U.S. patent application number 12/310693 was filed with the patent office on 2009-11-12 for pharmaceutical formulation for use in hiv therapy.
Invention is credited to Abhijit Mukund Deshmukh, Akhilesh Ashok Dixit, Sourav Dilipkumar Mitra, Sanjeev Meharchand Sethi, Kiran Kumar Narsaiah Velaveni, Sanjay Deshraj Verma.
Application Number | 20090281132 12/310693 |
Document ID | / |
Family ID | 39157677 |
Filed Date | 2009-11-12 |
United States Patent
Application |
20090281132 |
Kind Code |
A1 |
Velaveni; Kiran Kumar Narsaiah ;
et al. |
November 12, 2009 |
Pharmaceutical formulation for use in hiv therapy
Abstract
The invention discloses a formulation prepared by granulating at
least one anti-retro viral drug and at least one pharmaceutically
acceptable additive, using an organic solvent; milling the product;
finally processing the milled product to form tablets or
capsules.
Inventors: |
Velaveni; Kiran Kumar Narsaiah;
(Secunderabad, IN) ; Verma; Sanjay Deshraj;
(Secunderabad, IN) ; Dixit; Akhilesh Ashok;
(Secunderabad, IN) ; Deshmukh; Abhijit Mukund;
(Secunderabad, IN) ; Sethi; Sanjeev Meharchand;
(Secunderabad, IN) ; Mitra; Sourav Dilipkumar;
(Secunderabad, IN) |
Correspondence
Address: |
ALIX YALE & RISTAS LLP
750 MAIN STREET, SUITE 1400
HARTFORD
CT
06103
US
|
Family ID: |
39157677 |
Appl. No.: |
12/310693 |
Filed: |
August 31, 2007 |
PCT Filed: |
August 31, 2007 |
PCT NO: |
PCT/IN07/00382 |
371 Date: |
March 4, 2009 |
Current U.S.
Class: |
514/274 ;
215/227; 514/365 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 31/00 20130101; A61K 9/2009 20130101; A61K 9/2031 20130101;
A61K 31/00 20130101; A61P 31/18 20180101; A61K 9/2013 20130101;
A61K 9/2027 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/274 ;
514/365; 215/227 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 31/427 20060101 A61K031/427; B65D 39/00 20060101
B65D039/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 4, 2006 |
IN |
1597/CHE/2006 |
Claims
1-30. (canceled)
31. A process of preparing a pharmaceutical formulation, comprising
essentially of: a. dissolving or suspending at least one anti-retro
viral drug and optionally at least one pharmaceutically acceptable
additive, in an organic solvent to obtain a solution or dispersion;
b. drying said solution or dispersion to obtain granules; c.
optionally lubricating said granules; d. compressing said granules
into tablets or filling it into capsules.
32. The process according to claim 31, wherein said anti-retro
viral drug is selected from the group consisting of HIV protease
inhibitors, Nucleoside Reverse Transcriptase Inhibitors and/or
Non-Nucleoside Reverse Transcriptase Inhibitors and their
mixtures.
33. The process according to claim 32, wherein said anti-retro
viral drug is lopinavir, ritonavir or a combination thereof.
34. The process according to claim 31, wherein said
pharmaceutically acceptable additive is selected from a group
consisting of: a. solubilizing agents; b. muco-adhesive agents and
optionally c. glidants.
35. The process according to claim 34, wherein said solubilizing
agent is selected from a group consisting of:
polyethylene-polypropylene glycol copolymer (Poloaxamer), glyceryl
mono-oleate, sorbitan esters, polyoxyl castor oil, and
polyoxyethylene stearates.
36. The process according to claim 34, wherein said muco-adhesive
agent is selected from a group consisting of: cellulose ethers,
polyacrylic acid, polymethacrylates, polydextrose, co-povidone,
polyvinyl alcohol, chitosan, guar gum, sodium alginate, dextrin and
polyethylene glycol.
37. The process according to claim 31, wherein said organic solvent
is selected from a group consisting of: dichloromethane, methanol,
ethanol, acetone, ethyl acetate, and isopropyl alcohol.
38. The process according to claim 31, wherein said pharmaceutical
formulation additionally contains acceptable pharmaceutical
excipients selected from a group consisting of: diluents, binders,
disintegrants, and surfactants.
39. The process according to claim 33, wherein lopinavir and
ritonavir is present in a proportion of 4:1 by weight.
40. A method of treating an HIV infection comprising administering
a pharmaceutical composition prepared by the process of claim 31 to
a mammal in need of such treatment.
41. A process of preparing a pharmaceutical formulation, consisting
essentially of: a. dissolving lopinavir, ritonavir, poloxamer,
glyceryl mono-oleate and povidone, in methanol to obtain a
solution; b. drying said solution to obtain granules; c.
lubricating said granules with colloidal silicon dioxide,
hydrogenated cotton seed oil and sodium lauryl sulfate; d.
compressing said lubricated granules into tablets or filling it
into capsules.
42. A method of treating an HIV infection comprising administering
a pharmaceutical composition prepared by the process of claim 41 to
a mammal in need of such treatment.
43. A bottle-pack for storing an anti-retro viral composition,
wherein said bottle pack comprises a body having a mouth opening
and a closure, said closure being designed to hold a desiccant
within itself.
44. The bottle-pack according to claim 43, wherein said closure has
a cavity to hold said desiccant.
45. The bottle-pack as claimed in claim 44, wherein said cavity is
detachable or fixed permanently within said closure.
Description
FIELD OF INVENTION
[0001] The present invention relates to a pharmaceutical
formulation and in particular to pharmaceutical formulations for
use in HIV therapy. It also discloses the processes to make the
same. The invention has been developed primarily for use as a
formulation to be used for treatment in HIV therapy and will be
described hereinafter with reference to this application. Also
disclosed is an improved bottle pack for storing the formulations.
However, it will be appreciated that the invention is not limited
to this particular field of use.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
[0002] Any discussion of the prior art throughout the specification
should in no way be considered as an admission that such prior art
is widely known or forms part of the common general knowledge in
the field.
[0003] There are multiple formulations known for use in HIV
treatment therapy. The active substance Ritonavir [NORVIR soft
gelatin capsule] is characterized by low aqueous solubility, a lack
of bioavailability when given in the solid state, instability once
in solution under ambient conditions and a metallic taste. U.S.
Pat. No. 5,484,801 discloses a formulation wherein Ritonavir
formulation has been optimized with respect to the vehicle, which
essentially is a solvent comprising a mixture of (1) (a) a solvent
selected from propylene glycol and polyethylene glycol or (b) a
solvent selected from polyoxyethyleneglycerol triricinoleate,
polyethylene glycol 40 hydrogenated castor oil, fractionated
coconut oil, polyoxyethylene (20) sorbitan monooleate and
2-(2-ethoxyethoxy) ethanol or (c) a mixture thereof and (2) ethanol
or propylene glycol to improve the bioavailability.
[0004] Whereas Kaletra.RTM. is a formulation of two HIV protease
inhibitors [Lopinavir and Ritonavir] in a single formulation. Till
recently, this formulation was available in a soft gel capsule,
embodied in the patent U.S. Pat. No. 6,458,818 granted to Abbott.
The patent covers a solution of Lopinavir and Ritonavir in a long
chain fatty acid organic solvent. This soft gel formulation has
been criticized due to stability problems and need for keeping the
formulation in refrigerated condition. Abbott has now introduced a
new tablet formulation for combined administration of Lopinavir and
Ritonavir, instead of the previously known soft gel formulation. It
has also filed patent applications related to this tablet
formulation. For instance, WO2005039551 covers a combination of
Lopinavir and Ritonavir in a water soluble polymer and surfactant
wherein the tablet is formulated by melt extrusion process.
Specifically, the disclosed process comprises following steps:
[0005] a) preparing a mixture of combination HIV protease
inhibitors, a water-soluble polymer and a surfactant, [0006] b)
feeding the mixture in a twin screw extruder while maintaining a
high temperature [133.degree. C.] to form a homogeneous melt,
[0007] c) feeding this melt to a calendar with counter rotating
rollers to be pressed into tablets.
[0008] HIV therapy formulations need to be made in the most
economical manner thereby reducing the final prices for AIDS
patients across the world, especially in third world and developing
countries. The above formulation and related melt extrusion process
on account of its requiring expensive extrusion machinery & use
of multiple surfactants [N Vinyl pyrrolidone and Sorbitan
monolaureate or polyoxyethyleneglycerol oxystearate] may not
necessarily result in an economical formulation. Also, since the
disclosed process requires heating the drug constituents to high
temperatures [exceeding 100.degree. C.] it may possibly result in
degradation of the drug constituents.
OBJECTS OF THE INVENTION
[0009] It is an object of the present invention to overcome or
ameliorate at least one of the disadvantages of the prior art, or
to provide a useful alternative.
[0010] It is an object of the invention in its preferred form to
provide an economical formulation for administration of at least
one anti-retro viral drug.
[0011] It is an object of the invention in its preferred form to
provide an economical formulation for administration of a plurality
of anti-retro viral drugs in a single formulation.
[0012] It is an object of the invention in its preferred form to
provide an economical formulation for administration of a plurality
of protease inhibitors in a single formulation.
[0013] It is an object of the invention in its preferred form to
provide an economical formulation for administration of Lopinavir
and Ritonavir in a single formulation.
[0014] It is another object of the invention to provide a
formulation which does not require use of expensive melt extrusion
equipment.
[0015] It is another object of the invention to provide a
formulation which does not require heating the drug constituents
and thereby reduce chances of degradation of the drug
constituents.
[0016] It is a further object of the invention to provide an
improved bottle pack for storing the formulations wherein the
desiccant is packed within the closure of the bottle.
SUMMARY OF THE INVENTION
[0017] According to the invention there is provided a
pharmaceutical formulation for use in HIV therapy. According to one
aspect of the invention there is also provided a process to make
the same.
[0018] As presently contemplated, in one broad form, the invention
provides a process to make a pharmaceutical formulation comprising
the following steps: [0019] a. granulating at least one anti-retro
viral drug and at least one pharmaceutically acceptable additive
such as a solubilizing agent, using an organic solvent; [0020] b.
milling product of step [a]; [0021] c. compressing milled product
of step [b] into tablets or filling it into capsules.
[0022] Another aspect of the invention provides for a
pharmaceutical formulation prepared by a process disclosed
above.
[0023] As presently contemplated, in another broad form the
invention provides a process to make a pharmaceutical formulation
comprising the following steps: [0024] a. granulating a plurality
of anti-retro viral drugs and at least one pharmaceutically
acceptable additive such as a solubilizing agent, using an organic
solvent; [0025] b. milling the granules so formed; [0026] c.
processing the milled product into pharmaceutical formulations such
as tablets or capsules.
[0027] Another aspect of the invention provides for a
pharmaceutical formulation prepared by a process disclosed
above.
[0028] Another aspect of the invention provides for process to make
pharmaceutical formulation comprising the steps of: [0029] a)
mixing a plurality of anti-retro viral drugs with pharmaceutical
additives such as a solubilizing agent in an organic solvent;
[0030] b) mixing a glidant and a muco-adhesive excipients in a
solvent; [0031] c) mixing product of step [a] and [b] [0032] d)
drying product of step [c]; [0033] e) milling product of step [d];
[0034] f) processing the milled product into pharmaceutical
formulations such as tablets or capsules.
[0035] Another aspect of the invention provides for a
pharmaceutical formulation prepared by a process described
above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] A preferred embodiment of one the aspects of the invention,
i.e. the bottle pack for packing anti retro viral formulations will
now be described, by way of example only, with reference to the
accompanying drawings in which:
[0037] FIG. 1 is a cross section view of a closure of the bottle
pack according to the invention, while FIG. 1A shows a cross
section view of an alternative closure of the bottle pack.
[0038] In FIG. 1, closure [2] has a receptacle [3] for holding a
desiccant [4] within closure itself. Here the receptacle [3] is a
distinct part that is attached/fixed to the closure [2].
[0039] While in the embodiment in FIG. 1A, the receptacle [3] is
molded within the closure [2] itself such that it is a permanent
part of the closure body.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE
INVENTION
[0040] The bioavailability of drugs is directly related to their
dissolution in the gastrointestinal fluids. The anti retro viral
drug may be selected from HIV protease inhibitor[s] such as
Lopinavir, Ritonavir, Saquinavir, Nelfinavir, Atazanavir,
Indinavir, Tipranavir, Palinavir, Amprenavir, Fosemaprenavir &
Darunavir etc. Also, other anti-retro viral drugs such as
Nucleoside Reverse Transcriptase Inhibitors [NRTIs] or
Non-Nucleoside Reverse Transcriptase Inhibitors [NNRTIs] can be
effectively employed without undue experimentation in the present
invention to render a stable and economical formulation. For e.g.
Nucleoside Reverse Transcriptase Inhibitors could be selected from
Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine,
Zidovudine & Zalcitabine. Similarly, NNRTIs could be selected
from Nevirapine, Delavirdine or Efavirenz. Also, Nucleotide Reverse
Transcriptase Inhibitors such as Tenofovir could also be employed.
The preferred single drug is Ritonavir.
[0041] Thus, even a combination of any of the above anti-retro
viral drugs and at least one pharmaceutically acceptable additive
granulated in an organic solvent subsequently milled, and
subsequently processed to pharmaceutical formulations such as
tablets or capsules would also come within the ambit of the process
of present invention. The preferred drug combination is
Lopinavir:Ritonavir in a proportion of 4:1.
[0042] Formulation methods such as melt extrusion, spray drying and
solvent evaporation with melt extrusion have been suggested to make
tablet formulations of Lopinavir and Ritonavir combination. These
methods need specialized equipment and heating at high
temperatures.
[0043] The present invention avoids factors such as use of
specialised melt extrusion equipment, processing at high
temperatures and provides a stable, solid pharmaceutical dosage
form comprising at least one protease inhibitor admixed with
pharmaceutical additives, granulated in an organic solvent, milled
and finally processing the milled product into pharmaceutical
formulations such as tablets or capsules. Thus, using wet
granulation manufacturing process and standard equipment a novel,
stable and economical formulation for delivering at least one
anti-retro viral drug is disclosed. The formulation may also
consist of a plurality of HIV protease inhibitors. The process of
granulation is carried out in presence of an organic solvent. The
process sequence consists broadly of: [0044] a) Mixing at least one
anti-retro viral drug with an organic solvent and a pharmaceutical
additives, preferably a solubilizer; [0045] b) Mixing and sifting
excipients[s] and then adding them to an organic solvent,
preferably the same as used in step [a]. The excipients can be one
that has muco-adhesive property such as HPMC along with more
excipients such as a glidant for e.g. colloidal silicon dioxide;
[0046] c) Mixing the above two to form a uniform thick paste;
[0047] d) Drying the paste using vacuum or nitrogen stream or heat;
[0048] e) Milling the above dried mass; [0049] f) Optionally,
adding lubricants to the milled mixture. [0050] g) This milled
product can be compressed into tablets or filled in capsules.
[0051] It is to be noted that all the steps [a] and [b] can be
combined, such that all the items are mixed in the organic solvent
to form a paste. Also, instead of one drug, more than one drug can
also be mixed in step [a]. The process may be is carried out in a
Nitrogen atmosphere. Examples have been provided that will clarify
the above general process steps.
[0052] The solvents to be used are organic solvents such as
methanol, dichloromethane, ethanol, acetone, ethyl acetate,
isopropyl alcohol, preferably, dichloromethane.
[0053] The term `pharmaceutically acceptable additive` includes
`pharmaceutically acceptable excipient` within its ambit and the
singular term includes plural as well. Pharmaceutically acceptable
additives such as a solubilizing agent or a combination of
solubilizing agents, pharmaceutically acceptable excipients having
muco-adhesive properties, a glidant, a lubricant and a
disintegrating agent can be added to further enhance the properties
of the formulation. The solubilizing agent may be either a
pharmaceutically acceptable polymer or a pharmaceutically
acceptable copolymer or any pharmaceutically acceptable fatty acid
ester, used singly or in combination and should ideally be
dispersible or soluble in organic solvent selected. Examples of
solubilizing agents are glyceryl mono-oleate,
polyethylene-polypropylene glycol copolymer [Poloaxamer], sorbitan
esters, polyoxyl castor oil, polyoxyethylene stearates.
Commercially available substances such as Poloaxamer 124/407 can
also serve as the solubilizing agent. The pharmaceutically
acceptable excipient having muco-adhesive properties include
cellulose ethers, polyacrylic acid, polymethacrylates, poloxamer,
polydextrose, copovidone, polyvinyl alcohol, chitosan, guar gum,
sodium alginate, dextrin, polyethylene glycol etc. An e.g. for
excipient having muco-adhesive property is Hydroxypropylmethyl
cellulose [HPMC, commercially available as Hypromellose].
[0054] Glidants improve the flowability of the powder making up the
tablet during production. Glidants can be selected from selected
from the group consisting of: silicon dioxide, colloidal silicon
dioxide, fumed silicon dioxide, sodium aluminosilicate, calcium
silicate, powdered cellulose, microcrystalline cellulose, corn
starch, sodium benzoate, calcium carbonate, magnesium carbonate,
asbestos free talc, metallic stearates, calcium stearate, magnesium
stearate, zinc stearate, stearowet C, starch, starch 1500,
magnesium lauryl sulfate, or magnesium oxide, where colloidal
silicon dioxide is the preferred glidant.
[0055] Lubricants may be selected from the group of magnesium
stearate, calcium stearate, sodium stearyl fumarate, stearic acid,
hydrogenated cottonseed oil, sodium benzoate, sodium lauryl sulfate
etc.
[0056] Skilled professionals will appreciate that although the
examples disclosed below involve use of rapid mixer granulator,
alternative equipments like planetary mixers, ribbon blender etc.
can also be employed without any undue experimentation to get the
desired results. Although the invention has been described with
reference to specific examples, it will be appreciated by those
skilled in the art that the invention may be embodied in other
forms.
[0057] In one aspect of the invention, the pharmaceutical dosage
form comprises: [0058] a) from about 5 to about 30% by weight of
the total dosage form (preferably from about 10 to about 25% by
weight of the total dosage form) of at least one anti-retro viral
drug; [0059] b) from about 10 to about 40% by weight of the total
dosage form (preferably from about 10 to about 25% by weight of the
total dosage form) of a solubilizing agent (or any combination of
thereof) [0060] c) from about 3 to about 70% by weight of the total
dosage form (preferably from about 50 to about 65% by weight of the
total dosage form) of a muco-adhesive excipient (or any combination
of thereof) [0061] d) quantities of lubricants and glidants are to
be added using conventional knowledge. [0062] d) solvent for
granulation is also added in terms of standard wet granulation
parameters.
[0063] The milled product post granulation is processed further,
for e.g. it can be compressed to form tablets or filled into
capsules, using standard machines/processes, known to persons
skilled in the art.
[0064] In its preferred form, the process involves: [0065] a)
mixing lopinavir and ritonavir and at least one solubilizing agent,
in the presence of an organic solvent; [0066] b) mixing a polymer
and glidant in an organic solvent; [0067] c) mixing the products of
step[a] and [b] to form a uniform paste, [0068] d) drying the
paste; [0069] e) milling the dried product; [0070] f) processing
the milled product into pharmaceutical formulations such as tablets
or capsules.
[0071] The formulations of the present invention can be stored in
ordinary HDPE/plastic bottles. However, we have disclosed an
improved bottle pack for storing such formulations. Normal bottles
have a closure with a cavity that closes around the bottle's neck
such that the neck of the bottle fits within the closure's cavity.
When medicines are stored in bottles, a desiccant is also added to
absorb moisture. But this practice means an additional processing
step on the packing line as also the risk that some patients may
ingest the desiccant confusing it with medicine.
[0072] Our improved bottle pack consists of a bottle and a closure
that has a receptacle within its cavity such that the receptacle
holds the desiccant. The closure is fitted by the bottle pack
supplier with a desiccant within the receptacle and hence there is
no need for putting in a desiccant at the time of filling the
medicines. The receptacle may be formed as a part of the closure
itself or it may be attached/added inside the closure. The
receptacle may fixed within the closure or it may be removably
fixed within the closure. FIG. 1 illustrates a closure where the
receptacle is added inside the closure, while FIG. 1A illustrates a
closure where the receptacle is a part of the closure body
itself.
[0073] Such a closure with a pre-fitted desiccant has the following
advantages: [0074] a) The desiccant in the top portion of the
bottle helps in capturing all the moisture in the head space much
faster as moisture is vaporizing in an upward direction. In a
normal bottle where the desiccant sachet is put inside along with
the pharmaceutical product, it absorbs the moisture whenever
moisture settles down. [0075] b) Different quantities of desiccant
can be fixed within the receptacle without changing the
bottle/closure dimensions. [0076] c) The present closure eliminates
one extra operation of inserting the desiccant on machine and also
reduced inventory, reduced storage space as this desiccant i.e.
pre-filled inside the closures.
EXAMPLE 1
Wet Granulation Process
TABLE-US-00001 [0077] Ingredient % w/w Lopinavir 20.0 Ritonavir 5.0
Poloxamer 124 12.0 Hypromellose (6 cps) 58.0 Colloidal silicon
dioxide 3.0 Sodium stearyl fumarate 2.0 Dichloromethane q.s.
[0078] Manufacturing Steps: [0079] a Lopinavir, Ritonavir and
Poloxamer 124 were dissolved in dichloromethane; [0080] b.
Colloidal silicon dioxide and hypromellose were sifted through a
size 20 mesh; [0081] c. The mixture from step [b] was loaded into a
rapid mixer granulator; [0082] d. The drug mixture of step [a] was
added to the granulator and processed; [0083] e. The product was
dried under vacuum at about 40.degree. C.; [0084] f. The dry
product was then milled in a multimill; [0085] g. Sodium lauryl
sulfate was mixed with milled product and sifted for about 10
minutes; [0086] h. This sifted product was finally compressed into
tablets.
EXAMPLE 2
TABLE-US-00002 [0087] Ingredient % w/w Lopinavir 20.0 Ritonavir 5.0
Glyceryl mono-oleate 4.0 Poloxamer 407 63.0 Colloidal silicon
dioxide 5.0 Sodium stearyl fumarate 2.0 Talc 1.0 Methanol q.s.
[0088] Manufacturing Steps: [0089] a. Lopinavir, Ritonavir and
glyceryl mono-oleate were dissolved in methanol; [0090] b.
Colloidal silicon dioxide and Poloxamer 407 were sifted through a
size 20 mesh; [0091] c. The mixture from step [b] was loaded into a
rapid mixer granulator; [0092] d. The drug solution of step [a] was
added to the granulator and processed; [0093] e. The product was
dried under vacuum at about 40.degree. C.; [0094] f. The dry
product was then milled in a multimill; [0095] g. Sodium lauryl
sulfate and talc was mixed with milled product and sifted for about
10 minutes; [0096] h. This sifted product was finally compressed
into tablets.
EXAMPLE 3
TABLE-US-00003 [0097] Ingredient % w/w Lopinavir 15.0 Ritonavir
3.75 Glyceryl monooleate 5.0 Poloxamer 407 15.0 Hypromellose (3
cps) 55.25 Colloidal silicon dioxide 3.0 Hydrogenated cottonseed
oil 2.0 Sodium lauryl sulfate 1.0 Methanol q.s.
[0098] Manufacturing Steps: [0099] a. Lopinavir, Ritonavir and
glyceryl monooleate were dissolved in methanol; [0100] b. Colloidal
silicon dioxide and hypromellose were sifted through a size 20
mesh; [0101] c. The mixture from step [b] was loaded into a rapid
mixer granulator; [0102] d. The drug solution of step [a] was added
to the granulator and processed; [0103] e. The product was dried
under vacuum at about 45.degree. C.; [0104] f. The dry product was
then milled in a multimill; [0105] g. Sodium lauryl sulfate and
hydrogenated cottonseed oil was mixed with milled product and
sifted for about 10 minutes; [0106] h. This sifted product was
finally compressed into tablets.
EXAMPLE 4
TABLE-US-00004 [0107] Ingredient % w/w Lopinavir 22.0 Ritonavir 5.5
Sorbitan laureate 10.0 Poloxamer 407 56.5 Colloidal silicon dioxide
3.0 Sodium stearyl fumarate 3.0 Ethyl acetate q.s.
[0108] Manufacturing Steps: [0109] a. Lopinavir, Ritonavir and
sorbitan laureate were dissolved in ethyl acetate; [0110] b.
Colloidal silicon dioxide and Poloxamer 407 were sifted through a
size 20 mesh; [0111] c. The mixture from step [b] was loaded into a
rapid mixer granulator; [0112] d. The drug solution of step [a] was
added to the granulator and processed; [0113] e. The product was
dried under vacuum at about 45.degree. C.; [0114] f. The dry
product was then milled in a multimill; [0115] g. Sodium lauryl
sulfate was mixed with milled product and sifted for about 10
minutes; [0116] h. This sifted product was finally compressed into
tablets.
EXAMPLE 5
TABLE-US-00005 [0117] Ingredient % w/w Lopinavir 16.4 Ritonavir 4.1
Sorbitan laurate 6.8 Copovidone 70.1 Colloidal silicon dioxide 1.6
Sodium stearyl fumarate 1.0 Ethyl acetate q.s.
[0118] Manufacturing Steps: [0119] a. Lopinavir, Ritonavir and
sorbitan laurate were dissolved in ethyl acetate; [0120] b.
Colloidal silicon dioxide and Copovidone were sifted through a size
20 mesh; [0121] c. The mixture from step [b] was loaded into a
rapid mixer granulator; [0122] d. The drug solution of step [a] was
added to the granulator and processed; [0123] e. The product was
dried under vacuum at about 40.degree. C.; [0124] f. The dry
product was then milled in a multimill; [0125] g. Sodium stearyl
sulfate was mixed with milled product and sifted for about 10
minutes; [0126] h. This sifted product was finally compressed into
tablets.
EXAMPLE 6
TABLE-US-00006 [0127] Ingredient % w/w Lopinavir 16.4 Ritonavir 4.1
Sorbitan laurate 6.8 Copovidone 70.1 Colloidal silicon dioxide 1.6
Sodium stearyl fumarate 1.0 Dichloromethane q.s.
[0128] a. Lopinavir, Ritonavir, Sorbitan monolaurate, Copovidone
and colloidal silicon were put in a rapid mix granulator and mixed;
[0129] b. Dichloromethane was added and the mixture was processed
till a uniform wet mass was formed; [0130] c. The wet mass was
dried under vacuum at about 45.degree. C.; [0131] d. The dry
product was then milled in a comminuting mill; [0132] e. Sodium
lauryl sulfate was mixed with milled product and product was
finally compressed into tablets.
[0133] An alternative embodiment of the invention is disclosed
below:
EXAMPLE 7
TABLE-US-00007 [0134] Ingredient % w/w Ritonavir 10.0 Poloxamer 124
10.0 Copovidone 77.0 Colloidal silicon dioxide 2.0 Sodium stearyl
fumarate 1.0 Dichloromethane q.s.
[0135] a. Ritonavir, copovidone colloidal silicon dioxide and
Poloxamer 124 were put in a planetary mixer and mixed for 30
minutes [0136] b. Dichloromethane was added and the mixture was
mixed continuously till a uniform wet mass was obtained. [0137] c.
The wet mass was then removed from the planetary mixer and
transferred to the tray dryer and dried at 40-50.degree. C.
preferably under vacuum. [0138] d. The dried material was then
milled using comminuting mill. [0139] e. The sodium stearyl
fumarate was mixed with milled material and finally compressed into
tablets.
[0140] An alternative formulation is disclosed below:
EXAMPLE 8
TABLE-US-00008 [0141] Ingredient % w/w Ritonavir 10.0 Sorbitan
monolaurate 14.0 Copovidone 71.0 Colloidal silicon dioxide 2.0
Sodium stearyl fumarate 1.0
[0142] a. Ritonavir, copovidone colloidal silicon dioxide and
Sorbitan monolaurate were put in a jacketed vessel and mixed for 30
minutes [0143] b. The mixture was heated with constant stirring
till the mixture temperature reached the melting point of
Ritonavir. [0144] c. The heating was stopped and the material was
allowed to cool down. [0145] d. The dried material was then milled
using comminuting mill. [0146] e. The sodium stearyl fumarate was
mixed with milled material and finally compressed into tablets.
EXAMPLE 9
TABLE-US-00009 [0147] Ingredient % w/w Lopinavir 20.0 Ritonavir 5.0
Poloxamer 124 12.0 Hypromellose (6 cps) 58.0 Colloidal silicon
dioxide 3.0 Sodium stearyl fumarate 2.0 Dichloromethane q.s.
[0148] a. Lopinavir, Ritonavir and poloxamer were dissolved in
dichloromethane. [0149] b. Colloidal silicon dioxide and
hypromellose were sifted through 20 mesh. [0150] c. All the
material from [b] was loaded in a Stainless steel vessel fitted
with agitating device/stirrer, containing a small quantity of the
solvent. [0151] d. The product of [step c] was mixed with the drug
solution [step a] in the stainless steel vessel till a uniform
thick paste was formed. [0152] e. The paste was dried at about
40.degree. C. under vacuum [a nitrogen stream could also be used].
[0153] f. The dried mass was milled using multimill. [0154] g. The
milled granules were mixed with sodium lauryl sulfate for 10
minutes and compressed into the tablets.
EXAMPLE 10
TABLE-US-00010 [0155] Ingredient % w/w Lopinavir 15.0 Ritonavir
3.75 Glyceryl monooleate 5.0 Poloxamer 407 15.0 Hypromellose (3
cps) 55.25 Colloidal silicon dioxide 3.0 Hydrogenated cottonseed
oil 2.0 Sodium lauryl sulfate 1.0 Methanol q.s.
[0156] a. Lopinavir, Ritonavir, poloxamer glyceryl monooleate and
copovidone were dissolved in methanol. [0157] b. The methanolic
solution was then spray dried at 70.degree. C. [0158] c. The spray
dried powder was then mixed with colloidal silicon dioxide,
hydrogenated cottonseed oil and sodium lauryl sulfate for 10
minutes [0159] d. This was then compressed into the tablets.
EXAMPLE 11
TABLE-US-00011 [0160] Ingredient % w/w Lopinavir 16.4 Ritonavir 4.1
Sorbitan laurate 6.8 Copovidone 70.1 Colloidal silicon dioxide 1.6
Sodium stearyl fumarate 1.0 Dichloromethane q.s.
[0161] a. Lopinavir, Ritonavir and sorbitan laurate were dissolved
in dichloromethane. [0162] b. Colloidal silicon dioxide and
Copovidone were sifted through 20 mesh and loaded into in a
suitable stainless steel container fitted with agitating
device/stirrer and containing a small quantity of the solvent.
[0163] c. The powdered blend in the stainless steel container was
mixed with the drug solution till a homogeneous slurry was formed.
[0164] d. The slurry was dried at about 40.degree. C. [0165] e. The
dried mass was milled using multimill. [0166] f. The milled
granules were mixed with sifted sodium stearyl fumarate with for 10
minutes and compress into the tablets.
* * * * *