator for screening. Operate the roller compactor at a compressing force of about 50 to about 75 kN for a time sufficient to produce an acceptable compact. (An acceptable compact is normally produced with a single pass of the milled blend from step (3) through the compactor. The compacted material is thereafter directly fed into the oscillating mill equipped with a 16 mesh screen.) 5. Combine the compacted, screened blendin step 4 and charge the blend to the blE~nder used in Step 1. Blend for 10 minutes.
Remove s;~mples c~f the blend for tap density and sieve analysis testing.
6. Charge the magnesium stearate to the blend in step 5 and blend for about 3 rninutes ar a time sufficient to produce a uniform mixture.
7. Fill the uniform mixturein Step 6 into No. 1 white opaque, two-piece hard gelatin capsules using an appropriate high speed capsule filling equipment, N.g., a Zanasi AZ40 or H&K 1500.

8. Polish and dedust the filled capsules using a rotating brush capsule polishing machine, e.g., Key Turbo-Kleen CP-300 equipped with an empty capsule eliminator.
Footnote a. Analyze the Mended mixturefrom step(2)for blend uniformity.
Based on this anaiy:~is, it was then determined that a blending time of 10-to 15 minutes was sufficient to produce an acceptable blend uniformity.
Ribavirin is mutagenic and teratogenic and appropriate precautions must be taken to ensure the safety of the manufacturing personnel.
The following examples illustrate, but do not limit, the present invention:
Example 1 The above-~~escribed manufacturing procedure may be used to blend, compact, and mill the following compositions:
Inaredient m9 Ribavirin U~SP 150.0 to 250.0 Lactose Monohydrate NF 30.0 to 50.0 Microcrystalline Cellulose NF 37.5 to 62.5 Croscarmellose Sodium NF 4.5 to 7.5 Magnesium Stearaie NF 2.25 to 5.0 The above compositions have tap densities of at least 0.6 g/mL.
_g_ Example 2 The procedure of Example 1 was followed to prepare the following composition:
1n r ' nt m9 Ribavirin U:~P 200.0 Lactose Monohydrate NF 1 40.0 Microcrystalline Cellulose NF 50.0 Croscarmellose Sodium NF 6.0 Magnesium Stearate NF 4.0 Total 300 The tap density was 0.77 g/mL.

(1) Preferably the lactose monohydrate NF is spray dried.

The composition was filled into capsules and the following dissolution results were recorded:
weigr,t °i°,Ribavirin Wgt%Ribavirin Dissolved Dissolved avera a Ran Time (minute 15 99 (93 - 103) 30 101 (98 - 103) 45 101 (98 - 104) 60 102 (99 - 104) 12 capsule: of the formulation of Example 2 were tested using a USP
basket at 100 RPI~A in 900 mL of distilled water operated in accordance with the procedure described in USP 23, NF-18, procedure <711 >.
The formulation of Example 2 exhibited no signs of polymorphic changes in the ribavirin as determined by differential scanning caiorimetry.
USP 23, NF-18 Supplement 6, procedure <891>, 1997.
The disintegration time for the formulation of Example 2 was measured as described in Table 1; the capsules disintegrated in 7 - 9 minutes.
The effect of freeze-thaw cycling was determined for the formulation of Example 2 in capsules. ~'he capsules were subjected to three freeze-thaw cycles. The first two freeze and thaw cycles fasted 24 hours. The last freeze-thaw cycle was 7c' hours f~~llowed by 24 hours at ambient - i.e. room temperatures..
Physical ot~servation, disintegration, and dissolution studies were performed. No sii~nificant change in physical appearance the disintegration time or dissolution rates were observed compared to the initial test results.
Weight %Ribavirin Dissolved _ Weight %Ribavirin Dissolved Time minute Avg. for a capsule Ranae 93 (84 - 100) 15 30 96 (89 - 100) .. 45 96 (86 - 101 ) 60 96 (86-101 ) Essentially no changes were observed in the tap density, dissolution or disintegration r~~tes of the ribavirin composition of Example 2.
Example 3 The following composition represents the composition of a typical Virazole 200 mg capsule (uncompacted):
Ingredient n~

Ribavirin USP 200.0 Lactose Monohydrate NF Spray Dried 46.0 Microcrystaliine Cellulose NF 50.0 Magnesium Stearate NF 4.0 Capsule Fill Weight 300.0 Capsule Size No. 1 Capsule Type White Opaque _11-Ta le 1 Comparative dissolution and disintegration results for the rapidly dissolving ribavirin composition of Examples 2 and 3:
A. Dissolution Weight %
Ribavirin Dissolved (~ompacted Virazole Time Ribavirin' Composition B. Disintegration3 Disintegration Product Time minutes) Compacted ribaviri n 6 - 8 composition of Example of this invention Virazole cornposition of Example 3 - 20 1. 12 capsules of Example 2 were tested man USP basket at 100 RPM in 900 mL of distilled water operated in accordance with the procedure described in USP 23, NF 18, procedure <711> ,1995.
2. The uncompacted Virazole composition of Example 3 was used.
3. 6 caF~sules were tested in an USP apparatus operated in accordance with the procedure described in USP 23 NF 18 procedure <:701 >,1995.
Other modification may be made in this invention without deviating from the scope of the present inventor. For example, the formulations of Examples 1 or 2 imay be modified by substituting a portion of the croscarmellose sodium with polyvinylpyrrolidone and the so-formed composition may be' compressed into tablets.

Claims (25)

What is claimed is:

1. An orally administrable solid dosage form comprising a rapidly dissolving ribavirin compacted composition comprising ribavirin and a pharmaceutically acceptable disintegrant wherein said composition has a tap density of at least about 0.6 g/mL and wherein more than about 80% by weight of.the ribavirin dissolves in water in about 30 minutes.

2. A rapidly dissolving compacted ribavirin composition comprising:
(a) an antivirally effective amount of ribavirin;
(b) an effective amount of at least one filler selected from the group consisting of lactose anhydrous lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate and calcium sulfate trihydrate;
(c) an effective amount of a pharmaceutically acceptable disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starch, sodium carboxymethyl cellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium aluminium silicate, bentonite, alginic acid and alginates;
and;
(d) an effective amount of a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate,talc, propylene glycol, PEG 4000, PEG 5000, PEG 6000, and stearic acid;
and, wherein the tap density of the compacted composition is at least about 0.6 g/mL.

3. The orally administrable solid dosage form of claim 1 wherein the composition comprises about 200 to 400 mg of ribavirin.

4. A rapidly dissolving compacted ribavirin composition comprising:
Ingredients mg Ribavirin USP 150.0 to 250.0 Lactose Monohydrate NF 30.0 to 50.0 Microcrystalline Cellulose NF 37.5 to 62.5 Croscarmellose Sodium NF 4.5 to 7.5 Magnesium Stearate NF 2.25 to 5.0 and wherein the tap density of the compacted composition is at least about 0.6 g/mL.

5. The orally administrable solid dosage form of claim 1 to 3, wherein the disintegrant is croscarmellose sodium or polyvinylpyrrolidone or mixtures thereof.

6. The rapidly dissolving compacted ribavirin composition of claim 2, wherein the disintegrant is croscarmellose sodium or polyvinylpyrrolidone or mixtures thereof.

7. The orally administrable dosage solid form of claim 1, 2 or 5, wherein the ribavirin is substantially free of polymorphic forms of ribavirin.

8. The rapidly dissolving compacted ribavirin composition of claim 2 to 4, wherein the ribavirin is substantially free of polymorphic forms of ribavirin.

9. The rapidly dissolving compacted ribavirin composition of claim 2 or 4, wherein more than about 80% by weight of the ribavirin dissolves in water in about 30 minutes.

10. The rapidly dissolving compacted ribavirin composition of claim 2 or 4, wherein the disintegration time of the composition is less than about minutes.

11 The rapidly dissolving compacted ribavirin composition of claim 2 or 4, wherein the tap density of the composition is in the range of about 0.75 g/mL to about 0.85 g/mL.

12. The orally administrable dosage form of claim 1, 2, 5 or 7, in the form of a tablet or capsule.

13. The rapidly dissolving compacted ribavirin composition of claim 2, 4, 6, 7, 9, 10 or 11, in the form of a tablet or capsule.

14. A method of producing a rapidly dissolving compacted ribavirin composition which comprises the steps of:
(a) admixing an antivirally effective amount of ribavirin, an effective amount of a pharmaceutically acceptable disintegrant, and an effective amount of at least one filler for a time sufficient to form a homogeneous mixture;
(b) compacting the homogeneous mixture of Step (a) at a compressing force in the range of about 50 to about 75 kN
for a time sufficient to produce an acceptable compact wherein the ribavirin is substantially free of polymorphic forms of ribavirin; and (c) admixing the acceptable compact of Step (b) with an effective amount of a lubricant for a time sufficient to produce a uniform, rapidly dissolving compacted ribavirin composition.

15. The method of claim 14, wherein the rapidly dissolving compacted ribavirin has a tap density of at least about 0.06 g/mL.

16. The method of claim 14, wherein the rapidly dissolving compacted ribavirin has a tap density in the range of about 0.75 g/mL to about 0.85 g/mL.

17. The method of claim 14, 15 or 16, wherein more than about 80%
of the rapidly dissolving compacted ribavirin composition dissolves in water in about 30 minutes.

18. The method of claim 14, 15 or 16, wherein more than about 90%
of the rapidly dissolving compacted ribavirin composition dissolves in water in about 15 minutes.

19. The method of claim 14, 15, 16, 17 or 18, wherein the at least one filler is selected from the group consisting of lactose anhydrous, lactose monohydrate, sucrose, mannitol, microcrystalline cellulose, pregelatinized starches, dibasic calcium phosphate dehydrate, calcium sulfate dehydrate and calcium sulfate trihydrate.

20. The method of claim 14, 15, 16, 17, 18 or 19, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, corn starch, pregelatinized starch, sodium carboxymethyl cellulose, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, magnesium aluminium silicate, bentonite, alginic acid and alginates.

21. A method of claim 14, 15, 16, 17, 18, 19 or 20, therein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, talc, propylene glycol, PEG 4000, PEG 5000, PEG 6000 and stearic acid.

22. A rapidly dissolving compacted ribavirin composition comprising:
Ingredient ~mg Ribavirin USP ~~~200.0 Lactose Monohydrate NF ~~40.0 Microcrystalline Cellulose NF ~50.0 Croscarmellose Sodium NF ~6.0 Magnesium Stearate NF ~~4.0 wherein the tap density of the compacted composition is at least about 0.6 g/mL;
and wherein the ribavirin is substantially free of polymorphic forms of ribavirin; and wherein more than about 80% by weight of the compacted composition dissolves in water in about 30 minutes.

23. The rapidly dissolving compacted ribavirin composition of claim 22, wherein said composition is in the form of a capsule.

24. The rapidly dissolving compacted ribavirin composition of claim 22 or 23, wherein more than about 90% by weight of the compacted composition dissolves in water in about 15 minutes.

25. The rapidly dissolving compacted ribavirin composition of claim 22, 23, 24 or 25, wherein the tap density of the compacted composition is in the range of about 0.75 g/mL to about 0.85 g/mL.

CA002287056A 1997-12-22 1998-12-21 Orally administrable solid ribavirin dosage forms and process for making them Expired - Fee Related CA2287056C (en)

Priority Applications (1)

Applications Claiming Priority (5)

Related Child Applications (1)

Publications (2)

Family

ID=27130673

Family Applications (4)

Family Applications Before (3)

Country Status (27)

Families Citing this family (21)

* Cited by examiner, † Cited by third party

Family Cites Families (41)

* Cited by examiner, † Cited by third party

• 1998
  • 1998-12-21 JP JP2000525119A patent/JP2001526234A/en active Pending
  • 1998-12-21 US US09/582,060 patent/US6337090B1/en not_active Expired - Fee Related
  • 1998-12-21 IL IL13654998A patent/IL136549A/en not_active IP Right Cessation
  • 1998-12-21 PT PT98965983T patent/PT991415E/en unknown
  • 1998-12-21 DK DK98965983T patent/DK0991415T3/en active
  • 1998-12-21 CN CNB988124858A patent/CN1155388C/en not_active Expired - Fee Related
  • 1998-12-21 DE DE69812094T patent/DE69812094T2/en not_active Expired - Lifetime
  • 1998-12-21 PE PE1998001256A patent/PE20000066A1/en not_active Application Discontinuation
  • 1998-12-21 AR ARP980106567A patent/AR008977A1/en unknown
  • 1998-12-21 EP EP98965983A patent/EP0991415B1/en not_active Expired - Lifetime
  • 1998-12-21 KR KR1020007006927A patent/KR100575389B1/en not_active IP Right Cessation
  • 1998-12-21 PL PL98341230A patent/PL190267B1/en not_active IP Right Cessation
  • 1998-12-21 ZA ZA9811726A patent/ZA9811726B/en unknown
  • 1998-12-21 WO PCT/US1998/026222 patent/WO1999032128A1/en active IP Right Grant
  • 1998-12-21 NZ NZ504994A patent/NZ504994A/en unknown
  • 1998-12-21 CA CA002300452A patent/CA2300452C/en not_active Expired - Fee Related
  • 1998-12-21 SK SK894-2000A patent/SK284520B6/en not_active IP Right Cessation
  • 1998-12-21 HU HU0100433A patent/HUP0100433A3/en unknown
  • 1998-12-21 ES ES98965983T patent/ES2191987T3/en not_active Expired - Lifetime
  • 1998-12-21 AU AU21991/99A patent/AU762826B2/en not_active Ceased
  • 1998-12-21 CA CA002365412A patent/CA2365412C/en not_active Expired - Fee Related
  • 1998-12-21 MY MYPI98005792A patent/MY119656A/en unknown
  • 1998-12-21 CA CA002323849A patent/CA2323849C/en not_active Expired - Fee Related
  • 1998-12-21 EP EP02023032A patent/EP1321147A1/en not_active Withdrawn
  • 1998-12-21 AT AT98965983T patent/ATE234103T1/en active
  • 1998-12-21 CA CA002287056A patent/CA2287056C/en not_active Expired - Fee Related
  • 1998-12-21 BR BR9814367-0A patent/BR9814367A/en not_active Application Discontinuation
  • 1998-12-22 CO CO98075938A patent/CO4970774A1/en unknown
  • 1998-12-24 TW TW87121436A patent/TW575436B/en not_active IP Right Cessation
• 1999
  • 1999-05-07 US US09/307,008 patent/US6051252A/en not_active Expired - Fee Related
• 2000
  • 2000-03-06 US US09/518,871 patent/US6335032B1/en not_active Expired - Fee Related
  • 2000-06-21 NO NO20003234A patent/NO20003234L/en not_active Application Discontinuation
• 2001
  • 2001-07-31 HK HK01105338A patent/HK1034674A1/en not_active IP Right Cessation
• 2005
  • 2005-12-12 JP JP2005358349A patent/JP2006083189A/en active Pending

Also Published As

Similar Documents

Legal Events