MX2008007776A - Pharmaceutical combination comprising nucleotide and nucleoside reverse transcriptase inhibitors (such as tenofovir and lamivudine) in different parts of the dosage unit - Google Patents

Abstract

A pharmaceutical formulation for the treatment of HIV is provided. The formulation is a combination of a nucleoside reverse transcriptase inhibitor and a nucleotide reverse transcriptase inhibitor in which the combination has an increased stability over prior, art combination therapies. The invention also provides a pharmaceutical product containing the formulation.

Description

PHARMACEUTICAL COMBINATION THAT INCLUDES INHIBITORS OF INVERSE TRANSCRIPTASE OF NUCLEOTIDES AND NUCLEOSIDES (TAL LIKE TENOFOVIR AND LAMIVUDINE) IN DIFFERENT PARTS OF THE DOSE UNIT Field of the Invention The present invention relates to a pharmaceutical formulation for the treatment of infection by human immunodeficiency virus (HIV). In particular, the invention relates to a pharmaceutical formulation comprising a nucleoside reverse transcriptase inhibitor and a nucleotide reverse transcriptase inhibitor and a pharmaceutical product containing the pharmaceutical formulation and a non-nucleoside reverse transcriptase inhibitor. The invention also relates to a process for preparing the pharmaceutical formulation and its use in therapy.

Background of the Invention Human immunodeficiency virus (HIV) infection and related diseases are a major and global problem in the world today. HIV is the etiological agent of the complex disease that includes suppression or progressive destruction of the immune system known as Acquired Immunodeficiency Syndrome or AIDS and the degeneration of the central and peripheral nervous system. HIV too REF .: 194185 predisposes subjects to fatal opportunistic infections. The genetic material of HIV is stored in the form of RNA. To allow the incorporation of this genetic material into the DNA of the host cell, this viral RNA needs to be transformed into viral DNA. It is known that HIV is a retrovirus because it has this ability to copy RNA to DNA. Reverse transcriptase is an enzyme required for this reaction. To construct its viral DNA, HIV uses nucleotides from the cytoplasm of the host cell. Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs lacking a 3'-hydroxyl group. After these nucleoside analogs have been phosphorylated. { to the corresponding nucleotide), can be incorporated into the growing DNA chain. Due to the 3'-hydroxyl group absent in these analogues, the newly made strand of DNA is terminated promptly and polymerization is stopped by reverse transcriptase. The activity of these NRTIs is not limited only to HIV reverse transcriptase, but can also be used against other retroviruses. Tenofovir is a new nucleotide reverse transcriptase inhibitor recently approved in the United States for the treatment of HIV-1 infection in combination with other antiretroviral agents. Nucleotide analogs are very similar to nucleoside analogs but they are pre-phosphorylated, and in this way they require less processing by the body. Tenofovir DF (disoproxil fumarate) is disclosed in U.S. Patent Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230 and 6,069,249, while PMPA or Tenofovir DF is described in U.S. Patent Nos. 4,808,716, 5,733,788 and 6,057,305. US 2004/0224917 describes the combination of Tenofovir DF and Emtricitabine. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. The inhibition of this processing prevents the production of normally infectious viruses. The literature reports that the genetic inactivation of the HIV-encoded protease results in the production of non-infectious, non-infectious virus particles. These results indicate that the inhibition of HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of HIV infection. A substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the individual therapeutic agents used to treat the disease.

Several combinations have now been made available for this purpose and several attempts have been made to formulate combination regimes. An example is the combination of synthetic nucleoside analogues, Lamivudine (150 mg) and Zidovudine (300 mg), which is commercially available as Combivir ™ from GlaxoSmithKine. Another such combination is of the nucleoside analogues Abacavir and Lamivudine, which is described in Glaxo's patent application no. WO03 / 101467. Lamivudine (also known as 3TC) and its use in the treatment and prophylaxis of viral infections is described in US 5,047,407. Lamivudine and its use against HIV is described in WO 91/17159 and EP 0382526. In WO 92/21676, crystalline forms of lamivudine are described. Combinations of lamivudine with other nucleoside reverse transcriptase inhibitors, in particular zidovudine AZT, are described in WO 91/20344, WO 98/18477, and WO / 9955372. A number of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are known, such as Delavirdine, Capravirine, Efavirenz and Nevirapine. NNRTIS are common components of antiretroviral therapy of candid patients infected with HIV, and provide synergistic activity with nucleoside reverse transcriptase inhibitors (NRTIs).

Efavirenz is chemically known as (S) -6-chloro-4- (cyclopropylentinyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3, l-benzoxazin-2-one. Efavirenz is a reverse transcriptase inhibitor, not a nucleoside, specific for HIV-1. Efavirenz is useful for the treatment of HIV and has been reported to inhibit the reproduction of HIV in the body. Efavirenz is commercially available from Bristol-Myers Squibb Co, under the name SUSTIVAMR, for the treatment of HIV, and is described, for example, in U.S. Patent Nos. 5,519,021, 5,663,1699, 5,811,423 and 6,238,695. Navirapine, chemically, ll-Cyclopropyl-5-11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one is an inhibitor of non-nucleoside reverse transcriptase. Therapeutic uses of nevirapine and related compounds and their preparations are described in U.S. Patent No. 5,366,972. Nevirapine is commercially available as a 200 mg and 50 mg / 5 mL tablet in 240 mL oral suspension. It is sold under the name VIRAMUNEMR. The combination therapy reduces the daily dose that will be taken by patients and simplifies the dosing program, thereby increasing patient compliance. The combination therapy also increases the efficiency of the drug. The use of combination therapy can produce an equivalent antiviral effect with reduced toxicity. Despite the existence of these combinations, there remains the need to develop a combination for acute therapy and for resistant HIV viruses. Thus, it is an object of the present invention to provide a pharmaceutical composition which, inter alia, aids in the treatment of human immunodeficiency virus (HIV) and optionally related disorders that result in AIDS.

Detailed Description of the Invention The present invention provides an effective combination that solves or alleviates the problems of the prior art. In particular, the present invention provides a pharmaceutical formulation in a single unit dosage form that has increased patient compliance and improved stability. In a first aspect, the invention provides a pharmaceutical formulation in a single unit dosage form, wherein the dosage form comprises: (a) a nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof, and (b) an inhibitor of reverse transcriptase of nucleotides or physiologically functional derivative thereof, wherein the nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof is provided in a different region of the dose form to the nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof. In a second aspect, there is provided a pharmaceutical product comprising a pharmaceutical formulation according to the invention, and further comprising a non-nucleoside reverse transcriptase inhibitor. In a third aspect, there is provided a pharmaceutical product comprising: i) lamivudine, ii) a nucleotide reverse transcriptase inhibitor, and iii) a non-nucleoside reverse transcriptase inhibitor. In another aspect, there is provided the use of a nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof of a nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof in the manufacture of a pharmaceutical unit dosage form for the treatment or prevention of symptoms or effects of an HIV infection in an infected individual, where the inhibitor of Nucleoside reverse transcriptase or physiologically functional derivative thereof is provided in a different region of the dosage form to the nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof. In another aspect, the use of a pharmaceutical formulation according to the invention is provided in the preparation of a medicament for the treatment or prevention of symptoms or effects of an HIV infection in an infected individual. The present invention further provides pharmaceutical compositions for simultaneous, separate or sequential use in the treatment or prevention of viral infections. In particular, the invention provides a pharmaceutical product comprising a pharmaceutical formulation according to the invention and a non-nucleoside reverse transcriptase inhibitor for simultaneous, separate or sequential use. The present invention thus provides an effective and long-lasting therapy for AIDS that decreases HIV levels in patients at an undetectable level and increases the counts of CD4 cells for prolonged periods without the development of resistance. The combination therapies of the invention are a step forward in the art to improve the effectiveness in the treatment of AIDS and to make it impossible to develop resistance to individual therapeutic agents. In the first aspect of the invention, the nucleoside reverse transcriptase inhibitor is preferably chosen from lamivudine, abacavir, emtricitabine, zidovudine, stavudine or physiologically functional derivatives thereof. Preferably, lamivudine is used. The nucleotide reverse transcriptase inhibitor is preferably chosen from tenofovir DF or adefovir, and is preferably tenofovir DF. In the second aspect of the invention, the non-nucleoside reverse transcriptase inhibitor is preferably chosen from tenofovir DF or defovir physiologically functional derivatives thereof. Preferably, the non-nucleoside reverse transcriptase inhibitor is efavirenz. In the third aspect of the invention, the nucleotide reverse transcriptase inhibitor is preferably chosen from tenofovir DF or adefovir or physiologically functional derivatives thereof. Tenofovir DR is preferably used. The non-nucleoside reverse transcriptase inhibitor is preferably chosen from efavirenz, nevirapine, delavirdine or physiologically functional derivatives thereof. By way of Preferred, the non-nucleotide reverse transcriptase inhibitor is efavirenz. The composition can be provided as an oral dosage form. The composition or product according to the invention may be useful in the treatment of viral infections, particularly retroviral infections, which may include human immunodeficiency virus (HIV) and related disorders that result in AIDS. The term "physiologically functional derivative" as used herein means a pharmaceutically active compound with physiological functionality equivalent or almost equivalent to the named active compound when administered according to the present invention. As used herein, the term "physiologically functional derivative" includes any of the pharmaceutically acceptable salts, solvates, esters, prodrugs, derivatives, enantiomers or polymorphic substances of nucleoside reverse transcriptase inhibitors, nucleotides or non-nucleotides. nucleosides. A tablet in layers (two layers, three layers, etc.) as used herein refers to a tablet in which two or more layers of active material have been compressed successively. These tablets are also known as laminated tablets. Both or all layers of material active are exposed (although the tablet may be additionally coated). This differs from a core or coated core tablet, in which the core of a first active material is circumscribed, and in this way concealed from the outside of the tablet, by a coating layer of another active material. In addition, the invention provides a method for treating, reducing or inhibiting retroviral infections, in particular HIV infections in a mammal, including administering to a human, a safe and effective amount of a formulation or pharmaceutical product according to the invention. The reference to the word "treatment" as used herein extends to both prophylaxis and the treatment of a malignancy, infection or its symptoms. HIV causes a variety of clinical conditions that include acquired immunodeficiency syndrome (AIDS) and chronic neurological disorders. Multiple drug regimens dramatically improve the treatment of patients infected with HIV. Typically, treatment regimens with single drugs require long-term treatment that increases the evidence of unwanted side effects. In addition, single drug therapies are particularly vulnerable to mutation in HIV cycles, which lead to HIV variants that are resistant to drugs. The use of multi-drug therapies can reduce the development of strains resistant to HIV drugs because a drug will usually cancel mutations against other drugs. Multi-drug therapies inhibit replication of HIV viruses for a period of time sufficient to eliminate HIV from the body. However, not all combinations of drugs are equally effective, and some combinations may be ineffective or have undesirable side effects. In addition, certain combinations of drugs can result in undesirably poor stability. Effective multidrug treatments for HIV often require strict adherence to a complex treatment regimen that may require the administration of many different drugs per day, administered at carefully scheduled intervals with careful attention to diet. The non-compliance of the patient is a well-known problem that accompanies these complex treatment regimens in the treatment of HIV because this non-compliance can lead to the emergence of multiple strains resistant to HIV drugs and also to the abandonment of treatment by half of the therapy The combination therapy according to the invention thus provides a method for improving the effectiveness in the treatment of AIDS and for preventing the development of resistance to individual therapeutic agents. Therefore, it will be appreciated that the pharmaceutical formulations of the present invention, and in particular the preferred combination of lamivudine, tenofovir DF or a physiologically functional derivative thereof, and efavirenz or a physiologically functional derivative thereof, provide significant advantages with respect to to the prior art. The combination can conveniently be presented as individual pharmaceutical formulations in unit dosage form. In this regard, the present invention provides a kit or pharmaceutical product comprising (i) a first pharmaceutical formulation comprising lamivudine, together with one or more pharmaceutically acceptable carriers or excipients, and tenofovi DF or a physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (ii) a second pharmaceutical formulation comprising efavirenz or a physiologically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients; for separate or sequential use in the treatment or prevention of viral infections. The kit or pharmaceutical product can be provided in a patient package, optionally comprising an information insertion sheet containing instructions for the use of the kit / product. Lamivudine (also known as 3TC) is a synthetic analogue of nucleosides, chemically known as (2R, cis) -4-amino-1- (2-hydroxymethyl-l, 3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one (EpivirMR). Lamivudine has tested antiviral activity against HIV and other viruses such as HBV. Intracellular, lamivudine is phosphorylated to its metabolite 5'-active triphosphate, lamivudine triphosphate (L-TP). The main mode of action of L-TP is the inhibition of HIV-1 reverse transcriptase (RT) by DNA strand termination after incorporation of the nucleoside analogue into the viral DNA. L-TP is a weak inhibitor of DNA polymerases (alpha) and (beta), of mammals, and mitochondrial DNA polymerase (gamma). Lamivudine has also been referred to as (-) - l- [(2R, 5S) -2- (Hydroxymethyl) -1, 3-oxathiolan-5-yl] cystosine, (hydroxymethyl) -1, 3-oxathiolan-5-yl ] cystosine and has tested antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B. Lamivudine is commercially available from Glaxo Wellcome Inc under the trade name EPIVIR.

Tenofovir disoproxil fumarate is also known as PMPA. Tenofovir DF (a prodrug of tenofovir) is a salt of fumaric acid derived from bis-isopropoxycarbonyloxymethyl ester of tenofovir. The disoproxil fumarate of tenofovir is fumarate of 9 - [(R) -2- [[bis [[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine (1: 1). Tenofovir disoproxil fumarate requires initial hydrolysis of diester for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits HIV reverse transcriptase activity by competing with the natural substrate of deoxyadenosine-5'-triphosphate, and after incorporation into DNA, by DNA strand termination. Tenofovir diphosphate is a weak inhibitor of mammalian alpha and beta DNA polymerases and mitochondrial DNA polymerase. Tenofovir disoproxil fumarate is an adefovir analogue and is classified as a nucleotide reverse transcriptase inhibitor (NtRTI). Tenofovir DF is a competitive inhibitor of other nucleotides that occur naturally, and its final biological activity is chain termination of viral DNA. Tenofovir DF is a new nucleotide analog with antiviral activity against both HIV and HBV. The mechanism of tenofovir DF is similar to that of nucleoside analogs, which it interferes with reverse transcriptase and prevents the translation of viral genetic material into viral DNA. Unlike nucleoside analogues, nucleotide reverse transcriptase inhibitors are pre-activated chemically with the presence of the phosphate group. Since the passage of phosphorylation is not necessary, nucleotide analogs can be incorporated into the viral DNA strand more rapidly than nucleoside analogs. More importantly, this will derive a viral mechanism of nucleoside resistance. Tenofovir DF is commercially available from Gilead Science Inc., under the trade name VIREADMR. The chemical stability of the active ingredients in a pharmaceutical formulation is of significant interest, as is the appearance of the formulation and how it changes over time. The inventors of the present invention have surprisingly found that Lamivudine and Tenofovir DF, when intimately mixed to form a tablet (single layer) showed undesirable properties in stability test. The appearance of the tablets changed to brown at a controlled temperature (25 °) and even at an Accelerated temperature (40 ° C). However, the inventors have surprisingly found that this change in appearance is not found in the case of a tablet with two layers.

By means of a pharmaceutical formulation according to the present invention comprising a two-layer tablet comprising an NRTI and an NtRTI, treatment regimens for HIV and other viruses can be simplified in order to improve patient compliance by providing a simplified dose therapy. It is also possible to combine any of two of the NRTIs and NtRTIs employed in the present invention in a unit dose form for separate or sequential administration with a separate dosage form comprising an NNRTI. In a preferred embodiment, a typical unit dose may contain lamivudine and tenofovir DF, or physiologically functional derivatives thereof, and an additional unit dose may contain efavirenz, or a derivative physiologically functional thereof. In this regard, the present invention provides a pharmaceutical product comprising (i) a first pharmaceutical formulation comprising lamivudine and tenofovi DF physiologically functional derivatives thereof, optionally in the form of a two-layer tablet, together with one or more carriers or pharmaceutically acceptable excipients; and (ii) a second pharmaceutical formulation comprising efavirenz, or a physiologically functional derivative thereof together with one or more pharmaceutically acceptable carriers or excipients, for separate or sequential use in the treatment or prevention of viral infections, in particular retroviral infections, and especially the symptoms or effects of HIV infection, in an infected animal. The pharmaceutical and pharmaceutical formulation of the present invention employ a safe and therapeutically effective amount combination of at least two therapeutically active agents and preferably three therapeutically active agents, such as a safe and therapeutically effective amount of 2 ', 3' - dideoxy-3 '-thiathidine (lamivudine) or its physiologically functional derivatives, a safe and therapeutically effective amount of tenofovir DF, (R) -9- (2-phosphonylmethoxypropyl) adenine or its physiologically functional derivatives, optionally with a safe and therapeutically amount of efavirenz or its physiologically functional derivatives, together with safe and effective amounts of pharmaceutically acceptable excipients to maintain the homogeneity of dosage forms. The composition can be provided in the form of tablets or capsules. The pharmaceutical product of the present invention conveniently allows the administration of a pharmaceutical combination in a separate or subsequent dose containing three active compounds in oral dosage forms containing specific dose ranges for each compound. Preferably, a unit dosage form comprising an NRTI and an NtRTI is provided. Preferably, an additional dosage form comprising an NNRTI is provided for separate or sequential administration. Lamivudine can be present preferably in a range of 5-600 mg and more preferably 300 mg per unit dosage form. Tenofovir DF may preferably be present in a range of 75-600 mg and preferably 300 mg per unit dosage form. Efavirenz may preferably be present in a range of 50-600 mg and preferably 600 mg per unit dosage form.

The formulation and product of the present invention may further comprise pharmaceutical excipients to impact the beneficial characteristics of the dosage form. Typical excipients include, eluents or bulking agents, fillers, disintegrants, binders, lubricants, coating materials, wetting agents and the like. When present, a diluent or bulking agent may be selected to provide an increase in the size of the tablet. The skilled person can use known methods to select a bulking agent, which provides hardness, friability and disintegration time required for pharmaceutical advantage. Suitable diluents include microcrystalline cellulose, lactose and the like. The diluent is preferably present in an amount of 5% to 50% by weight of the formulation. Fillers suitable for use with the present invention may comprise one or more of sugars, sugar alcohols, starches, and inert materials, such as kaolin and the like, which are added to the volume of the formulation. The disintegrating agents suitable for use with the present invention may comprise one or more of celluloses and their derivatives, alginates, agar-agar, certain complex silicilates, starches, modified starches and their derivatives, polyvinyl pyrrolidones and the like. Preferred disintegrants include sodium starch glycolate and / or croscarmellose sodium. The disintegrant is preferentially present in an amount of 0.5% to 30? in weight of the formulation. The binders may comprise one or more but not limited to, natural and synthetic gums, celluloses, starches, gelatins and povidones and the like. Preferably, the binder comprises starch, maltodextrins, HPMC, HPC and / or povidone. The binder is preferably present in an amount of 1% to 50% of the formulation. Lubricants suitable for use with the present invention may comprise one or more of talc, magnesium stearate, starch, dextrin, sodium stearyl fumarate, hydrogenated vegetable oils, polyethylene glycols and their derivatives, sodium lauryl sulfate and the like. Preferably, the lubricants comprise one or more magnesium stearate, zinc stearate, calcium stearate and sodium stearyl fumarate. More preferably, the lubricant is magnesium stearate. The lubricant is preferably present in an amount of 0.25% to 3% by weight of the formulation. The tablets can be coated for the purpose of providing protection from moisture. The material of Coating can be selected from one or more of celluloses and their derivatives, polyethylene glycols and their derivatives, fatty acids such as stearic acid and its derivatives, and waxes, among other suitable coating materials well known in the art. The person skilled in the art can include wetting agent such as polysorbate 80, SLS, sucrose esters, polyethylene glycols, lutroles, cremophor and the like. When present, the wetting agent is preferably present in an amount of 0.1% to 5% by weight of the formulation. In a preferred embodiment, the formulation is in the form of a two-layer tablet. In another preferred embodiment, the product is in the form of a two-layer tablet and a subsequent unitary tablet formulation. In these embodiments, the first two layer tablet layer preferably contains about 5 to 55% by weight of lamivudine or a physiologically functional derivative thereof, of about 1 to 50% by weight of diluents, of about 1 to 50% by weight of binders, from about 1 to 30% by weight of disintegrant and from about 0.25 to 3.0% by weight of a lubricant. More preferably, the first tablet layer containing lamivudine or a derivative physiologically functional thereof in the formulation or product according to the present invention comprises from 5 to 55% by weight of lamivudine, from about 10 to 50% by weight of microcrystalline cellulose, from about 2 to 30% by weight of starch sodium glycolate, from about 1 to 10% by weight of starch and from about 0.25 to 2.5% by weight of a magnesium stearate. In these embodiments, the second two-layer tablet layer preferably contains from about 10 to 85% by weight of tenofovir DF or a physiologically functional derivative thereof, from about 1 to 50% by weight of diluent, of about 1 to 50% by weight of binder, from about 0.5 to 30% by weight of disintegrant and from about 0.25 to 3% by weight of a lubricant. More preferably, the second layer of the tablet comprises from about 35 to 85% by weight of tenofovir DF, from about 5 to 50% by weight of lactose or microcrystalline cellulose, from about 1 to 10% by weight of starch, about 1 to 20% by weight of sodium starch glycolate and from about 0.2 to 2% by weight of magnesium stearate. In the preferred pharmaceutical product of the present invention, a unit tablet dose containing at least one inhibitor is preferably provided. of non-nucleoside reverse transcriptase or a physiologically functional derivative thereof. In the preferred product according to the present invention, the unit dosage form comprises from about 10 to 50% by weight of efavirenz or a physiologically functional derivative thereof, from about 1 to 50% by weight of diluent, of about 1 to 50% by weight of binder, from about 0.5 to 30% by weight of disintegrant and from about 0.2 to 3% by weight of a lubricant. Various well-known techniques can be used to formulate the granules. In a preferred embodiment of the present invention, a method for preparing a pharmaceutical composition for a first layer of the two-layer tablet preferably includes the steps of mixing a disintegrating diluent with lamivudine; granulate them further with water and suitable binder in granules; drying the resulting granules; size and lubricate the granules. A preferred method for preparing a pharmaceutical composition for a second layer of the two-layer tablet preferably includes the steps of mixing a diluent with Tenofovir DF; granulate them further with water and suitable binder in granules; drying the resulting granules and dimeneionar; again mix with suitable color and disintegrant; lubricate the granules.

The lubricated granules of both layers can then be compressed together using a suitable compression machine. Both layers may optionally contain coloring agents. A preferred method for making the unit tablet preferably includes the steps of mixing a diluent with efavirenz; granulate them further with water and suitable binder in granules; drying the resulting granules and dimensioning; mix with appropriate color (if desired) and disintegrant; lubricate the granules. The present invention can be formulated as a multilayer tablet formulation, preferably two layers which can be typically administered to patients and allows or achieves distribution of pharmaceutically active and effective agents for the prevention and treatment of HIV infection and in the prevention or treatment of acquired immunodeficiency syndrome (AIDS) resulting. The present invention formulated as a two layer tablet can be further modified to act as a dispersible tablet comprising suitable excipients known to the person skilled in the art. Each part of the tablet of the present invention can be prepared by wet granulation or compression direct or dry granulation. In view of the relatively high dose of lamivudine, it is preferred to use wet granulation techniques. The formulation of the present invention can also be formulated as a three layer tablet. In this embodiment, a placebo layer is used as an intermediate layer between the layers of NNRT and NtRTI. Preferably, the placebo layer comprises pharmaceutical excipients but does not comprise any active ingredient. A suitable placebo comprises silica gel. This can further increase the stability of a tablet containing, for example, lamivudine and tenofovir DF in different layers. In a preferred embodiment of the present invention, a pharmaceutical product comprises a two-layer system with a subsequent unitary tablet formulation that includes pharmaceutically active agents effective for the treatment of HIV. More particularly, a product according to the present invention preferably comprises a two-layer formulation comprising a first layer comprising at least one nucleoside reverse transcriptase inhibitor, optionally comprising pharmaceutical excipients, and a second layer comprising at least one nucleotide reverse transcriptase inhibitor, which further comprises optionally pharmaceutical excipients; and a formulation comprising a non-nucleoside reverse transcriptase inhibitor wherein the two-layer formulation together forms a pharmaceutically stable preparation. The invention will now be described with further reference to the following examples which are specific embodiments only and is not limiting the scope of the invention.

Example 1 (A) Tablet of Lamivudine and Tenofovir DF (disoproxil fumarate) [B) Efavirenz Tablet Process for Preparation of Two-Layer Tablet The preparation of layer 1 includes the steps of mixing diluent, disintegrant and optionally suitable color with Lamivudine and then lubricate the mixture. The preparation of layer II includes the diluent mixing steps with Tenofovir DF; further granulating them with water and suitable binder to obtain granules; drying the resulting granules and dimensioning the granules; mix again the granules with color and suitable disintegrant; and lubricate the granules. The lubricated granules of both layers are then compressed together using a suitable compression machine. The preparation of the Efavirenz tablet includes the step of mixing the diluent with Efavirenz; granulate them further with water and suitable binder to obtain granules; drying the resulting granules and dimensioning the granules; mix again the granules with color and suitable disintegrant; and lubricate the granules.

Example 2 Processing process for Tenofovir layer: - Prepare a premix of tenofovir and lactose. This is mixed dry with croscarmellose sodium and starch. A binder solution of starch and polysorbate 80 is prepared in purified water. The dry mix is granulated using the binder solution, the wet granules are dried and sized and lubricated.

For the lamivudine layer - A dry mixture of lamivudine, microcrystalline cellulose, sodium starch glycollate and color is prepared. This is granulated with a binder solution (starch paste). The granules are sized, dried and lubricated. The tablets are compressed and coated using a redimix color solution. It will be appreciated that the invention can be modified.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (45)

1. Pharmaceutical formulation in a single unit dosage form, the dosage form is characterized in that it comprises: (a) a nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof, and (b) a nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof, wherein the formulation is in the form of a multilayer tablet or a reduced core tablet, and wherein the nucleoside reverse transcriptase inhibitor or derivative thereof Physiologically functional thereof is provided in a different region of the dosage form to the nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof.

2. Pharmaceutical formulation according to claim 1, characterized in that the nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof is provided in a first region of the dosage form, and the nucleotide reverse transcriptase inhibitor or physiologically functional derivative. of the same provided in a second region of the dosage form, wherein the first region is free, substantially free of the inhibitor of nucleotide reverse transcriptase, and the second region is free or substantially free of the nucleoside reverse transcriptase inhibitor.

3. Pharmaceutical formulation according to claim 1 or 2, characterized in that it is in the form of a multilayer tablet, a first layer of the tablet comprising the nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof and a second one. tablet layer comprising the nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof.

4. Pharmaceutical formulation according to claim 3, characterized in that the multilayer tablet is a two-layer tablet or a three-layer tablet.

5. Pharmaceutical formulation according to claim 4, characterized in that the multilayer tablet is a two-layer tablet.

6. Pharmaceutical formulation according to claim 4, characterized in that the multilayer tablet is a three-layer tablet, and wherein a third layer of the tablet is free and substantially free of the nucleoside reverse transcriptase inhibitor and the inhibitor of nucleotide reverse transcriptase.

7. Pharmaceutical formulation in accordance with the claim 6, characterized in that the third layer does not comprise or does not substantially comprise the pharmaceutically active agent.

8. Pharmaceutical formulation according to claim 6 or 7, characterized in that the third layer is intermediate to the first and second layers.

9. Pharmaceutical formulation according to claim 1 or 2, characterized in that the coated tablet is formed of a core comprising one of the first or second regions, and a coating layer comprising the other of the first or second regions.

10. Pharmaceutical formulation according to claim 9, characterized in that the coated tablet comprises an intermediate layer interposed between the core and the coating layer.

11. Pharmaceutical formulation according to claim 10, characterized in that the intermediate layer of the tablet comprises nothing or substantially nothing of the nucleoside reverse transcriptase inhibitor and the nucleotide reverse transcriptase inhibitor.

12. Pharmaceutical formulation according to claim 11, characterized in that the intermediate layer comprises a placebo or a non-pharmaceutically active agent.

13. Pharmaceutical formulation according to any preceding claim, characterized in that the Inhibitor of nucleoside reverse transcriptase is lamivudine, abacavir, emitricitabine, zidovudine or stavudine, or a physiologically functional derivative thereof.

14. Pharmaceutical formulation according to claim 13, characterized in that the nucleoside reverse transcriptase inhibitor is lamivudine or a physiologically functional derivative thereof.

15. Pharmaceutical formulation according to any preceding claim, characterized in that the nucleotide reverse transcriptase inhibitor is tenofovir DF or adefovir, or a physiologically functional derivative thereof.

16. Pharmaceutical formulation according to claim 15, characterized in that the nucleotide reverse transcriptase inhibitor is tenofovir DF.

17. Pharmaceutical formulation according to any preceding claim, characterized in that the inhibitor of nucleoside reverse transcriptase is lamivudine and the inhibitor of nucleotide reverse transcriptase is tenofovir DF.

18. Pharmaceutical formulation according to any preceding claim, characterized in that it comprises from 50 mg to 600 mg of the nucleoside reverse transcriptase inhibitor, per unit dose form.

19. Pharmaceutical formulation in accordance with any preceding claim, characterized in that it comprises from 150 mg to 450 mg of the nucleoside reverse transcriptase inhibitor, per unit dose form.

20. Pharmaceutical formulation according to any preceding claim, characterized in that it comprises approximately 300 mg of the nucleoside reverse transcriptase inhibitor, per unit dose form.

21. Pharmaceutical formulation according to any preceding claim, characterized in that it comprises from 75 mg to 600 mg of the nucleotide reverse transcriptase inhibitor, per unit dose form.

22. Pharmaceutical formulation according to any preceding claim, characterized in that it comprises from 150 mg to 450 mg of the nucleotide reverse transcriptase inhibitor, per unit dose form.

23. Pharmaceutical formulation according to any preceding claim, characterized in that it comprises approximately 300 mg of the nucleotide reverse transcriptase inhibitor.

24. Pharmaceutical formulation according to claim 3 or 6, characterized in that the first and / or second layer further comprise at least one pharmaceutically acceptable excipient.

25. Pharmaceutical formulation in accordance with claim 24, characterized in that the pharmaceutically acceptable excipient comprises at least one of diluent, filler, bulking agent, disintegrant, binder or lubricant.

26. Pharmaceutical formulation according to any preceding claim, characterized in that it is in the form of a tablet, optionally a two-layer tablet, wherein the tablet is coated.

27. Pharmaceutical formulation according to any of claims 3 to 8, characterized in that the first layer comprises from 5 to 55% by weight of nucleoside reverse transcriptase inhibitor, from 0.5 to 30% by weight of diluent, from 1 to 30. % by weight of disintegrant, from 1 to 50% by weight of binder and from 0.25 to 3.0% by weight of lubricant.

28. Pharmaceutical formulation according to any of claims 3 to 8 or 27, characterized in that the first layer comprises from 5 to 55% by weight of Lamivudine or a physiologically functional derivative thereof, from 0.5 to 30% by weight of diluent , from 1 to 30% by weight of disintegrant, from 1 to 50% by weight of binder and from 0.25 to 3.0% by weight of lubricant.

29. Pharmaceutical formulation according to any of claims 3 to 8, 27 or 28, characterized in that the second layer comprises from 10 to 85% by weight of nucleotide reverse transcriptase inhibitor, from 1 to 50% by weight of diluent, from 1 to 50% by weight of binder, from 0.5 to 30% by weight of disintegrant and from 0.25 to 3% by weight of lubricant.

30. Pharmaceutical formulation according to any of claims 3 to 8 or 27, characterized in that the second layer comprises from 35 to 85% by weight, from 5 to 50% by weight of diluent, from 1 to 10% by weight of binder. and from 0.2 to 2% by weight of lubricant.

31. Pharmaceutical formulation according to any of claims 27 to 29, characterized in that the nucleotide reverse transcriptase inhibitor is tenofovir DF.

32. Pharmaceutical product, characterized in that it comprises a pharmaceutical formulation according to any of claims 1 to 31, and further comprising a non-nucleoside reverse transcriptase inhibitor.

33. Pharmaceutical product according to claim 32, characterized in that the non-nucleoside reverse transcriptase inhibitor is efavirenz, nevirapine or delavirdine, or a physiologically acceptable derivative thereof.

34. Pharmaceutical product according to claim 32 or 33, characterized in that the inhibitor of Non-nucleoside reverse transcriptase is efavirenz.

35. Pharmaceutical product, characterized in that it comprises: i) Lamivudine, ii) a nucleotide reverse transcriptase inhibitor, and iii) a non-nucleoside reverse transcriptase inhibitor, wherein the product is in the form of a multilayer tablet or a coated core tablet, and wherein the nucleoside reverse transcriptase inhibitor is provided in a different region from the dosage form to lamivudine.

36. Pharmaceutical product according to claim 35, characterized in that the inhibitor of nucleotide reverse transcriptase is tenofovir DF.

37. Pharmaceutical product according to claim 35 or 36, characterized in that the non-nucleoside reverse transcriptase inhibitor is efavirenz.

38. Pharmaceutical product according to claim 35, 36 or 37, characterized in that the lamivudine and the nucleotide reverse transcriptase inhibitor are formulated as a pharmaceutical formulation according to any of claims 1 to 31.

39. Pharmaceutical product according to with any of claims 32 to 34, or 38, characterized in that the non-nucleotide reverse transcriptase inhibitor is formulated as a first dose form, and the nucleoside reverse transcriptase inhibitor and the nucleotide reverse transcriptase inhibitor are formulated as a second separate unit dosage form

40. Pharmaceutical product according to claim 39, characterized in that the separate dosage form comprises from 10 to 50% by weight of the non-nucleoside reverse transcriptase inhibitor, from 1 to 50% by weight of diluent , from 1 to 50% by weight of binder, from 0.5 to 30% by weight of disintegrant and from 0.2 to 3% by weight of lubricant.

41. Pharmaceutical product according to claim 39 or 40, characterized in that the non-nucleoside reverse transcriptase inhibitor is efavirenz.

42. Pharmaceutical product according to claim 39, 40 or 41, characterized in that the separate dosage form is in the form of a tablet, powder or tablets in capsules, tablet tablets, tablets, granules, oral powder, solution or suspension .

43. Use of a pharmaceutical formulation according to any of claims 1 to 31, in the preparation of a medicament for the treatment or prevention of symptoms or effects of an HIV infection in an individual infected

44. Use according to claim 43, wherein the medicament further comprises a non-nucleoside reverse transcriptase inhibitor.

45. Use of a nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof and a nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof in the manufacture of a pharmaceutical unit dosage form for the treatment or prevention of symptoms or effects of an HIV infection in an infected individual, wherein the formulation is in the form of a multilayer tablet or a coated core tablet, and wherein the nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof is provided in a different region of the dosage form to the nucleotide reverse transcriptase inhibitor or physiologically functional derivative thereof.