Pharmaceutical Composition
Field of Invention
The present invention relates to a pharmaceutical composition comprising an
antiretroviral drug, a process for preparing such composition, therapeutic uses and method of
treatment employing the same.
Background & Prior Art
Efavirenz is the international non-proprietary name for non-nucleoside reverse transcriptase
inhibitor (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro-2H-3 ,1-
benzoxazin-2-one belonging to class of benzoxazinones. Efavirenz has the following
structural formula:
Efavirenz is effective in the treatment of the human immunodeficiency virus (HIV) which is
the retrovirus that causes progressive destruction of the human immune system resulting in
onset of ADDS. Efavirenz is a highly potent reverse transcriptase inhibitor and is effective
against HIV reverse transcriptase resistance. It is a crystalline lipophilic solid with a log
octanol water partition coefficient of 5.4 and an aqueous solubility of 9.0 g/ml.
Efavirenz is classified in class II drugs (low solubility, high permeability) of the
Biopharmaceutical Classification System. Class II drugs like efavirenz demonstrate poor
gastrointestinal (GI) absorption due to inadequate drug solubility in GI fluids. Furthermore,
efavirenz is a crystalline lipophilic solid with an aqueous solubility of 9.0 mg mL and with a
low intrinsic dissolution rate (IDR) of 0.037 mg/cm 2 /min. The drugs with less than 0.1
mg/cm /min of DR have dissolution as a rate-limiting step in absorption, which is further
affected by the fed/fasted state of the patient. This in turn can affect the peak plasma
concentration, making calculation of dosage and dosing regimens more complex.
This suggests the importance of dissolution improvement for efavirenz. Moreover, most of
these new chemical entities despite their high permeability, are only absorbed in the upper
small intestine. Consequently, if these drugs are not completely released in gastro intestinal
tract area, they have low bioavailability. Thus, there is a need to increase the therapeutic dose
of the drug in order to obviate this disadvantage; however increasing the dose may lead to
increase in the side effects of the drug.
Various prior art formulations have been reported to improve the solubility of the efavirenz in
the GI tract. For example, one of the approaches used is encapsulation of drug in
cyclodextrins using 1:1 molar ratio as reported by Indrajit et al in Macromolecular symposia
in 2010, 287, 51-59. However considering the high dose of efavirenz, it is practically
difficult to develop oral dosage form using cyclodextrins.
Solid dispersion and PEGylation techniques have also been proposed by Madhavi et al in
"Dissolution enhancement of efavirenz by solid dispersion and PEGylation techniques";
International Journal of Pharmaceutical Investigation, 2011 (1) , 29-34, wherein the drug and
the carrier are added to a common solvent followed by homogenization and evaporation of
the solvent to form solid dispersion of efavirenz. However recrystallization of amorphous
solid dispersions due to temperature, humidity, and the amount of polymer may lead to a
reduction in the dissolution rate, and consequently reduce bioavailability. Further the article
also states that drug-PEG conjugates in 1:1 and 1:2 w/w ratios were prepared by dissolving
efavirenz and PEG 6000 separately in organic solvent and then pouring the solution of the
drug into the solution of PEG while stirring, incubating the mixture overnight and then
evaporating the solvent to yield the PEGylated compound. However PEGylation is a complex
procedure requiring many processing steps.
WO99/61026 discloses a tablet dosage form of efavirenz wherein lactose is added
extragranularly to obtain a stable tablet formulation which is bioequivalent to the capsule
formulation of efavirenz. However, the patent does not provide any bioequivalence data.
US6555133 B2 provides improved oral dosage forms of efavirenz containing one or more
super disintegrants that enhance the dissolution rate of the drug in the gastrointestinal tract
thereby improving the rate and extent of absorption of drug in the body. However use of
higher amount of a super disintegrant like sodium starch glycolate may lead to a negative
effect on the disintegration of the tablets due to formation of a viscous gel layer formed by
sodium starch glycolate that may form a thick barrier to the further penetration of the
disintegration medium and hinder the disintegration of tablets [Development of Fast
Dispersible Aceclofenac Tablets: Effect of Functionality of Superdisintegrant, C.
Mallikarjuna Setty and et al; Received February 7, 2007; Revised January 16, 2008;
Accepted March 12, 2008]
Therefore, the improvement of efavirenz solubility thereby its oral bio-availability while
reducing the dose of drug remains one of most challenging aspects especially for oral drug
delivery system. It is desirable to provide compositions of efavirenz exhibiting enhanced
bioavailability compared to the prior art formulations. Thus there still exists an unmet need to
develop an efavirenz formulation with improved solubility and dissolution properties of the
drug.
Object of the Invention
The object of the present invention is to provide a pharmaceutical composition of efavirenz
having improved solubility and dissolution.
Another object of the present invention is to provide a method of manufacturing a
pharmaceutical composition comprising efavirenz.
Summary of the invention:
According to one aspect of the invention there is provided a composition comprising
efavirenz in the form of particles, wherein substantially all the particles have a particle size
less than or equal to 1 micrometre.
In a preferred embodiment, the composition further comprises at least one surface stabilizer,
at least one viscosity building agent and at least one polymer, wherein substantially all the
particles have a particle size less than or equal to 1 micrometre.
In a preferred embodiment, all the particles have a particle size above 1 nanometre.
The composition described above may comprise a pharmaceutical composition, or may be
used to form a pharmaceutical composition.
According to another aspect of the present invention there is provided a pharmaceutical
composition comprising efavirenz or a pharmaceutically acceptable salt, solvate, derivative,
hydrate, polymorph, or mixtures thereof wherein the particle size of efavirenz is in nanometer
range.
According to yet another aspect of the present invention there is provided a process for
preparing a pharmaceutical composition comprising efavirenz or a pharmaceutically
acceptable salt, solvate, derivative, hydrate, polymorph, or mixtures thereof wherein the
particle size of efavirenz is in nanometer range.
According to another aspect of the present invention there is provided a method of treatment
using a pharmaceutical composition according to present invention.
Detailed Description:
Efavirenz is a class P drug having low solubility and low dissolution. Bioavailability is the
degree to which a drug becomes available to the target tissue after administration. Many
factors can affect bioavailability including the dosage form, particle size, various properties,
e.g., dissolution rate of the drug. Poor bioavailability is a significant problem encountered in
the development of pharmaceutical compositions, particularly for those containing an active
ingredient that is poorly soluble in water. Poorly water soluble drugs, i.e., those having a
solubility less than about 10 mg/ml, tend to be eliminated from the gastrointestinal tract
before being absorbed into the circulation. Therefore development of efavirenz formulations
poses a challenge to an inventor. The inventors of the present invention have surprisingly
found that the dissolution property of efavirenz was greatly improved by reducing the particle
size of efavirenz to nanometer range thus leading to better absorption and bioavailability of
the drug from the GI tract.
The present invention thus provides a pharmaceutical composition comprising efavirenz in
nano form and a process for preparing the same.
The term "efavirenz" as used herein in the entire specification and claims is employed in a
broad sense to include not only efavirenz but its pharmaceutically acceptable salts, solvates,
derivatives, prodrugs, racemic mixtures, polymorphs thereof
Nanonization of hydrophobic 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
drugs for ex: Huabing Chen and et al, discusses the various methods to develop
nanoformulations in "Nanonization strategies for poorly water-soluble drugs," Drug
Discovery Today, Volume 00, Number 00, March 2010.
The nanoparticles of the present invention may be obtained by any of the process such as but
not limited to milling, precipitation and homogenization.
According to one embodiment of the present invention, the process of milling comprises
dispersing efavirenz particles in a liquid dispersion medium in which efavirenz is poorly
soluble, followed by applying mechanical means in the presence of grinding media like
milling pearls to reduce the particle size of efavirenz to the desired average particle size.
According to another embodiment of the present invention, the process of precipitation
involves the formation of crystalline or semi-crystalline efavirenz nanoparticles by nucleation
and the growth of drug crystals. In a typical procedure, drug molecules are first dissolved in
an appropriate organic solvent such as acetone, tetrahydrofuran or N-methyl-2-pyrrolidone at
a super saturation 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 as Tween 80, Poloxamer 188 or lecithin. The choice of solvents and
stabilizers and the mixing process are key factors to control the size and stability of the drug
nanocrystals.
According to one another embodiment of the present invention, the process of
homogenization involves passing a suspension of crystalline efavirenz and stabilizers through
the narrow gap of a homogenizer at high pressure (500-2000 bar). The pressure creates
powerful disruptive forces such as cavitation, collision and shearing, which disintegrate
coarse particles to nanoparticles.
According to one more embodiment of the present invention, the process of spray-freeze
drying involves the atomization of an aqueous efavirenz solution into a spray chamber filled
with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as chlorofluorocarbon
or fluorocarbon. The water is removed by sublimation after the liquid droplets solidify.
According to a still another embodiment of the present invention, the process of supercritical
fluid technology involves controlled crystallization of efavirenz from dispersion in
supercritical fluids, carbon dioxide.
According to another embodiment of the present invention, the process of double
emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions
with subsequent removal of the oil phase through evaporation. The emulsions are prepared by
emulsifying the organic phase containing efavirenz, polymer and organic solvent in an
aqueous solution containing emulsifier. The organic solvent diffuses out of the polymer
phase into the aqueous phase, and is then evaporated, forming efavirenz-loaded polymeric
nanoparticles.
According to a further embodiment of the present invention, the process of PRINT (Particle
replication in non-wetting templates) involves utilization of a low surface energy
fluoropolymeric mold that enables high-resolution imprint lithography, to fabricate a variety
of organic particles. PRINT can precisely manipulate particle size of efavirenz ranging from
20 nm to more than 100 nm.
According to one further embodiment of the present invention, the process of thermal
condensation involves use of capillary aerosol generator (CAG) to produce high
concentration condensation submicron to nano sized aerosols from efavirenz solutions.
According to still further embodiment of the present invention, the process of ultrasonication
involves application of ultrasound during particle synthesis or precipitation, which leads to
smaller particles of efavirenz and increased size uniformity.
According to another embodiment of the present invention, the process of spray drying
involves supplying the feed solution at room temperature and pumping it through the nozzle
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, thus forming dry
particles of efavirenz.
According to a preferred embodiment of the present invention, the nanonization of efavirenz
involves nanomilling efavirenz with at least one surface stabilizer, at least one viscosity
building agent and at least one polymer.
The nanomilled efavirenz according to present invention exhibits a particle size of less than
or equal o5m , preferably less than or equal to 3 h , more preferably less than or equal to
Imih.
The present invention thus provides a pharmaceutical composition comprising granules of
nanomilled efavirenz wherein the granules comprise at least one surface stabilizer, at least
one viscosity building agent and at least one polymer along with efavirenz and optionally
other pharmaceutically acceptable carriers.
The expression surface stabilizer according to the present inventions means a surfactant that
is capable of stabilizing the increased surfaced charge of the nanomilled drug. Any surfactant
is suitable, whether it may be amphoteric, non-ionic, cationic or anionic. Suitable surfactants
may be included in the solid dosage form as provided by the present invention. Non-limiting
examples from anionic, cationic, non-ionic and amphoteric groups include Polysorbates,
Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate
sodium, Cetyl trimethyl ammonium bromide (CTAB)
Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, Ndimethyldodecylamine-
N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10
lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil,
Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride.
Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates,
Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural
oils & fats, Sulphated esters, Sulphated alkanolamides, 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.
The term viscosity builder means excipients that are capable of stabilizing the nanoparticles
by increasing the viscosity of the formulation and thus preventing physical interaction of
nanoparticles under the operating conditions employed. Examples of such excipients are
derivatives of sugars, such as lactose, sucrose, saccharose, hydrolyzed starch (maltodextrin)
and the like. Mixtures are also suitable.
Suitable examples of polymers include but are not limited to cellulose derivates like
hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose,
methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose,
carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid,
acrylamide, and maleic anhydride polymers and copolymers. Polymer blends are also
suitable.
The present invention provides a process of preparing a pharmaceutical composition, which
process comprises the steps of: homogenizing a drug, at least one surface active agent, at
least one viscosity building agent, at least one polymer to produce a homogenized dispersion
of the drug in the surface active agent, the viscosity building agent and the polymer;
nanomilling the homogenized dispersion of step one to produce a nanomilled slurry;
adsorbing the nanomilled slurry on a carrier to form granules.
In one embodiment the percentage weight of active ingredient in the slurry ranges from 5%
to 60%w/w.
The granules may either be encapsulated in capsules or be compressed to form tablets or may
be provided as sachets or be provided as powders for reconstitution.
The solid dosage form according to the present invention may optionally be coated. More
preferably, the formulation may be seal coated and further film coated.
Alternatively the nanomilled slurry may be used to formulate liquid dosage forms like
suspension.
The term carrier used herein includes one more of pharmaceutically acceptable ingredients
but not limited to carriers, diluents or fillers, binders, lubricants, glidants and disintegrants.
Non-limiting examples of suitable pharmaceutically acceptable carriers, diluents or fillers for
use in the solid dosage form as provided by the present invention include lactose (for
example, spray-dried lactose, a-lactose, b-lactose), lactose available under the trade mark
Tablettose, various grades of lactose available under the trade mark Pharmatose or other
commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates,
dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for
example, microcrystalline cellulose available under the trade mark Avicel),
hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl
methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A,
Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium
carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other
cellulose derivatives, starches or modified starches (including potato starch, corn starch,
maize starch and rice starch) and the like.
Typically glidants and lubricants may also be included in the solid dosage form as provided
by the present invention. Non-limiting examples include 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)
and glycerides, 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 alumino metasilicate), sucrose ester of fatty
acids, hydrogenated vegetable oils (for example, hydrogenated castor oil) , or mixtures
thereof or any other suitable lubricant.
Suitably one or more binders are also present in the solid dosage form as provided by the
present invention and non-limiting examples of suitable binders are, for example, polyvinyl
pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar,
calcium carrageenan, cellulose derivatives such as ethyl cellulose, methyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose,
dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof or
any other suitable binder.
Suitable disintegrants may also be present in the formulation according to the present
invention, which includes, but are not limited to hydroxylpropyl cellulose (HPC), low density
HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium;
starches exemplified under examples of fillers and also carboxymethyl starch,
hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic
acid or a salt thereof, such as sodium alginate or their equivalents and any combination
thereof.
In one embodiment of the present invention there is provided a process of preparing a
pharmaceutical composition according to the present invention which process comprises the
step of 1. Homogenizing the dispersion of Efavirenz, docusate sodium, sucrose, HPMC 2.
Nanomilling the homogenized dispersion of step one 3. Adsorbing the nanomilled slurry of
step 2 on a mixture of lactose monohydrate, microcrystalline cellulose and crospovidone to
form granules.
In yet another preferred embodiment of the present invention there is provided a process of
preparing a pharmaceutical composition, which process comprises: (1). preparing a
dispersion of Efavirenz with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose in
purified water under stirring conditions (2). Homogenizing the step (1) dispersion and then
Nanomilling the homogenized dispersion (3) Adsorbing the nanomilled drug by spraying the
nanomilled slurry on lactose monohydrate, microcrystalline cellulose and crospovidone
mixture in fluidized bed granulator. (4) Drying and blending the granules obtained. (5)
Lubricating the granules and finally compressing into tablets (6) the tablets obtained were
seal coated and then film coated.
The nanomilled efavirenz composition prepared according to the present invention exhibited
a dissolution profile which is showing an improvement over the prior art composition as
evident from Fig 1. This might further lead to a considerably enhanced bioavailability of the
active ingredient compared to that obtained with the compositions of the prior art. Further as
may be noted from the dissolution data, a suitable dose of efavirenz that may be administered
according to the present invention may be in the range of about 300mg to about 600mg,
which may lead to reduced side effects of the active ingredient.
There is further provided by the present invention a solid dosage form substantially as
hereinbefore described, for use in treating disorders or conditions that respond to, or are
prevented, ameliorated or eliminated by, the administration of efavirenz. More preferably,
there is further provided by the present invention a solid dosage form substantially as
hereinbefore described, for use in the treatment of Human immunodeficiency virus [HIV].
Efavirenz is also used in combination with other antiretroviral agents as part of an expanded
post exposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a
significant risk
It can be appreciated from the above mentioned method of treatment description in
accordance with the present invention that it can be beneficial to provide, recommend or
label a solid dosage form according to the present invention for administration with one or
more other therapeutically active compounds used for treatment of HIV infection.
The present invention is further explained with the following non-limiting examples and with
the aid of dissolution profile of Efavirenz tablets prepared according to present invention
with innovators tablets.
The following example is for the purpose of illustration of the invention only and
intended in any way to limit the scope of the present invention.
Example 1
Formula:
Process:
1. Dispersion of efavirenz with Docusate sodium, HPMC, sodium lauryl sulphate and
sucrose was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then nanomilled
3. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator
4. Granules obtained were sized and lubricated
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then film coated.
Example 2
Formula:
Process:
1. Dispersion of efavirenz with Docusate sodium, HPMC, sodium lauryl sulphate and
sucrose was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then nanomilled
3. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator
4. Granules obtained were sized and lubricated
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then film coated.
Example: 3 Dissolution of a composition according to the invention and a composition
according to the prior art.
According to present invention dissolution study was carried out in an aqueous medium
containing a surfactant, 2% SLS. The paddle method (US Pharmacopoeia) was used under
the following conditions: volume of mediumlOOO ml; medium temperature: 37' C ; blade
rotation speed 50 rpm; samples taken: every 10 minutes.
Table 1:
The composition according to present invention consisted of Efavirenz 300mg tablets
prepared according to Example 2. The prior art composition contained Efavirenz [600mg]
croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, and sodium lauryl sulfate.
The results obtained are shown graphically in FIG. 1, on which the percentage of dissolution
is shown. As shown in table 1 and Fig 1, approximately 75% of the active from nano
composition dissolved in 10 minutes and almost 100% of active dissolved within an hour
while prior art formulation dissolved only 88% in one hour. These results clearly show that
the compositions of the present invention have a dissolution profile which is distinctly better
than the prior art composition.
It will be readily apparent to one skilled in the art that varying substitutions and
modifications may 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.
Claims
1. A composition comprising efavirenz in the form of particles, wherein substantially all
the particles have a particle size less than or equal to 1 micrometre.
2. A composition according to claim 1, further comprising at least one surface stabilizer,
at least one viscosity building agent and at least one polymer, wherein substantially all the
particles have a particle size less than or equal to 1 micrometre.
3. A composition according to claim 2, wherein the surface stabilizer is a surfactant.
4. A composition according to claim 3, wherein the surfactant is an amphoteric, nonionic,
cationic or anionic surfactant.
5. A composition according to claim 3 or 4, wherein the surfactant is a polysorbates;
sodium dodecyl sulfate (sodium lauryl sulfate); lauryl dimethyl amine oxide; docusate
sodium; cetyl trimethyl ammonium bromide (CTAB); a polyethoxylated alcohol; a
polyoxyethylene sorbitan; Octoxynol; N,N-dimethyldodecylamine-N-oxide; hexadecyl
trimethylammonium bromide, polyoxyl 10 lauryl ether, brij, a bile salt, such as sodium
deoxycholate or sodium cholate; a polyoxyl castor oil; nonylphenol ethoxylate; a
Cyclodextrin; lecithin; methylbenzethonium chloride; a carboxylate; a sulphonate; a
petroleum sulphonate; an alkylbenzenesulphonates; a naphthalenesulphonate; and olefin
sulphonate; a sulphate surfactant; an alkyl sulphate; a sulphated natural oil or fat; a sulphated
ester; a sulphated alkanolamide; an alkylphenol, optionally ethoxylated and sulphated; an
ethoxylated aliphatic alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol
esters; an anhydrosorbitol ester or an ethoxylated derivative therof; a glycol ester of a fatty
acid; a carboxylic amide; a monoalkanolamine condensate; a polyoxyethylene fatty acid
amide; a quaternary ammonium salt; an amine with amide linkages; a polyoxyethylene alkyl
amine; a polyoxyethylene alicyclic amine; a N,N,N,N tetrakis substituted ethylenedi amine; a
2-alkyl-l-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid or a sodium salt
thereof; N-tallow-3-iminodipropionate disodium salt; N-carboxymethyl-n-dimethyl-n-9
octadecenyl ammonium hydroxide; n-cocoamidethyl-n-hydroxyethylglycine sodium salt; or
mixtures thereof.
6. A composition according to any preceding claim, wherein the surfactant is docusate
5 sodium and/or sodium lauryl sulphate.
7. A composition according to any preceding claim, wherein the viscosity building agent
is lactose; sucrose; saccharose; a hydrolyzed starch, such as maltodextrin; or mixtures
thereof.
10
8. A composition according to claim 7, wherein the viscosity building agent is sucrose.
9. A composition according to any preceding claim, wherein the polymer is
hydroxypropylcellulose; hydroxymethylcellulose; hydroxypropylmethylcellulose; a
15 methylcellulose polymer; hydroxyethylcellulose; sodium carboxymethylcellulose;
carboxymethylene hydroxyethylcellulose and/or carboxymethyl hydroxyethylcellulose; an
acrylic polymer, such as acrylic acid, acrylamide, and maleic anhydride polymers and
copolymers; or a blend thereof; or mixtures thereof.
20 10. A composition according to claim 9, wherein the polymer is
hydroxypropylmethylcellulose.
11. A composition according to any one of the preceding claims, wherein substantially all
the particles have a particle size above 1 nanometre.
25
12. A composition according to any one of the preceding claims, further comprising a
pharmaceutically acceptable carrier, wherein said particles have been adsorbed onto the
surface of the carrier.
30 13. A pharmaceutical composition comprising a composition according to any one of
claims 1 to 12.
14. A pharmaceutical composition according to claim 13, wherein the carrier comprises:
one or more diluents or fillers; one or more binders; one or more lubricants; one or more
glidants; one or more disintegrants; or a mixture thereof.
5 15. A pharmaceutical composition according to claim 13 or 14, wherein the carrier
comprises lactose monohydrate, microcrystalline cellulose and crospovidone or mixtures
thereof.
16. A pharmaceutical composition according to claim 13, 14 or 15, which is in the form
10 of a tablet dosage form, a powder dosage form, a capsule dosage form or a liquid dosage
form.
17. A process for preparing a pharmaceutical composition, which process comprises the
steps of: homogenizing efavirenz, at least one surface stabiliser, at least one viscosity
15 building agent, and at least one polymer to produce a homogenized dispersion of the
efavirenz in the surface active agent, the viscosity building agent and the polymer; milling
said homogenized dispersion to produce a slurry of particles having a particle size less than
or equal to 1 micrometre; and adsorbing the milled slurry on a carrier to form granules.
20 18. A process according to claim 17, wherein the granules are compressed to form tablets,
or are encapsulated in capsules, or are provided as a powder dosage form.
19. A process according to claim 17, wherein the granules are used to form a liquid
dosage formulation.
25
20. A process according to any one of claims 17 to 19, wherein the surface stabilizer is a
surfactant.
21. A process according to claim 20, wherein the surfactant is an amphoteric, non-ionic,
30 cationic or anionic surfactant.
22. A process according to claim 20 or 21, wherein the surfactant is a polysorbates;
sodium dodecyl sulfate (sodium lauryl sulfate); lauryl dimethyl amine oxide; docusate
sodium; cetyl trimethyl ammonium bromide (CTAB); a polyethoxylated alcohol; a
polyoxyethylene sorbitan; Octoxynol; N,N-dimethyldodecylamine-N-oxide; hexadecyl
trimethylammonium bromide, polyoxyl 10 lauryl ether, brij, a bile salt, such as sodium
deoxycholate or sodium cholate; a polyoxyl castor oil; nonylphenol ethoxylate; a
Cyclodextrin; lecithin; methylbenzethonium chloride; a carboxylate; a sulphonate; a
petroleum sulphonate; an alkylbenzenesulphonates; a naphthalenesulphonate; and olefin
sulphonate; a sulphate surfactant; an alkyl sulphate; a sulphated natural oil or fat; a sulphated
ester; a sulphated alkanolamide; an alkylphenol, optionally ethoxylated and sulphated; an
ethoxylated aliphatic alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol
esters; an anhydrosorbitol ester or an ethoxylated derivative therof; a glycol ester of a fatty
acid; a carboxylic amide; a monoalkanolamine condensate; a polyoxyethylene fatty acid
amide; a quaternary ammonium salt; an amine with amide linkages; a polyoxyethylene alkyl
amine; a polyoxyethylene alicyclic amine; a N,N,N,N tetrakis substituted ethylenediamine; a
2-alkyl-l-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid or a sodium salt
thereof; N-tallow-3-iminodipropionate disodium salt; N-carboxymethyl-n-dimethyl-n-9
octadecenyl ammonium hydroxide; n-cocoamidethyl-n-hydroxyethylglycine sodium salt; or
mixtures thereof.
23. A process according to claim 20, 2 1 or 22, wherein the surfactant is docusyl sodium
and/or sodium lauryl sulphate.
24. A process according to any one of claims 19 to 23, wherein the viscosity building
agent is lactose; sucrose; saccharose; a hydrolyzed starch, such as maltodextrin; or a mixture
thereof.
25. A process according to claim 24, wherein the viscosity building agent is sucrose.
26. A process according to any one of claims 17 to 25, wherein the polymer is
hydroxypropylcellulose; hydroxymethylcellulose; hydroxypropylmethylcellulose; a
methylcellulose polymer; hydroxyethylcellulose; sodium carboxymethylcellulose;
carboxymethylene hydroxyethylcellulose and/or carboxymethyl hydroxyethylcellulose; an
acrylic polymer, such as acrylic acid, acrylamide, and maleic anhydride polymers and
copolymers; or a blend thereof; or a mixture thereof.
27. A process according to claim 26, wherein the polymer is
hydroxypropylmethylcellulose.
5 28. A process according to any one of the preceding claims, wherein substantially all the
particles have a particle size above 1 nanometre.
29. A process according to any one of claims 17 to 28, wherein the carrier comprises: one
or more diluents or fillers; one or more binders; one or more lubricants; one or more glidants;
10 one or more disintegrants; or a mixture thereof.
30. A process according to any one of claims 17 to 29, wherein the carrier comprises
lactose monohydrate, microcrystalline cellulose and crospovidone or mixtures thereof.
15 31. A process according to any one of claims 17 to 30, wherein the milled slurry is
adsorbed onto the particles by spraying the slurry onto the granules in a fluidized bed
granulator.
32. A process according to any one of claims 17 to 31, further comprising drying and
20 blending the granules after the step of adsorbing the milled slurry.
33. A composition comprising efavirenz in the form of particles, wherein substantially all
the particles have a particle size less than or equal to 1micrometre, for use in the treatment of
HIV.
25
34. The use of a composition comprising efavirenz in the form of particles, wherein
substantially all the particles have a particle size less than or equal to 1 micrometre,
in the manufacture of a medicament for treating HIV.
30 35. A method of treating HIV comprising administering a therapeutically effective
amount of a composition comprising efavirenz in the form of particles, wherein substantially
all the particles have a particle size less than or equal to 1 micrometre.