GB2400552A - Pharmaceutical combinations for treating viral infections - Google Patents
Pharmaceutical combinations for treating viral infections Download PDFInfo
- Publication number
- GB2400552A GB2400552A GB0308603A GB0308603A GB2400552A GB 2400552 A GB2400552 A GB 2400552A GB 0308603 A GB0308603 A GB 0308603A GB 0308603 A GB0308603 A GB 0308603A GB 2400552 A GB2400552 A GB 2400552A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pharmaceutically acceptable
- acceptable derivative
- pharmaceutical
- efavirenz
- zidovudine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A pharmaceutical combination comprising lamivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; for simultaneous, separate or sequential use in the treatment or prevention of viral infections in an infected animal.
Description
1 2400552
PHARMACEUTICAL COMBINATIONS FOR TREATING VIRAL INFECTIONS
The present invention relates to pharmaceutical combinations for treating viral infections, in particular retroviral infections, and especially human immunodeficiency virus (HIV) infections, in an infected animal. The present invention is also concerned with pharmaceutical formulations containing said pharmaceutical combinations and their use in the treatment of the above mentioned viral infections.
A retrovirus designed human immunodeficiency virus (HIV) is the Biological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome or AIDS) and degeneration of the central and peripheral nervous system. A common feature of retrovirus replication is the extensive post-translation processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function.
Inhibition of this processing prevents the production of the normally infectious virus.
Literature reports have shown that genetic inactivation of the HIV encoded protease has resulted in the production of immature, non- infectious virus particles and as such that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV has shown the presence of a Dot gene in one open reading frame [as reported in 'Nature', 313, 277 (1985) by Ratner, L. et al]. Amino acid sequence homology provides evidence that the Dol sequence encodes reverse transcriptase, an endonuclease and a HIV protease [Tofu, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al. , Nature, 329, 351 (1987)].
One 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 employed to treat the disease. Thus, a need remains for an efficacious and long lasting therapy for AIDS which lowers HIV viral levels of patients to undetectable levels and raises CD4 cell counts for prolonged periods of time without the development of resistance.
It is a particular object of the present invention to provide pharmaceutical combinations, which, inter alla, will assist in inhibiting the human immunodeficiency virus (HIV).
In the present invention, therefore, two or more nucleoside reverse transcriptase inhibitors, or pharmaceutically acceptable derivatives thereof, are combined for administration with a non-nucleoside reverse transcriptase inhibitor, or a pharmaceutically acceptable derivative thereof. This pharmaceutical combination therapy as provided by the present invention provides enhanced effectiveness in treating AIDS and substantially precludes the development of resistance to the individual therapeutic agents employed. In particular, it is a feature of the present invention that the use of the herein described pharmaceutical combination will provide synergistic antiviral effects.
The nucleoside reverse transcriptase inhibitors employed according to the present invention can preferably be lamivudine, zidovudine, or pharmaceutically acceptable derivatives thereof.
The non-nucleoside reverse transcriptase inhibitor employed according to the present invention can preferably be efavirenz, or a pharmaceutically acceptable derivative thereof There is provided by the present invention, therefore, a pharmaceutical combination comprising lamivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; for simultaneous, 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.
It will be appreciated from the above that in certain embodiments of the present invention, the therapeutic agents of a pharmaceutical combination according to the present invention can be administered simultaneously, for example as a single combined formulation. In alternative embodiments of the present invention, the therapeutic agents of a pharrnacoutical combination according to the present invention can be administered separately or sequentially.
Lamivudine (also known as 3TC) is a synthetic analogue, chemically known as (2R- cis)-4-Amino- 1 -[2-(hydroxymethyl) 1,3 -oxathiolan-5-yl] -2(1 H)pyrimidinone.
Lamivudine has also been referred to as (-)-1-[(2R, 5S) 2-(Hydroxymethyl)1,3- oxathiolan-5-yl] cystosine, or (Hydroxymethyl)-1,3-oxathiolan-5-yl] cystosine.
Lamivudine has proven antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B and is commercially available from Glaxo Wellcome Inc. under the trade mark Epivir. Lamivudine and its use against HIV are described in WO 91/17159 and EP 0382526. Crystalline forms of lamivudine are also described in WO 92/21676.
Pharmaceutical combinations of lamivudine with other reverse transcriptase inhibitors, in particular zidovudine, are described for example in WO 92/20344, WO 9818477, and W09955372. US patent 5,047,407 discloses (2R, cis)-4-ammino- 1-(2hydroxymethyl-1,3-oxathiolan-5yl)-(lH)-pyrimidin-2-one (lamivudine) and its use in the treatment and prophylaxis of viral infections. In addition to lamivudine's proven antiviral activity against HIV as referred to above, lamivudine also exhibits antiviral activity against other viruses such as HBV. As can be seen according to the present invention, lamivudine exhibits unexpected advantages when used in combination with known inhibitors of HIV replication. In particular, lamivudine shows a synergistic antiviral effect when used in combination with zidovudine and efavirenz substantially as herein described.
Zidovadine, chemically known as 3'-azido-3'deoxythymidine, is a pyrimidine nucleoside analogue, which is well established as an important and useful chemotherapeutic agent for the treatment and / or prophylaxis of HIV infections including related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection and who are anti-HIV antibody positive. Zidovudine is commercially available from Glaxo Wellcome Inc. under the trade mark Retrovir for treatment of HIV, and is described, for example, in US patents 4,818,538, 4,828,838, 4,724,232 and 4,833,130. Methods of preparation of zidovudine are also described in US patent 5,011,828. Zidovodine is also, for example, further described in US patents 4,818,538, 4,828,838, 4,724,232, 4,833,130 and 4,837,208.
Efavirenz is chemically known as (S)-6-chloro-4-(cyclopropylethynyl)-1,4dihydro-4- (trifluoromethyl)-2H-3,1-benzoxazin-2-one. Efavirenz is a HIV-1 specific, non- nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is useful for the treatment of HIV and has been reported to inhibit reproduction of HIV in the body.
Efavirenz is commercially available from Bristol Mayer Squibb Co, under the trade mark Sustiva, for treatment of HIV, and is described, for example, in US patents 5,519,021, 5,663,169, 5,811,423 and 6,238,695.
Efavirenz has been used in conjunction with other retroviral agents. Surprisingly, it has now been found by the present invention that efavirenz is very effective when used in anti-retroviral regimens that include the nucleoside reverse transcriptase inhibitors lamivudine and zidovodine.
The wording "pharmaceutically acceptable derivative" as used herein with reference to any of the above mentioned therapeutic agents employed in the present invention is intended to include any pharmaceutically acceptable salt, solvent, ester or salt of such ester, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) the intended active ingredient or any active metabolite or residue thereof The synergistic effects of a pharmaceutical combination of lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, according to the present invention are particularly seen over a weight ratio, for example, of efavirenz, or a pharmaceutically acceptable derivative thereof, to lamivudine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 2 to about 1:4 and a weight ratio of efavirenz, or a pharmaceutically acceptable derivative thereof, to zidovudine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 1 to about 1:4. In these embodiments, a pharmaceutically acceptable salt or ester can be substituted for any one or more of the therapeutic agents per se. In yet another aspect of the present invention, the weight ratio of efavirenz to lamivudine and zidovudine can be any one of the weight ratios set forth above.
Suitably dosage ranges for the therapeutic agents employed in a pharmaceutical combination according to the present invention can be as follows: lamivudine in a dosage range of about 100-300 mg per unit dosage form and more particularly about 300 mg per unit dosage form; zidovudine in a dosage range of about 300- 600 mg per unit dosage form and more particularly about 600 mg per unit dosage form; and efavirenz about 600 mg per unit dosage form.
While it is possible for the therapeutic agents of a pharmaceutical combination according to the present invention to be administered as the raw chemicals it is preferable to present them as a pharmaceutical formulation or formulations.
Pharmaceutical formulations according to the present invention comprise a pharmaceutical combination according to the invention substantially as hereinbefore described, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. It will also be appreciated that pharmaceutical combinations and formulations according to the present invention employ "safe and effective amounts" of the therapeutic agents employed according to the present invention and the carrier(s) employed therewith, and for example the wording "safe and effective amounts" as used herein with reference to the therapeutic agents employed is intended to refer to a sufficient amount of the therapeutic agent required to abate or reverse or treat a viral infection in a human or other mammal without severely harming the tissues of the human or other mammal to which the therapeutic agent is administered.
When individual therapeutic agents of a pharmaceutical combination according to the present invention are administered separately or sequentially, they can each be presented as a pharmaceutical formulation. It will be appreciated, therefore, that a pharmaceutical combination of lamivudine, zIdovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, according to the present invention may conveniently be presented as individual pharmaceutical formulations in unitary dosage form and in this respect the present invention can provide a pharmaceutical kit comprising (i) a first pharmaceutical formulation comprising larnivudine, or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers or excipients; (ii) a second pharmaceutical formulation comprising zidovudine, or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (iii) a third pharmaceutical formulation comprising efavirenz, or a pharmaceutically acceptable 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.
Alternatively, it is also possible to combine any two of the therapeutic agents employed in the present invention in a unitary dosage form for separate or sequential administration with the third therapeutic agent employed in the present invention, for example, a typical unitary dosage may contain lamivudine and zidovudine, or pharmaceutically acceptable derivatives of any thereof, and a further unitary dosage may contain efavirenz, or a pharmaceutically acceptable derivative thereof. In this respect the present invention can provide a pharmaceutical kit comprising (i) a first pharmaceutical formulation comprising larnivudine and zidovudine, or pharmaceutically acceptable derivatives of any thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (ii) a second pharmaceutical formulation comprising efavirenz, or a pharmaceutically acceptable 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.
Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the therapeutic agents employed in the present invention with one or more pharmaceutically acceptable carriers or excipients, which constitute one or more accessory ingredients.
In general, the formulations are prepared by uniformly and intimately bringing into association the therapeutic agents with finely divided solid carriers or liquid carriers or both, and then if necessary shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets each containing a predetermined amount of the therapeutic agents; as a powder or granules; as a solution or a suspension; or as an emulsion.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients and a tablet is a preferred dosage form according to the present invention. In a preferred embodiment of the present invention, there is provided, therefore, one or more pharmaceutical formulations in tablet form, where the tablet or tablets comprises either independently, or in any pharmaceutical combination, lamivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; together with one or more pharmaceutically acceptable carriers or excipients, for simultaneous, 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 tablet formulations provided by the present invention may be provided in the form of a coated tablet having a tablet core and a coating, wherein suitably the therapeutic agents may be substantially evenly dispersed through the tablet core.
Suitably tablet formulations according to the present invention may further comprise conventional accessory ingredients, such as an effective amount of disintegrant and typically an effective amount of a diluent, such as microcrystalline cellulose, lactose, starch, dicalcium phosphate or the like, typically present in an amount of about 5 % to % of the tablet formulation. The tablets may also comprise lubricants, such as magnesium stearate, zinc stearate, calcium stearate, magnesium oxide or the like, and in particular magnesium stearate, typically present in an amount of about 0.5% to 1.0% of the tablet formulation.
Typically, the present invention provides first and second tablets which in a particular example may substantially include the following ingredients in mg per unit dosage form.
Tablet I (to be provided in a pharmaceutical kit substantially as herein described!: Lamivudine 300 mg Zidovudine 600 mg Microcrystalline cellulose 120 mg Sodium starch glycollate 6.0 mg Magnesium stearate 7.0 mg Talc 7.0 mg Color 0.5 mg Tablet II (to be provided in a pharmaceutical kit substantially as herein described): Efavirenz 600.0 mg Lactose 42.5 mg Microcrystalline cellulose 116.0 mg Sodium starch glycollate 25.0 mg Starch 35.0 mg Purified water q.s.
Magnesium stearate 6.5 mg Coating: Hydroxypropyl cellulose 11.6 mg Polyethylene glycol 6000 2.4 mg Solvent q.s.
Tablet I may form a first tablet of a pharmaceutical kit according to the present invention and tablet II may form a second tablet of a pharmaceutical kit according to the present invention.
In a particularly preferred embodiment of the present invention there is provided a pharmaceutical kit comprising (i) a first tablet comprising lamivudine and zidovudine, or pharmaceutically acceptable derivatives of any thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (ii) a second tablet comprising efavirenz, or a pharmaceutically acceptable 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. It will be appreciated that by means of such a pharmaceutical kit in accordance with the invention, treatment regimens for HIV and other viruses can be simplified with the goal of enhancing patient compliance by providing a simplified dosage therapy containing a pharmaceutical combination of pharmaceutically acceptable amounts of lamivodine, zidovadine and efavirenz or pharmaceutically acceptable derivatives thereof Suitably a pharmaceutical kit according to the present invention comprises a pharmaceutical combination of lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, present in a weight ratio, for example, of efavirenz, or a pharmaceutically acceptable derivative thereof, to lamiwdine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 2 to about 1:4 and a weight ratio of efavirenz, or a pharmaceutically acceptable derivative thereof, to zidovudine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 1 to about 1:4. In these embodiments, a pharmaceutically acceptable salt or ester can be substituted for any one or more of the therapeutic agents per se. In yet another aspect of the present invention, the weight ratio of efavirenz to lamivudine and zidovudine can be any one of the weight ratios set forth above.
Suitably dosage ranges for the therapeutic agents employed in a pharmaceutical kit according to the present invention are substantially as hereinbefore described and can be as follows: lamivudine in a dosage range of about 100-300 mg per unit dosage form and more particularly about 300 mg per unit dosage form; zidovudine in a dosage range of about 300-600 mg per unit dosage form and more particularly about 600 mg per unit dosage form; and efavirenz about 600 mg per unit dosage form.
It should be understood that in addition to the ingredients specifically mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
Also provided by the present invention is a process of preparing a pharmaceutical formulation according to the present invention and which process essentially comprises bringing into association the therapeutic agents employed in the present invention with one or more carriers or excipients therefor. In a preferred embodiment of the present invention the process comprises (i) preparing a first tablet containing lamivudine and zidovudine comprising the steps of blending one or more diluents with lamivudine and zidovudine; granulation; drying the resulting granules and sizing; blending the granules with one or more disintegrants; lubricating the granules; and compressing the lubricated granules into tablets; and (ii) preparing a second tablet containing efavirenz comprising the steps of blending one or more diluents with efavirenz; granulation; drying the resulting granules and sizing; blending the granules with one or more disintegrants; lubricating the granules; and compressing the lubricated granules into tablets.
Suitably a process according to the present invention may include the step of coating the tablets. More particularly, the tablets may be coated according to any method known to a person skilled in the art that would not interfere with tablet release properties, or other physical and chemical characteristics of the invention. The coated tablets suitably contain the therapeutic agents employed in the present invention substantially evenly dispersed through the tablet core.
The present invention further provides pharmaceutical combinations, formulations and kits substantially as hereinbefore described according to the present invention for use in therapy, particularly in the treatment and / or prophylaxis of viral infections, in particular retroviral infections, and especially HIV infection, including for example infections with HIV mutants bearing resistance to nucleoside inhibitors and nonnucleoside inhibitors. Furthermore, the pharmaceutical combinations, formulations and kits substantially as hereinbefore described according to the present invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), AIDSrelated neurological conditions such as AIDS dementia complex, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
According to another aspect, the present invention provides a method for the treatment or prevention of viral infections, in particular retroviral infections, and especially the symptoms or effects of HIV infection, in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a pharmaceutical combination, formulation or kit substantially as hereinbefore described according to the present invention. It will be appreciated that the therapeutic agents of a pharmaceutical combination, formulation or kit according to the present invention may be administered simultaneously or separately or sequentially. If there is separate or sequential administration, the delay in administering the second (if appropriate) and / or third therapeutic agent should not be such as to lose the benefit of a synergistic therapeutic effect of the pharmaceutical combination of the therapeutic agents as achieved according to the present invention.
It will also be understood that lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, whether presented simultaneously or sequentially or separately, may be administered individually or in multiples or in any pharmaceutical combination thereof. Substantially as hereinbefore described larnivudine and zidovudine and are preferably administered simultaneously in a single pharmaceutical formulation, with efavirenz preferably being administered separately or sequentially in a separate pharmaceutical formulation.
It will be appreciated, therefore, that in certain embodiments of the present invention, therefore, the therapeutic agents of a pharmaceutical combination or formulation according to the present invention are administered simultaneously, for example as a single combined formulation. Alternatively, the therapeutic agents of a pharmaceutical combination, formulation or kit according to the present invention are administered separately or sequentially.
The present invention also provides the use of lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, in the manufacture of a medicament for administration of lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, simultaneously, separately or sequentially for the treatment and / or prophylaxis of viral infections, in particular retroviral infections, and especially HIV infections, and associated clinical conditions substantially as hereinbefore described.
The amount of a pharmaceutical combination, formulation or kit comprising lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, required to be effective as for example an anti-HIV agent will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the route of administration and nature of the formulation employed, the animal's body weight, age and general condition and the nature and severity of the disease to be treated. Suitable dosage regimens are substantially as hereinbefore described.
The therapeutic agents of a pharmaceutical combination, formulation or kit of the present invention may be obtained in a conventional manner and for example synthesis thereof is known in the art substantially as hereinbefore described.
Furthermore, the therapeutic agents of a pharmaceutical combination, formulation or kit of the present invention are also commercially available again substantially as hereinbefore described.
The present invention will now be further illustrated by the following Examples, which are intended for illustration only and are not intended to limit the scope of the invention in any way.
Examples
The following general process techniques were employed in manufacturing tablets I and II in the following Examples.
Tablet I
A process of manufacturing tablet I included the steps of blending a diluent or diluents with lamivodine and zidovudine; granulation thereof with a suitable binder or water; drying the resulting granules and sizing; blending the granules with a disintegrant; lubricating the granules; and compressing the lubricated granules into
tablets.
The method may include the step of suitably coating tablets I.
Tablet II
A process of manufacturing tablet II included the steps of blending a diluent or diluents with efavirenz; granulation thereof with a suitable binder or water; drying the resulting granules and sizing; blending the granules with a disintegrant; lubricating the granules; and compressing the lubricated granules into tablets.
Example 1
Pharmaceutical formulation according to the present invention for a pharmaceutical kit containing lamivudine, zidovudine and efavirenz.
Tablet I:
Ingredient ma/tablet
Lamivudine 300.0 Zidovudine 600.0 Microcrystalline cellulose 120.0 Sodium starch glycollate 6.0 Magnesium stearate 7.0 Talc 7.0 Color 0.5
Tablet II:
Efavirenz600.0 Lactose42.5 Microcrystalline cellulose116.0 Starch35.0 Sodium starch glycollate25.0 Magnesium stearate6.5 Film coat: Hydroxypropyl methyl cellulose10.0 Polyethylene glycol 60002.4 Solventq.s.
Tablet I and tablet II form a pharmaceutical kit for use in therapy according to the present invention substantially as herein described.
Example 2
Pharmaceutical formulation according to the present invention for a pharmaceutical kit containing lamivudine, zidovudine and efavirenz.
Tablet I:
Ingredient mg/tablet
Larnivodine 300.0 Zidovudine 600.0 Microcrystalline cellulose 75.0 Starch 26.0 Sodium starch glycollate 20.0 Magnesium stearate 6.0 Talc 6.0 Color 1.0
Tablet II:
Efavirenz 600.0 Lactose 55.0 Microcrystalline cellulose 115.5 Starch 45.0 Starch (as paste) 40.0 Sodium starch glycollate 25.0 Magnesium stearate 6.5 Film coat: Hydroxypropyl methyl cellulose 10.0 Polyethylene glycol 6000 2.4 Solvent q.s.
Tablet I and tablet II form a pharmaceutical kit for use in therapy according to the present invention substantially as herein described.
Example 3
Pharmaceutical formulation according to the present invention for a pharmaceutical kit containing lamivodine, zidovudine and efavirenz.
Tablet I:
Ingredient mg/tablet
Lamivudine 300.0 Zidovudine 600.0 Microcrystalline cellulose 75.0 Starch 1 6.0 L-HPC 10.0 Sodium starch glycollate 20.0 Magnesium stearate 6.0 Talc 6.0 Color 1.0
Tablet II:
Efavirenz 600.0 Lactose 42.5 Microcrystalline cellulose 116.0 Starch (as paste) 35.0 Sodium starch glycollate 25.0 Magnesium stearate 6.5 Film coat: Hydroxypropyl methyl cellulose 10.0 Polyethylene glycol 6000 2.4 Solvent q.s.
Tablet I and tablet II form a pharmaceutical kit for use in therapy according to the present invention substantially as herein described.
Example 4
Pharmaceutical formulation according to the present invention for a pharmaceutical kit containing lamivudine, zidovudine and efavirenz.
Tablet I:
Ingredient mg/tablet
Lamivudine 300.0 Zidovudine600.0 Microcrystalline cellulose75.0 PVPK-3020. 0 Sodium starch glycollate20.0 Magnesium stearate6.0 Talc6.0 Color1.0 Film coat: Hydroxypropyl methylcellulose 10.0 Polyethylene glycol 6000 2. 4 Titanium Dioxide 2.0 Solvent q.s.
Tablet II:
Efavirenz600.0 Lactose55.0 Microcrystalline cellulose115.5 Starch45.0 Starch (as paste)40.0 Sodium starch glycollate25.0 Magnesium stearate6.5 Film coat: Hydroxypropyl methyl cellulose 10.0 Polyethylene glycol 6000 2. 4 Solvent q.s.
Tablet I and tablet II form a pharmaceutical kit for use in therapy according to the present invention substantially as herein described.
Claims (42)
1. A pharmaceutical combination comprising lamivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharrnaccutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; for simultaneous, separate or sequential use in the treatment or prevention of viral infections in an infected animal.
2. A pharmaceutical combination according to claim 1, for the treatment or prevention of retroviral infections in an infected animal.
3. A pharmaceutical combination according to claim 2, for the treatment or prevention of the symptoms or effects of HIV infection and associated clinical conditions in an infected animal.
4. A pharmaceutical combination according to any of claims 1 to 3, wherein larnivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; are administered simultaneously as a single combined formulation.
5. A pharmaceutical combination according to any of claims 1 to 3, wherein larnivodine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; are administered separately or sequentially.
6. A pharmaceutical combination according to any of claims 1 to 5, which comprises a weight ratio of efavirenz, or a pharmaceutically acceptable derivative thereof, to lamivudine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 2 to about 1:4, and a weight ratio of efavirenz, or a pharmaceutically acceptable derivative thereof, to zidovudine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 1 to about 1:4.
7. A pharmaceutical combination according to any of claims 1 to 6, which comprises lamivudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 100-300 mg per unit dosage form.
8. A pharmaceutical combination according to claim 7, which comprises lamivudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 300 mg per unit dosage form.
9. A pharmaceutical combination according to any of claims 1 to 8, which comprises zidovudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 300-600 mg per unit dosage form.
10. A pharmaceutical combination according to claim 9, which comprises zidovudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 600 mg per unit dosage form.
11. A pharmaceutical combination according to any of claims 1 to 10, which comprises efavirenz, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 600 mg per unit dosage form.
12. A pharmaceutical formulation which comprises a pharmaceutical combination according to any of claims 1 to 11, together with one or more pharmaceutically acceptable carriers or excipients therefor and optionally other therapeutic agents.
13. A pharmaceutical formulation according to claim 12, which is a tablet.
14. One or more tablet formulations where the tablet or tablets comprises either independently, or in any pharmaceutical combination, lamivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; together with one or more pharmaceutically acceptable carriers or excipients.
15. A pharmaceutical kit comprising (i) a first pharmaceutical formulation comprising lamivudine, or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers or excipients; (ii) a second pharmaceutical formulation comprising zidovudine, or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (iii) a third pharmaceutical formulation comprising efavirenz, or a pharmaceutically acceptable 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 an infected animal.
16. A pharmaceutical kit comprising (i) a first pharmaceutical formulation comprising lamivudine and zidovudine, or pharmaceutically acceptable derivatives of any thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (ii) a second pharmaceutical formulation comprising efavirenz, or a pharmaceutically acceptable 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 an infected animal.
17. A pharmaceutical kit according to claim 15 or 16, wherein the pharmaceutical formulations of the kits are in tablet form.
18. A pharmaceutical kit comprising (i) a first tablet comprising lamivudine and zidovudine, or pharmaceutically acceptable derivatives of any thereof, together with one or more pharmaceutically acceptable carriers or excipients; and (ii) a second tablet comprising efavirenz, or a pharmaceutically acceptable 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 an infected animal.
19. A pharmaceutical kit according to any of claims 15 to 18, which comprises a weight ratio of efavirenz, or a pharmaceutically acceptable derivative thereof, to lamiwdine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 2 to about 1:4, and a weight ratio of efavirenz, or a pharmaceutically acceptable derivative thereof, to zidovudine, or a pharmaceutically acceptable derivative thereof, ranging from about 1: 1 to about 1:4.
20. A pharmaceutical kit according to any of claims 15 to 19, which comprises lamivudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 100-300 mg per unit dosage form.
21. A pharmaceutical kit according to claim 20, which comprises lamivudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 300 mg per unit dosage form.
22. A pharmaceutical kit according to any of claims 15 to 21, which comprises zidovudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 300-600 mg per unit dosage form.
23. A pharmaceutical kit according to claim 22, which comprises zidovudine, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 600 mg per unit dosage form.
24. A pharmaceutical kit according to any of claims 15 to 23, which comprises efavirenz, or a pharmaceutically acceptable derivative thereof, in a dosage range of about 600 mg per unit dosage form.
25. A pharmaceutical kit according to any of claims 15 to 24, for use in the treatment or prevention of retroviral infections in an infected animal.
26. A pharmaceutical kit according to claim 25, for use in the treatment or prevention of the symptoms or effects of HIV infection and associated clinical conditions in an infected animal.
27. A pharmaceutical formulation according to claim 13 or 14, or a pharmaceutical kit according to claim 17 or 18, wherein the tablet or tablets further comprise an effective amount of one or more diluents selected from the group consisting of microcrystalline cellulose, lactose, starch and dicalcium phosphate, present in an amount of about 5 % to 35 % of the tablet or tablets.
28. A pharmaceutical formulation according to claim 13 or 14, or a pharmaceutical kit according to claim 17 or 18, wherein the tablet or tablets further comprise an effective amount of one or more lubricants selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate and magnesium oxide present in an amount of about 0.5% to 1.0% of the tablet or tablets.
29. A process of preparing a pharmaceutical formulation according to any of claims 12 to 14, 27 or 28, or as present in a pharmaceutical kit according to any of claims 15 to 28, which process comprises bringing into association (i) lamivudine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; with (ii) one or more pharmaceutically acceptable carriers or excipients therefor and optionally other therapeutic agents.
30. A process according to claim 29, as dependent on claim 18, which comprises (i) preparing a first tablet containing lamivudine and zidovudine comprising the steps of blending one or more diluents with lamivudine and zidovudine; granulation; drying the resulting granules and sizing; blending the granules with one or more disintegrants; lubricating the granules; and compressing the lubricated granules into tablets; and (ii) preparing a second tablet containing efavirenz comprising the steps of blending one or more diluents with efavirenz; granulation; drying the resulting granules and sizing; blending the granules with one or more disintegrants; lubricating the granules; and compressing the lubricated granules into tablets.
31. A process according to claim 30, which further comprises the step of coating
the tablets.
32. A pharmaceutical combination according to any of claims 1 to 11; a pharmaceutical formulation according to any of claims 12 to 14, 27 or 28; or a pharmaceutical kit according to any of claims 15 to 28; for use in the treatment and / or prophylaxis of viral infections in an infected animal.
33. A pharmaceutical combination, a pharmaceutical formulation or a pharmaceutical kit according to claims 32, for use in the treatment or prevention of retroviral infections in an infected animal.
34. A pharmaceutical combination, a pharmaceutical formulation or a pharmaceutical kit according to claims 33, for use in the treatment or prevention of the symptoms or effects of HIV infection and associated clinical conditions in an infected animal.
35. A method for the treatment or prevention of viral infections in an infected animal, which comprises treating said animal with a therapeutically effective amount of a pharmaceutical combination according to any of claims 1 to 11; a pharmaceutical formulation according to any of claims 12 to 14, 27 or 28; or a pharmaceutical kit according to any of claims 15 to 28.
36. A method according to claim 35, for the treatment or prevention of retroviral infections in an infected animal.
37. A method according to claim 36, for the treatment or prevention of the symptoms or effects of HIV infection and associated clinical conditions in an infected animal.
38. A method according to any of claims 35 to 37, wherein lamivadine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; are administered simultaneously as a single combined formulation.
39. A method according to any of claims 35 to 37, wherein lamivodine, or a pharmaceutically acceptable derivative thereof; zidovudine, or a pharmaceutically acceptable derivative thereof; and efavirenz, or a pharmaceutically acceptable derivative thereof; are administered separately or sequentially.
40. Use of lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, in the manufacture of a medicament, for administration of lamivudine, zidovudine and efavirenz, or pharmaceutically acceptable derivatives of any thereof, simultaneously, separately or sequentially for the treatment and / or prophylaxis of viral infections
41. Use according to claim 40, for the treatment or prevention of retroviral infections in an infected animal.
42. Use according to claim 41, for the treatment or prevention of the symptoms or effects of HIV infection and associated clinical conditions in an infected animal.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0308603A GB2400552A (en) | 2003-04-14 | 2003-04-14 | Pharmaceutical combinations for treating viral infections |
| PCT/GB2004/001612 WO2004089382A1 (en) | 2003-04-14 | 2004-04-14 | Pharmaceutical combinations comprising lamivudine, zidovudine and efavirenz for treating viral infections |
| CL200401262A CL2004001262A1 (en) | 2003-04-14 | 2004-05-25 | PHARMACEUTICAL COMPOSITION THAT INCLUDES LAMIVUDINE, ZIDOVUDINA AND EFAVIRENZ, OR DERIVATIVES OF THEM; PHARMACEUTICAL KIT; PROCEDURE FOR PREPARATION; AND USE IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OR PREVENTION OF VIRAL INFECTIONS, AND |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0308603A GB2400552A (en) | 2003-04-14 | 2003-04-14 | Pharmaceutical combinations for treating viral infections |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB0308603D0 GB0308603D0 (en) | 2003-05-21 |
| GB2400552A true GB2400552A (en) | 2004-10-20 |
Family
ID=9956763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0308603A Withdrawn GB2400552A (en) | 2003-04-14 | 2003-04-14 | Pharmaceutical combinations for treating viral infections |
Country Status (3)
| Country | Link |
|---|---|
| CL (1) | CL2004001262A1 (en) |
| GB (1) | GB2400552A (en) |
| WO (1) | WO2004089382A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006114709A1 (en) * | 2005-04-25 | 2006-11-02 | Aurobindo Pharma Limited | Pharmaceutical compositions of antiretrovirals |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200171039A1 (en) * | 2017-08-09 | 2020-06-04 | Viiv Healthcare Company | Combinations and uses and treatments |
| WO2019030625A1 (en) * | 2017-08-09 | 2019-02-14 | Viiv Healthcare Company | Combinations and uses and treatments thereof |
| CN114392239B (en) * | 2022-01-10 | 2023-06-27 | 安徽贝克生物制药有限公司 | Compound tablet of lamivudine, zidovudine and efavirenz and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051301A2 (en) * | 2001-12-14 | 2003-06-26 | Hemispherx Biopharma | USE OF dsRNAs IN STRATEGIC THERAPEUTIC INTERVENTION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY |
-
2003
- 2003-04-14 GB GB0308603A patent/GB2400552A/en not_active Withdrawn
-
2004
- 2004-04-14 WO PCT/GB2004/001612 patent/WO2004089382A1/en active Application Filing
- 2004-05-25 CL CL200401262A patent/CL2004001262A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051301A2 (en) * | 2001-12-14 | 2003-06-26 | Hemispherx Biopharma | USE OF dsRNAs IN STRATEGIC THERAPEUTIC INTERVENTION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY |
Non-Patent Citations (4)
| Title |
|---|
| BIOSIS abstract no.PREV199900120286 of AIDS, 1998, vol.12, Ruiz et al., pp.S35. * |
| BIOSIS abstract no.PREV200000068726 of New England Journal of Medicine, 1999, vol.341, Staszewski et al., pp.1865-1873. * |
| BIOSIS abstract no.PREV200000484835 of Antimicrobial Agents and Chemotherapy, 2000, vol.44, Bacheler et al., pp.2475-2484 * |
| BIOSIS abstract no.PREV200100559895 of Obstetrics & Gynecology, 2001, vol.98, Hill et al., pp.909-911. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006114709A1 (en) * | 2005-04-25 | 2006-11-02 | Aurobindo Pharma Limited | Pharmaceutical compositions of antiretrovirals |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004089382A1 (en) | 2004-10-21 |
| GB0308603D0 (en) | 2003-05-21 |
| CL2004001262A1 (en) | 2005-05-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2006325404B2 (en) | Pharmaceutical combination comprising nucleotide and nucleoside reverse transcriptase inhibitors (such as tenofovir and lamivudine) in different parts of the dosage unit | |
| US7635690B2 (en) | HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine | |
| JP2818299B2 (en) | Use of dideoxynucleoside analogs in the treatment of viral infections | |
| JP2012051915A (en) | Combination of pyrimidine-containing nnrti with rt inhibitor | |
| WO1997006804A1 (en) | 1,3-oxathiolane nucleoside analogues in the treatment of hepatitis c | |
| WO2015022351A1 (en) | Medicament comprising a pharmaceutical combination of dolutegravir, emtricitabine and tenofovir | |
| CA2793749C (en) | Novel schedules for administering combination therapies useful for treating persons afflicted with the human immunodeficiency virus (hiv) | |
| CA2793751A1 (en) | Quadruple therapy useful for treating persons afflicted with the human immunodeficiency virus (hiv) | |
| GB2400552A (en) | Pharmaceutical combinations for treating viral infections | |
| GB2400553A (en) | Antiviral pharmaceutical combination of lamivudine, stavudine and efavirenz, or derivatives thereof | |
| US7115584B2 (en) | HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine | |
| US6177435B1 (en) | Therapeutic combinations | |
| EP1931358B1 (en) | Pharmaceutical combinations containing lamivudine, stavudine and nevirapine | |
| EP1143976B9 (en) | Beta-d-2', 3' -didehydro-2', 3' -dideoxy-5-fluorocytidine for use in the treatment of hiv infections | |
| WO2000051615A1 (en) | Synergistic combinations of guanosine analog reverse transcriptase inhibitors and inosine monophosphate dehydrogenese inhibitors and uses therefor | |
| CA2502625A1 (en) | Dioxolane thymine and combinations for use against resistant strains of hiv | |
| ES2349479T3 (en) | PHARMACEUTICAL COMBINATION THAT INCLUDES NUCLEOTID AND NUCLEOSIDIC INHIBITORS OF THE REVERSE TRANSCRIPT (SUCH AS TENOFOVIR AND LAMIVUDINE) IN DIFFERENT PARTS OF THE DOSAGE UNIT. | |
| WO2004002498A1 (en) | Antiviral regimens | |
| EP1731155A2 (en) | Beta-D-2', 3' -Didehydro-2',3' -Dideoxy-5-Fluorocydine for use in the treatment of HIV infections | |
| EA014840B1 (en) | Combinations of a pyrimidine containing nnrti with rt inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1070813 Country of ref document: HK |
|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1070813 Country of ref document: HK |