Pharmaceutical Antiretroviral Composition
FIELD OF INVENTION
The present invention relates to a pharmaceutical antiretroviral composition comprising
At least one o more anti-retroviral agents, the manufacturing process thereof and use of
the said composition for the prevention, treatment or prophylaxis of diseases caused by
retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
BACKGROUND AND PRIOR ART
Demographically the second largest country in the world, India also has the third largest
number of people living with HIV/AIDS. As per the provisional HIV estimate of 2008-
09, by NACO (National AIDS Control Organization) there are an estimated 22.7 lakh
people living with HIV/AIDS in India. The HIV prevalence rate in the country is 0.29
percent.
Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the
body's immune system as well as progressive deterioration of the central and peripheral
nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly
and has now reached epidemic proportions within a relatively limited segment of the
population. Intensive research has led to the discovery of the responsible agent, human Tlymphotropic
retrovirus . 1 (HTLV-1 1), now more commonly referred to as the human
immunodeficiency virus or HIV.
Human immunodeficiency virus (HIV) is the etiological agent of Acquired Immune
Deficiency Syndrome (AIDS) that has created a major health care problem not only in
India but .also globally.
HIV is a member of the class of viruses known as retroviruses. The retroviral genome is
composed of A, which is converted to DNA by reverse transcription. This retroviral
DNA is then stably integrated into a host cell's chromosome and, employing the
replicative processes of the host cells, produces new retroviral particles and advances the
infection to other cells. HIV appears to have a particular affinity for the human T- 4
lymphocyte cell which plays a vital role in the body's immune system. HIV infection of
these white blood cells depletes this white cell population. Eventually, the immune
system is rendered inoperative and ineffective against various opportunistic diseases.
The current strategy for the treatment of HIV infection is Highly Active Antiretroviral
Therapy (HAART). HAART normally consists of a combination of three or more
antiretroviral drugs (ARV) taken together.
Currently available antiretroviral drugs for the treatment of HIV include nucleoside
reverse transcriptase inhibitors (NRTI) or approved single pill combinations: zidovudine
or AZT (Retrovir®), didanosine or DDI (Videx®), stavudine or D4T (Zenith®),
lamivudine or 3TC (Epivir®), zalcitabine or DDC (Hivid®), abacavir succinate (Ziagen®),
tenofovir disoproxil marate salt (Viread®), emtricitabine (Emtriva®), Combivir®
(contains 3TC and AZT), Trizivir® (contains abacavir, 3TC and AZT); non-nucleoside
reverse transcriptase inhibitors (N RTI): nevirapine (Viramune®), delavirdine
(Rescriptor®) and efavirenz (Sustiva®), peptidomimetic protease inhibitors or approved
formulations: saquinavir (Invirase®, Fortovase®), indinavir (Crixivan®), ritonavir
(Norvir®), nelfinavir (Viracept®), amprenavir (Agenerase®), atazanavir (Reyataz®),
fosamprenavir (Lexiva®), Kaletra® (contains lopinavir and ritonavir), one fusion inhibitor
enfuvirtide (T-20, .Fuzeon®), Truvada® (contains Tenofovir and Emtricitabine) and
Atripla® (contains fixed-dose triple combination of tenofovir, emtricitabine and
efavirenz).
The goal of HAART therapy is to maximize viral suppression thus limiting and reversing
damage to the immune system, leading to decline in opportunistic infections. The
durability of response depends on various factors such as viral, drug and patient related
factors.
Viral factors include the genetic barrier to resistance development, the capacity to remain
latent and ongoing replication. Drug related factors include the potency, tolerability and
convenience of a regimen and pharmacologic barriers to resistance as a function of
concentrations achieved by these drugs. However, the most important patient related
factor is adherence, but other factors such as toxicities, quality of life, and psychosocial
issues also need to be addressed to ensure the success of therapy.
Adherence is critical for success of HAART. Numerous studies have documented that
high level of adherence is needed to ensure maximal and durable suppression of the virus.
(Paterson DL. et .Adherence to protease inhibitor therapy and outcomes in patients with
HIV infection Annals of Internal Medicine, 2000; 133:21-30).
Various factors influence adherence, one of which is use of different drug combinations,
which are difficult to adhere to because of different dosage forms for administering each
antiretroviral drug separately, this is particularly important in case of elderly patients or it
may also be due to other factors such as food restrictions; treatment costs, difficulties in
accessing care, and unavailability of drugs in remote places.
Since eradication of HIV is unlikely with currently available HAART and since the
evidence for structured treatment interruption seems
disappointing (Jintanat A. et al. Swiss HIV Cohort Study. Failures of 1week on, 1 week
off antiretroviral therapies in a randomized trial AIDS, 2003; 17:F33-F37), HIV therapy
needs to be life-long coupled with high levels of adherence to the therapy; this is a
demanding task for HIV infected patients due to various reasons like low morale, social
stigma, low immunity attributed to the disease. Further, studies have shown that
adherence to prescribed drugs over long treatment periods is generally poor. Nonadherence
to HAART can lead to rebound in viral replication and, in presence of suboptimal
drug
concentrations, rapid development of drug resistance. The development of drug resistance
can be disastrous because of the complexity and cost associated with second line
regimens and the potential for transmission of drug resistant virus in the community.
Thus, development of a fixed dose combination is a main step in simplifying the multi¬
drug combination therapy for improving patient adherence to the therapy since such nonadherence
may contribute to the development of viral resistance and treatment failure.
Further, the multi-drug combination therapy reduces the cost and also provides
development of a fixed dose combination.Another advantage is that patients prefer taking
one pill twice a day -as compared to three pills twice a day. Convenience increases
adherence, which ultimately leads to durable response in therapy.
Combination therapy, thus, reduces the daily doses to be taken by patients and simplifies
dosing schedule thereby increasing patient compliance. Combination therapy also
increases the drug efficacy. Use of combination therapy can yield an equivalent antiviral
effect with reduced toxicity. Further, it may also reduce the risk of giving the wrong dose
(high or low) of individual drugs since high doses can lead to development of serious
adverse events, low doses can lead to suboptimal drug concentrations and development of
drug resistance.
WO2008043829 discloses a method of treating HIV wherein emtricitabine, tenofovir and
nevirapine are administered once a day. However, this application fails to mention
whether the said combination is administered in a single dosage form or as a kit of parts.
WO04087169 discloses a composition useful for the treatment or prophylaxis of viral
infections comprising nevirapine and at least one antiviral active compound such as
alovudine.
O200 154234 discloses extended release formulations of nevirapine. However, given
the processing involved to formulate extended release formulation, the said application
fails to mention as to how to formulate multi-active ingredients or medicaments with
such extended release formulation.
It wi l further be appreciated by a person skilled in the art that extended release
formulations are generally designed to be gradually absorbed during transit through the
intestines, where the pH is high. Nevirapine, being a weak base agent, can be expected to
exhibit low solubility in the intestines. For this reason, it is reasonable to expect that an
extended release formulation of nevirapine might transit the G tract and be excreted
without sufficient dissolution and absorption of the nevirapine. This would make an
extended release formulation unworkable.
In addition to the above challenge, and to meet the patient acceptance levels, patient
adherence and high value treatment consideration prospects, specifically, to combat such
dreadful disease/ syndrome, a single complete package of such medicaments have still
remained out of reach of the patients at large.
Hence, there exists a need to formulate a suitable pharmaceutical antiretroviral
composition in a single complete package comprising a nucleoside reverse-transcriptase
inhibitor selected from lamivudine and emtricitabine, (ii) extended release nevirapine,
and (iii) tenofovir which would be convenient for patient administration thereby
achieving patient adherence and exhibiting desirable dissolution.
Further, in spite of all the available antiretroviral formulations and various methods
suggested in prior art there still have been difficulties such as incorporating a nucleoside
reverse-transcriptase inhibitor selected from lamivudine and emtricitabine, (ii) extended
release nevirapine, and (iii) tenofovir to provide a once or twice a day formulation which
is stable and suitable for administration.
OBJECT OF THE INVENTION
The object of the present invention is to provide a pharmaceutical antiretroviral
composition which is suitable for oral administration as a single complete package i.e. a
single kit form or single unit dosage form, optionally with pharmaceutically acceptable
excipients.
Another object of the present invention is to provide a pharmaceutical antiretroviral
composition comprising a single complete package, i.e. a single kit form or single unit
dosage form optionally with pharmaceutically acceptable excipients for once or twice a
day administration.
Yet another object of the present invention is to provide a pharmaceutical antiretroviral
composition with ease of manufacture.
Still another object of the present invention is to provide a pharmaceutical antiretroviral
composition for use in the prevention, treatment or prophylaxis of diseases caused by
retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a pharmaceutical
antiretroviral composition comprising (i) a nucleoside reverse-transcriptase inhibitor
selected from lamivudine and emtricitabine, (ii) extended release nevirapine, and (iii)
tenofovir.
According to another aspect of the present invention there is provided a pharmaceutical
antiretroviral composition comprising (i) a nucleoside reverse-transcriptase inhibitor
selected from lamivudine and emtricitabine, (ii) extended release nevirapine, and (iii)
tenofovir, optionally with one or more pharmaceutically acceptable excipients, in a single
unit dosage form.
According to another aspect of the present invention there is provided a pharmaceutical
antiretroviral composition comprising (i) a nucleoside reverse-transcriptase inhibitor
selected from lamivudine and emtricitabine, (ii) extended release nevirapine, and (iii)
tenofovir, optionally with one or more pharmaceutically acceptable excipients, in a kit
form.
According to another aspect of the present invention there is provided a process of
manufacturing a pharmaceutical antiretroviral composition comprising (i) a nucleoside
reverse-transcriptase inhibitor selected from lamivudine and emtricitabine, (ii) extended
release nevirapine, and (iii) tenofovir, optionally with one or more pharmaceutically
acceptable excipients.
According to yet another aspect of the present invention there is provided a method of
preventing, treating or prophylaxis of diseases caused by retroviruses, especially acquired
immune deficiency syndrome or an HIV infection, which method comprises
administering a pharmaceutical antiretroviral composition comprising (i) a nucleoside
reverse-transcriptase inhibitor selected from lamivudine and emtricitabine, (ii) extended
release nevirapine, and (iii) tenofovir.
DETAILED DESCRIPTION OF THE INVENTION
As discussed above, there is a need to develop and formulate a suitable pharmaceutical
antiretroviral composition comprising once or twice a day formulation of emtricitabine or
lamivudine, tenofovir and extended release nevirapine which would, not only, be
convenient for patient administration but would also maintain patient adherence for such
therapy.
The present invention thus provides a pharmaceutical antiretroviral composition
comprising (i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine, (ii) extended release nevirapine, and .(iii) tenofovir as a combined
preparation, for simultaneous or separate use in the treatment of an HIV infection.
It will be well acknowledged by a person skilled in the art that the active ingredient
nevirapine, may suitably be provided by incorporation in a pharmaceutically acceptable
extended release system.
As used herein, "extended release nevirapine" means nevirapine formulated to provide a
reduction in dosing frequency as compared to immediate-release nevirapine formulation
as well as to provide an in vitro and/or in vivo drug release profile of extended duration,
in particular relative to the release profile of an immediate release nevirapine
formulation.
Further, the term "extended-release", as used herein, refers to the release of an active
ingredient from a pharmaceutical composition, in which the active ingredient is released
over an extended period of time and/or at a particular location and is taken to encompass
sustained-release, controlied-release, modified-release, prolonged-release, delayedrelease,
and the like.
Suitable nevirapine-containing extended release formulations may include, but are not
limited to dissolution controlled release system, diffusion controlled release system,
dissolution and diffusion controlled release system, ion exchange resin-drug complex, pH
dependent formulation and osmotic pressure controlled system and any other release
systems known to person skilled in the art.
It will be appreciated from the above, that the respective therapeutic agents of the
combined preparation can be administered simultaneously, either in the same or different
pharmaceutical formulations or separately. If there is separate administration, it will also
be appreciated that the subsequently administered therapeutic agents should be
administered to a patient within a time scale so as to achieve, or more particularly
optimize, synergistic therapeutic effect of a combined preparation.
Thus, the present invention provides a pharmaceutical antiretroviral composition
comprising (i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine, (ii) extended release nevirapine, and (iii) tenofovir for once or twice a day
administration.
In one embodiment of the invention, the nucleoside reverse-transcriptase inhibitor is
lamivudine. In an alternative embodiment of the invention, the nucleoside reversetranscriptase
inhibitor is emtricitabine.
The terms "Emtricitabine", "Lamivudine", "Tenofovir", and "Nevirapine" and are used in
broad sense to include not only,"Emtricitabine", "Lamivudine", "Tenofovir" and
"Nevirapine" per se but also, their pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, pharmaceutically acceptable esters, pharmaceutically acceptable
hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable
derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable
prodrugs, pharmaceutically acceptable complexes and the like.
Nevirapine, is chemically known as ll-cyclopropyl-5,1 l-dihydro-4- methyl-6Hdipyrido[
3,2-b:2',3'-e][l,4]diazepin-6-one, belongs to a category of non-nucleoside
reverse transcriptase inhibitor (NNRTI) which is used to treat infection by HIV-I (human
immunodeficiency virus, type 1). Nevirapine binds directly to reverse transcriptase (RT)
and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by
causing a disruption of the enzyme's catalytic site. A preferred form of nevirapine is
nevirapine free base. Particularly preferred forms of nevirapine include nevirapine
anhydrate and nevirapine hemihydrate. A preferred dosage of nevirapine is from about
50 to about 500 mg..
A preferred form of tenofovir is tenofovir disoproxil fumarate. Tenofovir disoproxil
fumarate is also known as PMPA. Tenofovir DF is a fumaric acid salt of bisisopropoxycarbonyloxymethyl
ester derivative of tenofovir. Tenofovir disoproxil
fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy]
propyl] adenine fumarate (1:1). Tenofovir disoproxil fumarate requires initial diester
hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular
enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of
HTV reverse transcriptase by competing with the natural substrate deoxyadenosine 5 -
triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir
diphosphate is a weak inhibitor of mammalian DNA polymerases alpha & beta and of
mitochondrial DNA polymerase.
Tenofovir disoproxil fumarate is an analog of adefovir and is classified as a nucleotide
reverse transcriptase inhibitor (NtRTI). Tenofovir DF is a competitive inhibitor of other
naturally occurring nucleotides, and its ultimate biological activity is viral DNA chain
termination. Tenofovir DF is a novel nucleotide analog with antiviral activity against
both HIV and HBV. The mechanism of tenofovir DF is similar to that of nucleoside
analogs, which interferes with reverse transcriptase and prevents translation of viral
genetic material into viral DNA. Unlike the nucleoside analogs, the nucleotide reverse
transcriptase inhibitors are chemically pre-activated with the presence of phosphate
group. Since the phosphorylation step is not necessary, nucleotide analogs can
incorporate into viral DNA chain more rapidly than nucleoside analogs. More
importantly, this will bypass a viral mechanism of nucleoside resistance. A preferred
dosage of tenofovir is from about 100 to about 300 mg.
Lamivudine (also known as 3TC) is a synthetic nucleoside analogue, chemically known
as (2R,cis)-4-amino-l-(2-hydroxymethyl-l,3-oxathiolan-5-yl)-(lH)-pyrimidin-2- one
(Epivir(R)). Lamivudine has proven antiviral activity against HIV and other viruses such
as HBV.
Intracellular^, lamivudine is phosphorylated to its active 5'-triphosphate metabolite,
lamivudine triphosphate (L-TP). The principal mode of action of L-TP is the inhibition of
H V- reverse transcriptase (RT) via DNA chain termination after incorporation of the
nucleoside analogue into viral DNA. L-TP is a weak inhibitor of mammalian DNA
polymerases (alpha) and (beta), and mitochondrial DNA polymerase (gamma).
Lamivudine has also been referred to as (-)-l-[(2R, 5S) 2-(Hydroxymethyi)-l,3-
oxathiolan-5-yl] cystosine, (Hydroxymethyl)-l,3-oxathiolan-5-yl] cystosine and it has
proven antiviral activity against human immunodeftciency virus (HIV) and other viruses
such as hepatitis B. A preferred form of lamivudine is lamivudine free base. A preferred
dosage of lamivudine is from about 30 to about 300 mg.
Emtricitabine, is chemically known as 4-amino-5-fluoro-l- [2- (hydroxymethyl) - 1, 3-
oxathiolan-5-yl] - pyrimidin-2-one, belongs to a category of nucleoside reverse
transcriptase inhibitor (N T ) which is used to treat infection by H V- . Specifically,
emtricitabine inhibits HBV DNA polymerase and V-1 reverse transcriptase (RT) both
in vivo and in vi/ro.Emtricitabine is anabolized to its triphosphate form which is the
active moiety that inhibits the polymerase. A preferred form of emtricitabine is
emtricitabine free base, A preferred dosage of emtricitabine is from about is from about
100 to about 300 mg.
According to a preferred embodiment, the present invention provides a pharmaceutical
antiretroviral formulation comprising (i) a nucleoside reverse-transcriptase inhibitor
selected from lamivudine and emtricitabine, ( ) extended release nevirapine, and (iii)
tenofovir in a single unit dosage form, wherein nevirapine is incorporated/presented in
any one of the extended release systems mentioned above.
It will be appreciated that the suitable extended release systems are we l known to person
skilled in the art, and are incorporated herein to be envisaged under the ambit of the
invention. In a preferred embodiment, the extended release nevirapine is formulated to
release nevirapine over a period of up to about 24 hours,
According to the above embodiment, the pharmaceutical antiretroviral composition of the
present invention may preferably comprise nevirapine in an extended release form
comprising at least one hydrophilic and/or hydrophobic polymer and/or water-swellable
polymers, wherein nevirapine may preferably be (i) coated with one or more of the
aforementioned polymers; (ii) provided in a blend form with any of the aforementioned
polymers; or (iii) provided as an active-polymer complex with suitable ratios of the active
and atleast one polymer.
Hydrophilic polymers that may be used herein are pharmaceutically acceptable polymeric
materials having a sufficient number and distribution of hydrophilic substituents such as
hydroxy and carboxy groups to impart hydrophilic properties to the polymer as a whole.
The amount of hydrophilic polymer in the composition depends on the particular polymer
selected, on the active pharmaceutical agent and on the desired extended release profile.
According to the present invention, pharmaceutically acceptable hydrophilic polymer for
use in the pharmaceutical antiretroviral composition of the present invention may
comprise one or more, but not limited to hydroxypropylrhethylcellulose (HPMC, also
known as hypromellose), hydroxypropylcellulose (HPC), methylcellulose, carmellose
(carboxymethylcellulose), hydroxyethylcellulose (HEC), hydroxymethylcellulose,
methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,
carboxymethylcellulose calcium, xanthan gum, sodium alginate, ammonium alginate,
polyethylene oxide, potassium alginate, calcium alginate, propylene glycol alginate,
alginic acid, polyvinyl alcohol, povidone, carbomer, guar gum, locust bean gum,
potassium pectate, potassium pectinate, .polyvinylpyrrolidone, . polysaccharide,
polyalkylene oxides , polyalkyleneglyco!, starch and derivatives and crosslinked
homopolymers and copolymers of acrylic acid or mixtures thereof.
According to one aspect of the present invention, the hydrophilic polymer is included in
an amount of from about 5% to about 50%, preferably from about 10% to about 35%, by
weight of the composition.
According to the present invention, pharmaceutically acceptable hydrophobic polymer
for use in the pharmaceutical antiretroviral composition of the present invention may
comprise one or more, but not limited to, ethyl cellulose, cellulose acetate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl
methylcellulose phthalate, poly (a ky ) methacrylate, and copolymers of acrylic or
methacrylic acid esters, ammonio methyacrylate copolymer, methyacrylic acid
copolymers, methacrylic acid-acrylic acid ethyl ester copolymer, methacrylic acid esters
neutral copolymer, polyvinyl acetate, waxes, such as, beeswax, carnauba wax,
macrocrystalline wax, candelilla wax, spermaceti, montan wax, hydrogenated vegetable
oil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, paraffin wax, shellac
wax, petrolatum, ozokerite, and the like, as well as, synthetic waxes, e. g., polyethylene,
and the like; fatty acids such as, stearic acid, palmitic acid, lauric acid, eleostearic acids,
and the like; fatty alcohols, such as, lauryl alcohol, cetostearyl alcohol, stearyl alcohol,
cetyl alcohol and myristyl alcohol; fatty acid esters, such as, glyceryl monostearate,
glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax,
glyceryl palmitostearate and glyceryl behenate; vegetable oil, such as, hydrogenated
castor oil; mineral oil or mixtures thereof.
According to one aspect of the present invention, the hydrophobic polymer is included in
an amount of from about 5% to about 50%, preferably from about 10% to about 35%, by
weight of the composition
According to the present invention, pharmaceutically acceptable water-swellable
polymer for use in the pharmaceutical antiretroviral composition of the present invention
may comprise one or more, polyethylene oxide having a molecular weight of 100,000 to
8,000,000; poly (hydroxy alkyl methacrylate) having a molecular weight of from 30,000
to 5,000,000; poly (vinyl) alcohol, having a low acetal residue, which is cross-linked with
glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from
200 to 30,000; a mixture of methyl cellulose, cross- linked agar and carboxymethyl
cellulose; a water-insoluble, water-swellable copolymer produced by forming a
dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene,
propylene, butylene or isobutylene cross-linked with from 0.001 to 0.5 moles of saturated
cross-linking agent per mole of maleic anhydride in the copolymer; Carbopol® carbomer
which is as acidic carboxy polymer having a molecular weight of 450,000 to 4,000,000;
Cyanamer® polyacrylamides; cross-linked water swellable indene- maleic anhydride
polymers; Goodrich® polyacrylic acid having a molecular weight of 80,000 to 200,000;
starch graft copolymers; Aqua Keeps® acrylate polymer polysaccharides composed of
condensed glucose units such as diester cross-linked polyglucan, and the like;
Amberlite® ion exchange resins; Explotab® sodium starch glycolate; Ac-Di-Sol®
croscarmellose sodium or mixtures thereof.
As discussed above and hereinafter, the pharmaceutical antiretroviral composition of the
present invention preferably comprises lamivudine or emtricitabine andtenofovir along
with one or more pharmaceutically acceptable excipients to form an admixture, and
nevirapine along with one or more extended release polymer and one or more
pharmaceutically acceptable excipients to form another admixture, which admixtures are
blended and/or layered to provide a single unit dosage form.
Suitably, the pharmaceutical antiretroviral composition according to the present invention
are presented in solid dosage form, conveniently in unit dosage form, and include dosage
form suitable for oral and buccal administration such as, but not limited to, tablets,
capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small
tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres,
multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro¬
pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and
microspheres, multiparticulates) and sprinkles, however, other dosage forms such as
liquid dosage form may be envisaged under the ambit of the invention.
It is further well known in the art that a tablet formulation is the preferred solid dosage
form due to its greater stability, less risk of chemical interaction between different
medicaments, smaller bulk, accurate dosage, and ease of production.
In another embodiment, the present invention provides a pharmaceutical antiretroviral
composition comprising (i) a nucleoside reverse-transcriptase inhibitor selected from
lamivudine and emtricitabine, (ii) extended release nevirapine, and ( i) tenofovir in a kit
form.
Accordingly, the pharmaceutical antiretroviral composition i a kit form may comprise a
separate unit dosage forms of a nucleoside reverse-transcriptase inhibitor selected from
lamivudine and emtricitabine, tenofovir and extended release nevirapine.
According to the preferred embodiment, the pharmaceutical antiretroviral composition
may be administered simultaneously, separately or sequentially in a single unit dosage
form wherein the drugs and excipients are present in a single layer entity (such as a tablet
or tablet in a capsule).
According to another preferred embodiment, the pharmaceutical antiretroviral
composition may be administered as a bilayer tablet wherein each layer separately
contains drug/drugs and pharmaceutically acceptable excipients which are then
compressed to give a bilayer tablet.
According to yet another preferred embodiment, the pharmaceutical antiretroviral
composition may be. administered as a trilayer tablet wherein each layer separately
contains drug/drugs a d pharmaceutically acceptable excipients which are then
compressed to give a trilayer tablet.
According to the present invention,the pharmaceutical antiretroviral composition of the
present invention comprises a nucleoside reverse-transcriptase inhibitor selected from
lamivudine and emtricitabine,, tenofovir, and one or more pharmaceutically acceptable
excipients to form a first admixture,' and nevirapine in an extended release system with
one or. more pharmaceutically acceptable excipients to form a second admixture, which
first and second admixtures are blended and compressed in a single layer to provide a
single unit dosage form.
According to a preferred embodiment, the pharmaceutical antiretroviral composition of
the present invention comprises a nucleoside reverse-transcriptase inhibitor selected from
lamivudine and emtricitabine, tenofovir and one or more pharmaceutically acceptable
excipients to form a first admixture, and nevirapine in an extended release system with
one or more pharmaceutically acceptable excipients to form a second admixture, which
first and second admixtures are blended and compressed to provide a bilayered unit
dosage form.
According to another preferred embodiment, the pharmaceutical antiretroviral
composition of the present invention comprises tenofovir and one or more
pharmaceutically acceptable excipients to form a first admixture, and a nucleoside
reverse-transcriptase inhibitor selected from lamivudine and emtricitabine, , nevirapine in
an extended release system and one or more pharmaceutically acceptable excipients to
form a second admixture, which first and second admixtures are blended and compressed
to provide a bilayered unit dosage form.
According to another preferred embodiment, the pharmaceutical antiretroviral
composition of the present invention comprises a nucleoside reverse-transcriptase
inhibitor selected from lamivudine and emtricitabine with one or more pharmaceutically
acceptable excipients to form a first admixture, and tenofovir, nevirapine in an extended
release system with one or more pharmaceutically acceptable excipients to form a second
admixture, which first and second admixtures are blended and compressed to provide a
bilayered unit dosage form.
According to another prefe ed embodiment, the pharmaceutical antiretroviral
composition of the present invention comprises a nucleoside reverse-transcriptase
inhibitor selected from lamivudine and emtricitabine, with one or more pharmaceutically
acceptable excipients to form a first admixture, tenofovir along with one or more
pharmaceutically acceptable excipients to form a second admixture and nevirapine in an
extended release system with one or more pharmaceutically acceptable excipients to form
a third admixture, which first, second and third admixtures are blended and compressed
to provide a trilayered unit dosage form.
According to one embodiment of the invention, there s provided a process for preparing
a pharmaceutical composition of the type described herein, which process comprises
admixing (i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine, (ii) extended release nevirapine, and (iii) tenofovir with one or more
pharmaceutically acceptable excipients.
The pharmaceutical antiretroviral composition, according to the present invention, may
be prepared through various techniques or processes known in the art which includes, but
are not limited to direct compression, wet granulation, dry granulation, melt granulation,
melt extrusion, spray drying, solution evaporation or combinations thereof.
It will be acknowledged to a person skilled in the art, that the above mentioned
techniques may be used either singly or in combination with other above mentioned
techniques to provide a single layer, bilayer or trilayer or multilayer unit dosage form.
Suitable excipients may be used for formulating the various dosage forms according to
the present invention.
According to the present invention, pharmaceutically acceptable carriers, diluents or
fillers for use in the pharmaceutical antiretroviral composition of the present invention
may comprise one or more, lactose (for example, spray-dried lactose, a-lactose, b-
lactose), white sugar.lactitol, saccharose, sucrose, sugar compressible, sugar
confectioners, glucose, calcium carbonate, calcium dihydrogen phosphate dihydrates,
calcium- phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, silicified
microcrystalline cellulose, cellulose powdered, fructose, kaolin, sorbitol, manmtoi,
dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline
cellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted),
hydroxypropyl methylcellulose (HPMC), methylcellulose polymers,
hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene,
carboxymethylhydroxyethylcellulose and other cellulose derivatives, starches or modified
starches (including potato starch, corn starch, maize starch and rice starch) and mixtures
thereof.
According to the present invention, pharmaceutically acceptable surfactant may comprise
one or more, Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl
dimethyl amine oxide, Docusate sodium, Cetyltrimethyl ammonium bromide (CTAB)
Polyethoxylated alcohols, Polyoxyethylenesorbitan, Octoxynol, N, Ndimethyldodecylamine-
N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10
lauryl ether, , Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil,
Nonylphenolethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride.
Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates,
Naphthalenesulphonates, Olefin sulphonates, Alky! sulphates, Sulphates, Sulphated
natural oils & fats, Sulphated esters, Sulphatedalkanolamides, Alkylphenols, ethoxylated
&sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters
Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol
esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates,
Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide
linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted
ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic
acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n
dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine
sodium salt etc.
According to the present invention, glidants, anti-adherents and lubricants may also be
incorporated in the pharmaceutical antiretroviral composition of the present invention,
which may comprise one or more, stearic acid and pharmaceutically acceptable salts or
esters thereof (for . example, magnesium stearate, calcium stearate, sodium stearyl
fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes),
glycerides, glyceryl behenate, light mineral oil, PEG, silica acid or a derivative or salt
thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers
thereof, crospovidone, magnesium aluminosilicate and/ or magnesium
aluminometasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for
example, hydrogenated castor oil), mineral oil, stearic acid, colloidal anhydrous silica,
sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and
mixtures thereof.
According to the present invention, suitable binders may also present in the
pharmaceutical antiretroviral composition of the present invention,which may comprise
one or more, , polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s),
acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl
cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth,
sodium alginate, starches, corn starch, pregelatinized starch, microcrystalline celluloses
(MCC), silicified MCC, microfine celluloses, lactose, calcium carbonate, calcium sulfate,
sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium
oxide, stearic acid, gums, hydroxypropyl methylcelluloses or hypromelloses and
mixtures thereof or any other suitable binder.
According to the present invention, suitable disintegrants may also be present in the
pharmaceutical antiretroviral composition of the present invention,which may comprise
one or more, but not limited tohydroxylpropy! cellulose (HPC), low density HPC,
carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium;
starches exemplified under examples of fillers and carboxymethyl starch, hydroxylpropyl
starch, modified starch, pregelatinized starch, crystalline cellulose, sodium starch
glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and
mixtures thereof.
According to the present invention, suitable coloring agents and flavoring agents may
also be present in the pharmaceutical antiretroviral composition of the present invention,
selected from FDA approved colors and flavors for oral use.
It would be appreciated by a person skilled in the art, that according to the present
invention, the pharmaceutical antiretroviral composition may optionally have one or
more coatings, which are functional or non-functional. Functional coatings include
extended-release coatings and non-functional coatings include seal coatings and elegant
coatings. Additional excipients such as f lm forming polymers, solvents, plasticizers,
anu-adherents, opacifiers, colorants, pigments, antifoam agents, and polishing agents can
be used in coatings.
Suitable film- forming agents include, but are not limited to, cellulose derivatives, such
as, soluble alkyl- or hydroalkyl-cellulose derivatives such as methylcellu loses,
hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses,
hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl
celluloses, insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins,
starches and starch derivatives, polymers based on carbohydrates and derivatives thereof,
natural gums such as gum Arabic, xanthans, alginates, polyacrylic acids, polyvinyl
alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives
thereof, chitosan and derivatives thereof, shellac and derivatives thereof, waxes, fat
substances and mixtures thereof.
Suitable enteric coating materials, include, but are not limited to, cellulosic polymers like
cellulose acetate phthalates, cellulose acetate trimelli rates, hydroxypropyl
methylcellulose phthalates, polyvinyl acetate phthalates, etc., methacrylic acid polymers
and copolymers and mixtures thereof.
Some of the excipients are used as adjuvant to the coating process, including excipients
such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like.
Suitable plasticizers include, but are not limited to, castor oil, diacetylated
monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols,
propylene glycols, triacetin, triethyl citrate, and mixtures thereof.
Suitable opacifier includes, but is not limited to, titanium dioxide.
Suitable anti-adhesive, includes, but is not limited to, talc.
Suitable polishing agents includes, but is not limited to, polyethylene glycols of various
molecular weights or mixtures thereof, talc, surfactants (glycerol monostearate and
poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl
alcohol) and waxes (carnauba wax, candelilla wax and white wax) and mixtures thereof.
Suitable solvents used in the processes of preparing the pharmaceutical antiretroviral
composition of the present invention, include, but are not limited to, water, methanol,
ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl
ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl
acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol
monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,Ndimethylformamide,
tetrahydrofuran, and mixtures thereof.
According to a preferred embodiment, the pharmaceutical antiretroviral composition of
the present invention is processed by wet granulation of tenofovir and emtricitabine or
lamivudine wherein the diluent, the disintegrant along with the actives tenofovir and
emtricitabine or lamivudine are sifted and dried. Then, binder solution is prepared by first
dissolving the binder in purified water. Granulation is carried out by spraying of the
binder solution to the above dry mixture of the ingredients, after which the formed
granules are dried, sifted through the specified mesh. Extended release nevirapine is
processed by wet granulation wherein the diluent along with extended release nevirapine
is sifted and dried. Granulation is carried out by spraying purified water to the above dry
mixture of the ingredients, after which the formed granules are dried-, sifted through the
specified mesh. After unloading, the granules of tenofovir, emtricitabine or lamivudine
and extended release nevirapine were lubricated. The granules as obtained above are
compressed to provide a single layered tablet or compressed separately to provide a
bilayered tablet or a trilayered tablet. The tablets thus obtained- via the process are then
sprayed with a coating suspension made of ready colour mix system.
Alternatively, after compression into tablets, they can be further seal coated and then
sprayed with a coating suspension made of ready colour mix system.
Alternatively, the pharmaceutical antiretroviral composition according to the present
invention may also comprise the actives in nanosizeform. Preferably, the active
pharmaceutical ingredients have average particle size less than about 2000 nm,
preferably less than about 1000 nm.
Nanonization of hydrophobic or poorly water-soluble drugs generally involves the
production of drug nanocrystals through either chemical precipitation (bottom-up
technology) or disintegration (top-down technology). Different methods may be utilized
to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing
Chen et al, discusses the various methods to develop nano-formulations in
"Nanonization strategies for poorly water-soluble drugs," Drug Discovery Today,
Volume 00, Number 00, March 2010].
Nano-sizing leads to increase in the exposure of surface area of particles leading to an
increase in the rate of dissolution.
The nanoparticles of the present invention can be obtained by any of the process such as
but not limited to milling, precipitation and homogenization.
Accordingly, the process of milling comprises dispersing drug particles in a liquid
dispersion medium in which the drug is poorly soluble, followed by applying mechanical
means in the presence of grinding media to reduce the particle size of drug to the desired
effective average particle size.
Accordingly, the process of precipitation involves the formation of crystallineor semicrystalline
drug nanoparticles by nucleation and thegrowth of drug crystals. In a typical
procedure, drug molecules arefirst dissolved in an appropriate organic solvent such as
acetone, tetrahydrofuran or N-methyl-2-pyrrolidone at a supersaturation concentration to
allow for the nucleation of drug seeds. Drug nanocrystals are- then formed by adding the
organic mixture to an antisolvent like water in the presence of stabilizers such surfactants.
The choice of solvents and stabilizers and the mixing process are key factors to control
the size and stability ofthe drug nanocrystals.
Accordingly, the process of homogenization involvespassing a suspension of crystalline
drug and stabilizers through the narrow gap of a homogenizer at high pressure (500-2000
bar). The pressure createspowerful disruptive forces such as cavitation, collision and
shearing,which disintegrate coarse particles to nanoparticles.
Accordingly, the process of high pressure homogenization comprises drug presuspension
(containing drug in the micrometer range) by subjecting the drug to air jet milling in the
presence of an aqueous surfactant solution. The presuspension is then subjected to highpressure
homogenization in which it passes through a very small homogenizer gap of ~25
mhi which leads to a high streaming velocity. High-pressure homogenization is based on
the principle of cavitations (i.e., the formation, growth, and implosive collapse of vapor
bubbles in a liquid).
Accordingly, the process of spray-freeze drying involvesthe atomization of an aqueous
drug solution into a spraychamber filled with a cryogenic liquid (liquid nitrogen)or
halocarbon refrigerant such as chlorofluorocarbon orfluorocarbon. The water is removed
by sublimation after the liquid droplets solidify.
Accordingly, the process of supercritical fluid technology involves controlled
crystallization of drug from dispersion in supercriticalfluids, carbon dioxide.
Accordingly, the process of double emulsion/solvent evaporation technique involves
preparation of oil/water(o/w) emulsions with subsequent removal ofthe oil phasethrough
evaporation. The emulsions are prepared by emulsifyingthe organic phase containing
drug, polymer and organic solvent in an aqueous solution containing emulsifier.
Theorganic solvent diffuses out of the polymer phase and into the aqueous phase, and is
then evaporated, forming drug-loaded polymeric nanoparticles.
Accordingly, the process of PRINT (Particle replication in non-wetting templates)
involves utilization of a low surface energy fluoropolymericmold that enables highresolution
imprint lithography, to fabricate a variety of organic particles. PRINT can
precisely manipulate particle size of drug ranging from 20 nm to more than 100 n .
Accordingly, the process of thermal condensation involves use of capillary aerosol
generator (CAG) to produce high concentration condensation submicron to micron
sizedaerosols from drug solutions.
Accordingly, the process of ultrasonication involves application of ultrasound during
particle synthesis o precipitation, which leads to smaller particles of drug and increased
size uniformity.
Accordingly, the process of spray drying involves supplying the feedsolution at room
temperature and pumping it through thenozzle where it is atomized by the nozzle gas.
The atomized solution is then dried by preheated drying gas in a special chamber to
remove water moisture from the system, thusforming dry particles of drug.
According to a preferred embodiment of the present invention, the nano-milled drugs
may be obtained by nano-milling of drugs with at least one surface stabilizer, at least one
viscosity building agent and at least one polymer.
The present invention provides a pharmaceutical antiretroviral composition comprising
(i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine, (ii) extended release nevirapine, and (iii) tenofovir for preventing, treating
or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency
syndrome or an HIV infection.
The present invention further provides a pharmaceutical antiretroviral composition
comprising (i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine, (ii) extended release nevirapine, and (iii) tenofovir for simultaneous,
separate or sequential for preventing, treating or prophylaxis of diseases caused by
retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
Examples
The following examples are for illustrative purposes only and are not intended in any way
to limit the scope of the present invention.
Example
Layer I : Tenofovir:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Tenofovir Disoproxil Fumarate 300.0
2. Lactose Monohydrate 59,5
3. Croscanhellose sodium 20.00
4. Corn starch 30.00
II Binder Preparation
5. Corn Starch 15.00
6. Polysorbate 80 3.0
7. Purified Water q.s.
III. Lubrication
8. Microcrystalline Cellulose 50.0
9. Croscarmellose sodium 20.00
10. Magnesium Stearate 2.50
Total 510.00
Layer II: Lamivudine:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Lamivudine 300.0
2. Microcrystalline Cellulose 33.2
3. Sodium starch glycolate 30.0
4. Colour 0.60
II Binder Preparation
5. Corn Starch 10.20
6. Purified Water q. s.
III. Lubrication
7. Sodium starch giycolate 20.00
8. Magnesium Stearate 6.00
Total 400.00
Layer III: Nevirapine:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Nevirapine 400.00
2. Lactose Monohydrate 200.00
3. Colour 0.01
II Binder Preparation
4. Purified Water q.s.
III. Blending
5. Hydroxypropyl methyl celluloseK4M Premium 270.00
CR
Lubrication
6. Magnesium Stearate 10.00
Total 880.00
Total of Layer I, Layer II & Layer III 1790.00
Film Coating:
Sr. No Name of Ingredients Qty/tab
M
1. Opadry AMB OY-B 29000 Translucent I 18.0
2. Purified water q.s.
Process:
A) Granulation
Preparation of Layer I
1) Premix of Tenofovir and lactose was prepared and dry mixed with croscarmellose
sodium and corn starch.
2) Binder solution of corn starch and polysorbate 80in purified water was prepared.
3) The dry mix obtained in step (1) was granulated using the binder solution prepared in
step (2).
4) The granules obtained in step (3) were dried, sized and lubricated with
microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
Preparation of Layer II
1) Dry mix of lamivudine, microcrystalline cellulose, Sodium starch glycolate and colour
was prepared.
2) Binder solution of corn starch in purified water was prepared
3) The dry mix obtained in step (1) was granulated using the binder solution prepared in
step (2).
4) The granules obtained in step (3) were dried, sized and lubricated with magnesium
stearate and Sodium starch glycolate.
Preparation of Layer III
1) Dry mix of nevirapirie, colour and lactose was prepared.
2) The dry mix obtained in step (1) was granulated using water as binder.
3) The granules obtained in step (2) were dried, sized and blended with hydroxypropyl
methyl celluloseK4M Premium CR and lubricated with magnesium stearate.
B) Compression
1) Lubricated blend of Layer I, Layer II and Layer III was compressed to produce a
trilayer tablet.
C) Coating
1) Tablets so obtained were coated with Opadry solution.
Example 2
Layer I : Emtricitabine & Tenofovir Disoproxil:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Tenofovir Disoproxil Fumarate 300.0
2. Emtricitabine 200.00
3. Lactose Monohydrate 50.0
4. Croscarmellose sodium 30.00
5. Microcrystalline Cellulose 200.00
6. Pregelatinized starch 25.00
II Binder Preparation
7. Pregelatinized Starch 25.00
8. Purified Water q. s.
III. Lubrication
9. Croscarmellose sodium 30.00
10. Magnesium Stearate 10.00
Total 850.00
Layer II: Nevirapine Extended Release:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Nevirapine 400.00
2. Lactose Monohydrate 200.00
3. Hydroxy Propyl Methyl cellulose 270.00
II Binder Preparation
4. Purified Water q.s.
III. Lubrication
5. Magnesium Stearate 10.00
Total 880.00
Total of Layer I & Layer II 1730:00
Film Coating:
Sr. No Name of Ingredients Qty tab
Mg
. • Opadry Blue II 32K 80963 INH 25.0
2. Purified water q.s.
Process:
A) Granulation
Preparation of Layer I
1) Tenofovir, Emtricitabine, lactose, croscarmellose, microcrystalline Cellulose,
pregelatinized starch were sifted through mesh of required pore size.
2) The sifted ingredients were loaded in a Fluid bed processor and dry mixed.
3) Binder solution was prepared using pregelatinized starch and purified water.
4) Binder solution so obtained was sprayed on the mixture obtained in step 2.
5) Granules so obtained were dried, sized and lubricated.
Preparation of Layer II
1) Nevirapine, lactose and HPMC were sifted through mesh of required pore size.
2) The sifted ingredients were loaded in a rapid mixer granulator and dry mixed.
3) Mixture obtained in step 2 was granulated using purified water
4) Granules so obtained were dried, sized and lubricated.
B) Compression
1) Lubricated blend of Layer I and Layer II was compressed to produce a bilayer tablets.
C) Coating
1) Tablets so obtained were coated with Opadry solution.
Example 3
Layer I : Tenofovir:
Sr. No Name of Ingredients Qry/tab
mg
I Dry Mix
1. Tenofovir Disoproxil Fumarate 300.0
2. Lactose Monohydrate 59.5
3. Croscarmellose sodium 20.00
4. Corn starch 30.00
II Binder Preparation
5. Corn Starch 15.00
6. Polysorbate 80 3.0
7. Purified Water q.s.
III. Lubrication
8. Microcrystalline Cellulose 50.0
9. Croscarmellose sodium 20.00
10. Magnesium Stearate 12.50
Total 510.00
Layer II-: Lamivudine:
Sr. No Name of Ingredients Qry/tab
mg
I Dry Mix
1. Lamivudine 300.0
2. Microcrystalline Cellulose 33.2
3. Sodium starch glycolate 30.0
4. Colour 0.60
II Binder Preparation
5. Corn Starch 10.20
6. Purified Water q. s.
III. Lubrication
7. Sodium starch glycolate 20.00
8. Magnesium Stearate 6.00
Total 400.00
Layer III- Nevirapine Extended Release:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Nevirapine 400.00
2. Lactose Monohydrate 200.00
3. Hydroxy Propyl Methyl cellulose 270.00
II Binder Preparation
4. Purified Water q.s.
III. Lubrication
5. Magnesium Stearate 10.00
Total 880.00
Total of Layer I, Layer II and Layer III 1790.00
Film Coating:
Sr. No Name of Ingredients Qty/tab
Mg
1. Opadry Blue I 32K 80963 H 25.0
2. Purified water q.s.
Process:
Preparation of Layer I
1) Premix of Tenofovir and lactose was prepared and dry mixed with croscarmellose
sodium and corn starch.
2) Binder solution of corn starch and polysorbate 80in purified water was prepared.
3) The dry mix obtained in step (1) was granulated using the binder solution prepared in
step (2).
4) The granules obtained in ste (3) were dried, sized and lubricated with
microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
Preparation of Layer II
1) Dry mix of lamivudine, microcrystalline cellulose, Sodium starch glycolate and colour
was prepared.
2) Binder solution of corn starch in purified water was prepared
3) The dry mix obtained in step (1) was granulated using the binder solution prepared in
step (2).
4) The granules obtained in step (3) were dried, sized and lubricated with magnesium
stearate and Sodium starch glycolate.
Preparation of Layer III
1) Nevirapine, lactose and HPMC were sifted through mesh of required pore size.
2) The sifted ingredients were loaded in a rapid mixer granulator and dry mixed.
3) Mixture obtained in step 2 was granulated using purified water
4) Granules so obtained were dried, sized and lubricated.
) Compression
1) Lubricated blend of Layer I, Layer II and Layer III was compressed to produce a
trilayer tablet.
C) Coating
) Tablets so obtained were coated with Opadry solution.
Example 4
Layer I : Emtricitabine & Tenofovir Disoproxil:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
. Tenofovir Disoproxil Fumarate 300.0
2. Emtricitabine 200.00
3. Lactose Monohydrate 50.0
4. Croscarmellose sodium 30.00
5. Microcrystalline Cellulose 200.00
6. Pregelatinized starch 25.00
II Binder Preparation
7. Pregelatinized Starch 25.00
8. Purified Water q. s.
III. Lubrication
9. Croscarmellose sodium 30.00
10. Magnesium Stearate 10.00
Total 850.00
Layer II: Nevirapine:
Sr. No Name of Ingredients Qty/tab
mg
I Dry Mix
1. Nevirapine 400.00
2. Lactose Monohydrate 200.00
3. Colour 0.01
II Binder Preparation
4. Purified Water q.s.
III. Blending
5. Hydroxypropyi methyl ceIluIoseK4M Premium 270.00
CR
Lubrication
6. . Magnesium Stearate 10.00
Total 880.00
Total of Layer I, Layer II &Layer III 1790.00
Film Coating:
Sr. No Name of Ingredients Qty/tab
Mg
1. Opadry AMB OY-B 29000 Translucent INH 18.0
2. Purified water q.s.
Process:
A) Granulation
Preparation of Layer I
1) Tenofovir, Emtricitabine, lactose, croscarmellose, microcrystalline Cellulose,
pregelatinized starch were sifted through mesh of required pore size.
2) The sifted ingredients were loaded in a Fluid bed processor and dry mixed.
3) Binder solution was prepared using pregelatinized starch and purified water.
4) Binder solution so obtained was sprayed on the mixture obtained in step 2,
5) Granules so obtained were dried, sized and lubricated.
Preparation of Layer II
1) Dry mix of nevirapine, colour and lactose was prepared.
2) The dry mix obtained in step (1) was granulated using water as binder.
3 The granules obtained in step (2) were dried, sized and blended with hydroxypropyl
methyl celluloseK4M Premium C and lubricated with magnesium stearate.
B) Compression
1) Lubricated blend of Layer I and Layer II was compressed to produce a bilayer tablets.
C) Coating
1) Tablets so obtained were coated with Opadry solution.
It will be readily apparent to one skilled in the art that varying substitutions and
modifications ay be made to the invention disclosed herein without departing from the
spirit of the invention. Thus, it should be understood that although the present invention
has been specifically disclosed by the preferred embodiments and optional features,
modification and variation of the concepts herein disclosed may be resorted to by those
skilled in the art, and such modifications and variations are considered to be falling
within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose
of description and should not be regarded as limiting. The use of "including,"
"comprising," or "having" and variations thereof herein is meant to encompass the items
listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular
forms "a," "an" and "the" include plural references unless the context clearly dictates
otherwise. Thus, for example, reference to "a propellant" includes a single propellant as
well as two or more different propellants; reference to a "cosolvent" refers to a single
cosolvent or to combinations of two or more cosolvents, and the like.
Claims
1. A pharmaceutical antiretroviral composition comprising (i) a nucleoside reversetranscriptase
inhibitor selected from lamivudine and emtricitabine, (ii) extended
release nevirapine, and (iii) tenofovir or its pharmaceutically acceptable salts,
solvates, esters, hydrates, enantiomers, derivatives, polymorphs, prodrugs,
complexes.
2. A pharmaceutical composition according to claim 1, wherein the nucleoside
reverse-transcriptase inhibitor is lamivudine or its pharmaceutically acceptable
salts, solvates, esters, hydrates, enantiomers, derivatives, polymorphs, prodrugs,
complexes.
3. A pharmaceutical composition according to claim 1, wherein the nucleoside
reverse-transcriptase inhibitor is emtricitabine or its pharmaceutically acceptable
salts, solvates, esters, hydrates, enantiomers, derivatives, polymorphs, prodrugs,
complexes.
4. A pharmaceutical composition according to any one of claims 1 to 3 adapted for
once or twice a day administration.
5. A pharmaceutical composition according to any preceding claim in single
complete package.
6. A pharmaceutical composition according to claim 5 in the form a single layer, or
a bilayer or trilayer or multilayer tablet.
7. A pharmaceutical composition according to any preceding claim, wherein
nevirapine is co-formulated with at least one hydrophilic and/or hydrophobic
and/or water-swellable. polymer.
8. A pharmaceutical composition according to claim 7, wherein nevirapine is coated
or blended or complexed with one or more hydrophilic and/or hydrophobic and/or
water-swellable polymers.
9. A pharmaceutical antiretroviral composition according to claim 1, comprising:
(i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine; tenofovir, and one or more pharmaceutically acceptable
excipients to form a first admixture; and
(ii) nevirapine in an extended release system with one or more
pharmaceutically acceptable excipients to form a second admixture,
which first and second admixtures are blended and compressed in a single layer to
provide a single unit dosage form.
10. A pharmaceutical antiretroviral compositionaccording to claim 1, comprising:
(i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine; tenofovir and one or more pharmaceutically acceptable
excipients to form a first admixture; and
(ii) nevirapine in an extended release system with one or more
pharmaceutically acceptable excipients to form a second admixture;
which first and second admixtures are blended and compressed to provide a
bilayer unit dosage form.
11. A pharmaceutical antiretroviral compositionaccording to claim 1, comprising:
(i) tenofovir and one or more pharmaceutically acceptable excipients to form
a first admixture; and
(ii) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine; nevirapine in an extended release system, and one or more
pharmaceutically acceptable excipients to form a second admixture;
which first and second admixtures are blended and compressed to provide a
bilayer unit dosage form.
12. A pharmaceutical antiretroviral compositionaccording to claim 1, comprising:
(i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine with one or more pharmaceutically acceptable excipients to
form a first admixture; and
(ii) tenofovir, nevirapine in an extended release system with one or more
pharmaceutically acceptable excipients to form a second admixture;
which first and second admixtures are blended and compressed to provide a
bilayer unit dosage form.
13. A pharmaceutical antiretroviral compositionaccording to claim 1, comprising:
(i) a nucleoside reverse-transcriptase inhibitor selected from lamivudine and
emtricitabine, with one or more pharmaceutically acceptable excipients to
form a first admixture; and
(ii) tenofovir along with one or more pharmaceutically acceptable excipients
to form a second admixture; and
(iii) nevirapine in an extended release system with one or more .
pharmaceutically acceptable excipients to form a third admixture;
which first, second and third admixtures are blended and compressed to provide a
trilayer unit dosage form.
14. A pharmaceutical composition according to any preceding claim as a combined
preparation for simultaneous or separate use in the treatment of an HIV infection.
15. A process for preparing a pharmaceutical composition according to any one of
claims 1 to 13, which process comprises admixing (i) a nucleoside reversetranscriptase
inhibitor selected from lamivudine and emtricitabine, (ii) extended
release nevirapine, an (iii) tenofovir with one or more pharmaceutically
acceptable excipients.
16. A method of preventing, treating or prophylaxis of diseases caused by
retroviruses, especially acquired immune deficiency syndrome or an HIV
infection, which method comprises administering a pharmaceutical antiretroviral
composition according to any one of claims 1to 3 to a patient in need thereof.
17. A pharmaceutical composition substantially as herein described with reference to
the examples.