WO2012062835A1

WO2012062835A1 - Novel pharmaceutical compositions

Info

Publication number: WO2012062835A1
Application number: PCT/EP2011/069796
Authority: WO
Inventors: Samuel Bruce Balik; Karen Elodie Crews; Dustin Jack Melton; Ronald Allen Sanftleben; Allen Wayne Wood
Original assignee: Glaxo Wellcome Manufacturing Pte Ltd; Glaxo Group Limited; Glaxosmithkline Inc.
Priority date: 2010-11-12
Filing date: 2011-11-10
Publication date: 2012-05-18
Also published as: CN103221037A

Abstract

The present invention is directed to novel pharmaceutical compositions comprising lamivudine and adefovir dipivoxil in a single dosage form, and the use of such compositions in the treatment of hepatitis B virus (HBV) infection.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION

HBV infection is a viral infection attacking the liver which can cause both acute and chronic disease. The virus is transmitted through contact with the blood or other bodily fluids of an infected person, for example by vertical transmission from infected or carrier mothers to their off-spring. In those areas of the world where the disease is common, vertical transmission at an early age results in a high proportion of infected individuals becoming chronic carriers of hepatitis B. An estimated 2 billion people worldwide have been infected with the virus and about 350 million people are chronically infected with hepatitis B. As many as 600,000 people die each year due to the acute or chronic consequences of hepatitis B.

Lamivudine (also known as (2R,cis)-4-amino-1-(2-hydroxymethyl-1 ,3-oxathiolan-5-yl)- pyrimidin-2-one, (-)-c/^'s-4-amino-1-(2-hydroxymethyl-1 ,3-oxathiolane-5-yl)-(1 H)-pyrimidin- 2-one, 3TC™, EPIVIR™, EPIVIR-HBV™, ZEFFIX™ or HEPTODIN™) and adefovir dipivoxil (also known as bis(pivaloyloxymethyl)(9-[(R)-2-

(phosphonomethoxy)ethyl]adenine), 9-[2-

[[bis[(pivaloyloxy)methoxy]phosphinyl]methoxy]ethy]adenine), bis-POM PMEA or HEPSERA™) each have proven antiviral activity against HBV. Long-term use of lamivudine frequently results in the emergence of drug-resistant HBV mutants. However, adefovir dipivoxil is known to suppress the replication of both wild-type and lamivudine- resistant HBV. Accordingly, lamivudine-adefovir dipivoxil combination therapy is recommended as a standard therapy for breakthrough hepatitis in, for example, Japan.

Lamivudine and adefovir dipivoxil when used as single drug products are each formulated as compressed tablets containing various excipients. Lamivudine tablets for the treatment of HBV infection contain 100mg lamivudine together with hypromellose, macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate 80, red iron oxide, sodium starch glycolate, titanium dioxide and yellow iron oxide. Adefovir dipivoxil tablets for the treatment of HBV infection contain 10mg adefovir dipivoxil together with pregelatinized starch, croscarmellose sodium, lactose monohydrate, talc and magnesium stearate. Patient compliance is an important issue in the treatment of viral infections. Formulation of multiple actives into a single dosage form may improve patient compliance leading to significant clinical benefit. However, in order to be pharmaceutically useful, such single dosage forms must meet various developability requirements such as stability. For example, the single dosage forms must be sufficiently stable to provide an acceptable shelf life, for example a shelf life of at least about 24 months.

There remains a need to provide stable pharmaceutical compositions comprising lamivudine and adefovir dipivoxil in a single dosage form.

SUMMARY OF THE INVENTION

The present invention is directed to stable pharmaceutical compositions comprising lamivudine and adefovir dipivoxil in a single dosage form. Specifically, the invention is directed to a pharmaceutical composition in the form of a capsule containing a blend which comprises about 100mg of lamivudine and about 10mg of adefovir dipivoxil.

Although lamivudine and adefovir dipivoxil when used as single actives are each formulated as compressed tablets, according to the present invention, it has been found that a pharmaceutical composition in the form of a capsule comprising about 100mg of lamivudine and about 10mg of adefovir dipivoxil provides a stable composition comprising lamivudine and adefovir dipivoxil in a single dosage form. In a preferred embodiment, the stability of the capsules of the invention is such that the stability of the adefovir dipivoxil component is at least as good as, preferably better than, the stability of adefovir dipivoxil in a compressed tablet containing 10mg adefovir dipivoxil, 7.5 mg pregelatinized starch, 9mg croscarmellose sodium, 1 13mg lactose monohydrate, 9mg talc and 1.5mg magnesium stearate.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a pharmaceutical composition in the form of a capsule containing a blend which comprises about 100mg of lamivudine and about 10mg of adefovir dipivoxil (hereinafter "pharmaceutical compositions of the invention").

In one aspect, the present invention is directed to a pharmaceutical composition in the form of a capsule containing a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil; and iii) from about 25% to about 66% w/w starch.

In one embodiment, the present invention provides a pharmaceutical composition in the form of a capsule containing a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) from about 25% to about 66% w/w starch; and

iv) from about 0.5% to about 2% w/w magnesium stearate. In another embodiment, the present invention provides a pharmaceutical composition in the form of a capsule containing a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) about 88mg of starch; and

iv) about 2mg of magnesium stearate.

In a further embodiment, the present invention provides a pharmaceutical compositi the form of a capsule containing a blend which contains:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) about 88mg of starch; and

iv) about 2mg of magnesium stearate.

Starch suitable for use in the pharmaceutical composition of the invention may be unprocessed starch such as maize starch, potato starch, rice starch, tapioca starch or wheat starch; pregelatinized starch or partially pregelatinized, for example partially pregelatinized maize starch such as Starch 1500™; a co-processed starch excipient, for example a co-processed starch excipient which is a co-processed mixture of conventional pharmaceutically acceptable excipients, corn starch and pregelatinzed starch such as StarCap 1500™; or a mixture thereof. In one embodiment, the starch is partially pregelatinized starch such as Starch 1500™. In another embodiment, the starch is a co- processed starch excipient such as StarCap 1500™. In a further embodiment, the starch is a mixture of partially pregelatinized starch such as Starch 1500™ and a co-processed starch excipient such as StarCap 1500™.

In order to produce capsules with a consistent fill weight it is necessary to ensure that the blend comprising lamivudine and adefovir dipivoxil has appropriate flow properties. Poor flowing blends may result in inconsistent quantities of blend in the capsules and thus poor fill weight reproducibility or dose uniformity. Examples of poor flow include material not freely flowing via gravity on blender discharging and the presence of "rat holing" in the encapsulation machine hopper. "Rat holing" refers to flow taking place within a narrow channel above an outlet while material on the periphery remains stationary.

In one embodiment, it has been found that in the pharmaceutical composition of the invention, in addition to the possible role of starch in stability, flow of the blend comprising lamivudine and adefovir dipivoxil may be improved by controlling the starch level and / or substituting some or all of the starch with a grade of starch exhibiting better flow characteristics.

In one embodiment, in the pharmaceutical composition of the invention the starch is present in an amount of from about 25% to about 66% w/w. In another embodiment, in the pharmaceutical composition of the invention the starch is present in an amount of from about 25% to about 57% w/w. In another embodiment, in the pharmaceutical composition of the invention the starch is present in an amount of from about 30% to about 50% w/w. In another embodiment, in the pharmaceutical composition of the invention the starch is present in an amount of from about 35% to about 45% w/w. In a further embodiment, in the pharmaceutical composition of the invention the starch is present in an amount of about 44% w/w.

In one embodiment, in the pharmaceutical composition of the invention the starch is a mixture of starches of different particle size grades, for example a mixture of smaller particle size grade starch such as Starch 1500™ and a larger particle size grade such as StarCap 1500™, such as a mixture of 75% Starch 1500™ and 25% StarCap 1500™, a mixture of 50% Starch 1500™ and 50% StarCap 1500™, or a mixture of 25% Starch 1500™ and 75% StarCap 1500™. In a further embodiment, in the pharmaceutical composition of the invention the starch is a larger particle size grade starch such as StarCap 1500™.

In a further aspect, the present invention is directed to a pharmaceutical composition in the form of a capsule containing a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) from about 1 % to about 5% w/w pregelatinized starch;

iv) from about 1 % to about 5% w/w croscarmellose sodium; v) from about 40% to about 50% w/w lactose monohydrate;

vi) from about 1 % to about 5% w/w talc; and

vii) from about 0.5% to about 2% w/w magnesium stearate. In one embodiment, the present invention is directed to a pharmaceutical composition in the form of a capsule containing a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) about 7.5mg of pregelatinized starch;

iv) about 9mg of croscarmellose sodium;

v) about 1 13mg of lactose monohydrate;

vi) about 9mg of talc; and

vii) about 2.5mg magnesium stearate. In a further embodiment, the present invention is directed to a pharmaceutical composition in the form of a capsule containing a blend which contains:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) about 7.5mg of pregelatinized starch;

iv) about 9mg of croscarmellose sodium;

v) about 1 13mg of lactose monohydrate;

vi) about 9mg of talc; and

vii) about 2.5mg magnesium stearate. The capsule shell for use in the pharmaceutical compositions according to the invention may be formed from any suitable material which does not reduce the stability of the blend. In one embodiment, the capsule is a hypromellose or hydroxypropyl methyl cellulose (HPMC) capsule. HPMC capsules are believed to be particularly suitable for use according to the invention due to their relatively low water content. For example, HPMC capsules typically have a water content of from about 2% to about 6% w/w. By comparison, gelatin capsules typically have a water content of from about 13% to about 16% w/w.

The capsule may be any suitable size, for example from size 3 to size 00. In one embodiment, the capsule is size 1 or size 2. In another embodiment, the capsule is size 1. In a further embodiment, the capsule is size 2. Capsules suitable for use according to the invention are commercially available from suppliers such as Capsugel™, Qualicaps™ and Shanghai Guang De Li Capsules Co. Ltd., No. 18 Zone 220, Bei Wu Road, Shanghai, China 200241. As the skilled person will appreciate, although there is no industry standard for capsule sizes, vendors of capsules typically manufacture capsules of dimensions close enough in tolerances such that all capsules of a certain size, for example size 3, size 2, size 1 , size 0 or size 00, can be used interchangeably on equipment throughout the industry. For example, technical information for VCaps™ capsules available from Capsugel™ are available on their website (http://www.capsugel.com/products/vcaps chart.php). A Capsugel™ size 2 VCaps™ capsule typically has an average weight of 60±4mg, a capacity in terms of volume of 0.37ml, a body length of 15.27±0.46mm, a cap length of 8.94±0.46mm, an external body diameter of 6.07mm, an external cap diameter of 6.35mm and an overall closed length of 18.0±0.30mm.

Tamp filing processes are widely used for filling powders into capsules, whereby a compressed plug of material is formed and dispensed into the capsule shell. However, it has now been found that tamping reduces the stability of the blend used according to the invention. Accordingly, the capsules of the invention are preferably filled with little or no tamping. In one aspect, in the pharmaceutical compositions of the invention the capsule contains an uncompressed or untamped blend where there is no or minimal plug formation or compaction.

Thus, in one embodiment, the present invention is directed to a pharmaceutical composition in the form of a capsule containing an uncompressed or untamped blend which comprises about 100mg of lamivudine and about 10mg of adefovir dipivoxil. In another embodiment, the present invention is directed to a pharmaceutical composition in the form of a capsule containing an uncompressed or untamped blend which comprises about 100mg of lamivudine, about 10mg of adefovir dipivoxil and from about 25% to about 66% w/w starch. In another embodiment, the present invention provides a pharmaceutical composition in the form of a capsule containing an uncompressed or untamped blend which comprises about 100mg of lamivudine, about 10mg of adefovir dipivoxil, from about 25% to about 66% w/w starch and from about 0.5% to about 2% w/w magnesium stearate. In another embodiment, the present invention provides a pharmaceutical composition in the form of a capsule containing an uncompressed or untamped blend which comprises about 100mg of lamivudine, about 10mg of adefovir dipivoxil, about 88mg of starch and about 2mg of magnesium stearate. In a further embodiment, the present invention provides a pharmaceutical composition in the form of a capsule containing an uncompressed or untamped blend which contains about 100mg of lamivudine, about 10mg of adefovir dipivoxil, about 88mg of starch and about 2mg of magnesium stearate.

As the skilled person will appreciate, the target fill weight for a capsule according to the invention may vary. In one embodiment, the target fill weight is from 150 to 300mg. In another embodiment, the target fill weight is about 200mg. In a further embodiment, the target fill weight is about 251 mg.

Lamivudine for use in the compositions according to the invention may be prepared according to the methods described in, for example, W095/29174 and WO92/20669.

Adefovir dipivoxil for use in the compositions according to the invention may be prepared according to the methods described in, for example, WO99/04774. As used herein, the term "% w/w" refers to the percentage of a substance present in a pharmaceutical composition on a weight by weight basis i.e. 1g/100g is equivalent to 1 % w/w.

The methods of treatment of the invention comprise administering a safe and effective dosage of a pharmaceutical composition of the invention to a patient in need thereof. In one embodiment, the invention provides methods of treating HBV infection by administering a safe and effective amount of a pharmaceutical composition of the invention to a patient in need thereof. As used herein, "safe and effective amount" in reference to a pharmaceutical composition of the invention means an amount sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.

Typically, a pharmaceutical composition of the invention is administered once per day.

The duration for which the pharmaceutical compositions of the invention are administered may depend on the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

As used herein, "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human.

In one embodiment, the invention thus provides a method of treating HBV infection comprising administering a safe and effective amount of a pharmaceutical composition of the invention to a patient in need thereof. In another embodiment, the invention provides a pharmaceutical composition of the invention for use in the treatment of HBV infection. In a further embodiment, the invention provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in the treatment of HBV infection. The pharmaceutical compositions of the invention may contain one or more additional pharmaceutical excipients. As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce efficacy when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be pharmaceutically acceptable eg of sufficiently high purity. Suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the active compounds once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance. Suitable pharmaceutically acceptable excipients include, but are not limited to, the following types: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled person will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other excipients are present in the formulation. For example, pregelatinized starch may function as a diluent, disintegrant and/or a stabilizer.

A skilled person possesses the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). For example, suitable diluents and fillers include, but are not limited to, lactose (e.g. lactose monohydrate), sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. In one embodiment, a filler suitable for use according to the invention is lactose monohydrate. The pharmaceutical compositions may further comprise a binder. Suitable binders include, but are not limited to, starch (e.g. corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). In one embodiment, a binder suitable for use according to the invention is pregelatinized starch. The pharmaceutical compositions may further comprise a disintegrant. Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, croscarmellose sodium, alginic acid, sodium carboxymethyl cellulose and pregelatinized starch. In one embodiment, a disintegrant suitable for use according to the invention is croscarmellose sodium. The pharmaceutical compositions may further comprise a lubricant. Suitable lubricants include, but are not limited to, stearic acid, magnesuim stearate, calcium stearate, and talc. In one embodiment, a lubricant suitable for use according to the invention is magnesium stearate.

In one embodiment, it has been found that in certain pharmaceutical compositions of the invention some excipients are either unnecessary for stability or have an unfavourable impact on stability. Accordingly, the present invention further provides a pharmaceutical composition in the form of a capsule containing a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil; and

iii) from about 25% to about 66% w/w starch;

wherein the blend does not contain talc, a glidant and/or a disintegrant.

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

A blend suitable for use in the pharmaceutical compositions of the invention may be prepared by, for example, admixture at ambient temperature and atmospheric pressure. EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compositions and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Rapid stability screen

A rapid stability screening technique aided the identification and selection of a capsule composition with suitable adefovir dipivoxil stability as compared with an adefovir dipivoxil tablet control.

Capsule composition samples, filled into HPMC capsules, were stored in an open container placed in a 40°C/75% RH (relative humidity) chamber exposed to the environmental conditions. The samples were tested for impurities after one week and/or two weeks to determine formation of major degradation impurities. Each sample result was compared to the control, adefovir dipivoxil tablets stored in an open container, under the same conditions.

The control adefovir dipivoxil tablets were compressed tablets containing 10mg adefovir dipivoxil, 7.5 mg pregelatinized starch, 9mg croscarmellose sodium, 1 13mg lactose monohydrate, 9mg talc and 1.5mg magnesium stearate. In the screen, the control tablets gave a total impurity level corresponding to 2.7% increase from initial after one week.

Determination of the impact of talc, glidant and disintegrant level on adefovir dipivoxil stability

Blends were prepared according to the formulations listed in Table 1. Size 1 HPMC capsules containing the blends were manually prepared and subjected to the rapid stability screen described above. The effect of adding talc or fumed silica as glidants (to improve material flow properties) and a disintegrant was screened to determine the impact on adefovir dipivoxil stability. The results of this stability screening are shown in Table 1.

Table 1 : Impact of talc, glidant and disintegrant level on adefovir dipivoxil stability

Blend A1 Blend A2 Blend A3

Blend A with glidant without glidant without glidant, talc or disintegrant

Component mg/ % mg/ % mg/ % mg/ % w/w w/w w/w w/w capsule capsule capsule capsule

Lamivudine 100 28.6 100 28.6 100 28.6 100 28.6

Adefovir 10 2.8 10 2.8 10 2.8 10 2.8 dipivoxil

Starch 1500 209.3 59.8 219.1 62.6 219.8 62.8 237.3 67.8 Croscarmellose 17.5 5.0 17.5 5.0 17.5 5.0 - -

Talc 10.5 3.0 - - - - - -

Cab-O-Sil - - 0.7 0.2 - - - -

Mg Stearate 3.5 1.0 3.5 1.0 3.5 1.0 3.5 1.0

Total 350 100 350 100 350 100 350 100

Total 1.6 2.4 1.4 1.2

Impurities¹

Change from

Initial (Δ)

¹ One week stability results stored at 40 C / 75% RH (relative humidity), exposed - size 1 HPMC capsules.

The results of this stability screening show that removal of the talc and disintegrant from the formulation had no significant impact on adefovir dipivoxil stability. The addition of a glidant (Cab-O-Sil) to the formulation had an unfavorable impact on adefovir dipivoxil stability based on increased impurity levels observed for Blend A1.

Effect of starch level and type on adefovir dipivoxil stability and material flow properties

Blends of differing starch levels and grades are prepared for this screening experiment to determine the impact of lowering the starch level and evaluating a different starch grade on adefovir dipivoxil stability and material flow properties. Size 0 HPMC capsules were manually filled and subjected to the rapid stability screen described above. The stability results are shown in Table 2.

Table 2: Impact of starch level and grade on adefovir dipivoxil stability

Blend B Blend B1 Blend B2 Blend B3

Component mg/ % mg/ % mg/ % mg/ % capsule w/w capsule w/w capsule w/w capsule w/w Lamivudine 100.0 50.0 100.0 66.6 100 28.6 100 28.6

Adefovir 10.0 5.0 10.0 6.6 10 2.8 10 2.8 dipivoxil

Starch 1500 88.8 44.0 38.7 25.8 - - 1 18.3 33.8

StarCap 1500 - - - - 237.3 67.8 1 18.3 33.8

Mg Stearate 2.0 1.0 1.5 1.0 3.5 1.0 3.5 1.0

Total 200.0 100 150.0 100 350 100 350 100

Total 0.9 1.2 1.3 1.4

Impurities¹

% Change

from Initial (Δ)

One week stability results stored at 40°C / 75% RH (relative humidity), exposed size 0 HPMC capsules.

The results of this experiment when compared with the previous experiment (Table 1) demonstrate that the best adefovir dipivoxil stability is achieved using a starch level of 44% w/w at a 200mg fill weight. In addition, if necessary, use of a larger particle size grade of starch (Starcap 1500) to improve flow does not have a significantly negative impact on adefovir stability. Improved material flow properties at the 44% Starch 1500 level were observed while encapsulating. The improved flow characteristics were evidenced based on the complete discharge of material from the blender and the absence of 'rat holing' in the encapsulation machine hopper.

Effect of capsule size and tamping force on adefovir stability

To evaluate the effects of capsule volume / headspace and tamping force on adefovir dipivoxil stability, the Blend A capsule formulation (listed in Table 1 above) was manually filled into various capsule sizes at a 350mg fill weight and subjected to the rapid stability screen described above for 2 weeks. For size 1 capsules, manually filled untamped powder was compared to a 'tamped' powder. Additionally, an alternate formulation concept (Blend C) was subjected to the same rapid stability screen, evaluating the effects of capsule size and the resulting head space on adefovir dipivoxil stability. Blend C is a blend of an uncompressed powder of 10mg adefovir dipivoxil, 7.5 mg pregelatinized starch, 9mg croscarmellose sodium, 113mg lactose monohydrate and 9mg talc, with 2.5mg magnesium stearate and 100mg lamivudine.

The stability screening results from this experiment on two different combination capsule formulations are summarized in Table 3.

Table 3: Effect of capsule size and tamping force observed on adefovir stability in two combination capsule formulation concepts

in capsule size indicated.

Same as Table 1 Blend A formulation

The Blend C formulation is described above.

The results of this experiment show that capsule size has no significant effect on adefovir dipivoxil stability. Comparing the untamped powder vs. 'tamped' powder filled into size 1 capsules, the impurity results show poorer adefovir dipivoxil stability for tamped material compared to bulk-filled powder. This observation is consistent with the two formulations subjected to this rapid stability screening. Effect of Starch 1500 level on adefovir dipivoxil stability

Blends were prepared and manually filled as bulk powder into size 00 capsules at three Starch 1500 levels. The results for this screening experiment are shown in Table 4.

Table 4: Effect of Starch 1500 level on adefovir dipivoxil stability

One and two week stability results stored at 40°C / 75% RH (relative humidity), exposed - size 00 capsules. The results of this experiment show that better adefovir dipivoxil stability is observed with Starch 1500 levels of less than 66% w/w. This result is consistent with the previous rapid stability screening experimental data where the best adefovir dipivoxil stability was observed at a 44% w/w starch level.

Preparation of Lamivudine / Adefovir Dipivoxil Fixed Dose Combination Capsule Informal Stability Batches Pilot-scale informal stability batches were prepared to obtain stability data on machine- filled lamivudine / adefovir dipivoxil fixed dose combination capsules. The formulations for the informal stability batches and the results from a one-week rapid stability screen are summarized in Table 5. Table 5: Rapid Stability Screen Results for Informal Pilot-Scale Stability Batch Formulations

Blend G Blend H

(44% w/w Starch 1500)

Batch Size: ~ 1 kg

Batch Size: (2 X 500g)

Component mg/capsule % w/w Component mg/capsule % w/w

Lamivudine 100 50.0 Lamivudine 100 39.84

Adefovir 10 5.0 Uncompressed 148.5 59.16 dipivoxil Adefovir

Dipivoxil

Blend¹

Starch 1500 88 44.0 - - -

Mg Stearate 2.0 1.0 Mg Stearate 2.5 1.0

Total 200 100 251 100

Capsule Size 2 Size 2

Size and Fill

200 mg 251 mg Weight (mg)

Total 1 wk 1.8 1 wk 3.1

Impurities²

% Change

from Initial

(Δ)

The uncompressed adefovir dipivoxil blend contains 10mg adefovir dipivoxil, 7.5 mg pregelatinized starch, 9mg croscarmellose sodium, 1 13mg lactose monohydrate and 9mg talc.

² One week stability results stored 40 C/ 75% RH, exposed - size 2 capsules

During encapsulation of Blend G, improved material flow properties were observed using the 44% Starch 1500 level formulation based on:

• Complete discharge of material from the blender without manual intervention, and

• The absence of "rat holing" in the machine hopper during encapsulation.

Claims

What is claimed is:

1. A pharmaceutical composition in the form of a capsule containing a blend which comprises about 100mg of lamivudine and about 10mg of adefovir dipivoxil.

2. A pharmaceutical composition according to claim 1 wherein the capsule contains a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil; and

iii) from about 25% to about 66% w/w starch.

3. A pharmaceutical composition according to claim 1 wherein the capsule contains a blend which comprises:

i) about 100mg of lamivudine;

ii) about 10mg of adefovir dipivoxil;

iii) from about 1 % to about 5% w/w pregelatinized starch;

iv) from about 1 % to about 5% w/w croscarmellose sodium;

v) from about 40% to about 50% w/w lactose monohydrate;

vi) from about 1 % to about 5% w/w talc; and

vii) from about 0.5% to about 2% w/w magnesium stearate.

4. A pharmaceutical composition according to any one of the preceding claims wherein the capsule is an HPMC capsule.

5. A pharmaceutical composition according to any one of the preceding claims wherein the capsule is size 1 or size 2.

6. A pharmaceutical composition according to any one of the preceding claims wherein the capsule contains an uncompressed or untamped blend.

7. A method of treating HBV infection comprising administering a safe and effective amount of a pharmaceutical composition as defined in any one of claims 1 to 6 to a patient in need thereof.

8. A pharmaceutical composition as defined in any one of claims 1 to 6 for use in the treatment of HBV infection.

9. The use of a pharmaceutical composition as defined in any one of claims 1 to 6 in the manufacture of a medicament for use in the treatment of HBV infection.