CN111759850A - Pharmaceutical composition of tenofovir oxalate - Google Patents
Pharmaceutical composition of tenofovir oxalate Download PDFInfo
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- CN111759850A CN111759850A CN202010826083.5A CN202010826083A CN111759850A CN 111759850 A CN111759850 A CN 111759850A CN 202010826083 A CN202010826083 A CN 202010826083A CN 111759850 A CN111759850 A CN 111759850A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- 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
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- 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
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and relates to a pharmaceutical composition which comprises an active agent containing tenofovir oxalate with effective dose and other optional anti-HIV drugs. The present invention also relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, wherein the active agent is present in an amount of more than 35% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition comprising an effective amount of tenofovir oxalate of the present invention has a bioavailability comparable to that of a commercial form of tenofovir oxalate or a pharmaceutically acceptable salt thereof.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and relates to a pharmaceutical composition which comprises an active agent containing tenofovir disoproxil oxalate with effective dose and a preparation method thereof. The composition may further comprise other additives used in the preparation of the composition.
Background
Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors, which block reverse transcriptase, an enzyme essential for the production of the virus in HIV infected patients. Tenofovir inhibits HIV reverse transcriptase activity by competing with the natural substrate deoxyadenosine 5' -triphosphate and incorporating into DNA via DNA chain termination. In particular, these drugs are analogs of the natural deoxynucleotides required for synthesis of viral DNA, and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA strand. However, unlike natural deoxynucleotide substrates, NRTI and NtRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) lack a 3' -hydroxyl group population on the deoxyribose moiety. As a result, after incorporation of an NRTI or NtRTI, the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond required to extend the DNA strand. Thus, when NRTI or NtRTI is incorporated, viral DNA synthesis is stopped, a process known as chain termination. All NRTIs and ntrtis are classified as competitive substrate inhibitors.
Tenofovir, sold under the trade name Gilidd Sciences
Tenofovir disoproxil fumarate (also known as tenofovir DF, tenofovir disoproxil TDF, Bis-POC-PMPA, 9- [ (R) -2- [ [ Bis [ [ (isopropoxycarbonyl) oxy ] oxy]Methoxy radical]Phosphinyl radical]Methoxy radical]-propyl radical]Adenine fumarate (1: 1), is also sold in combination with other antiretroviral drugs.
U.S. patent nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249 relate to tenofovir, tenofovir disoproxil and tenofovir disoproxil fumarate.
In addition, U.S. patent No. 8409009 relates to tenofovir hemifumarate and a method for preparing the same.
U.S. patent application No. 2011/0009368 discloses various solid forms of tenofovir disoproxil.
It relates to a solid form of tenofovir disoproxil and an organic acid selected from succinic acid, tartaric acid, saccharin, citric acid, salicylic acid.
WO 2010/142761 discloses succinic acid esters of tenofovir disoproxil and various dosage forms containing succinic acid esters of tenofovir disoproxil.
The present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate. The composition may further comprise other additives used in the preparation of the composition.
Disclosure of Invention
One embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, wherein the active agent is present in an amount of greater than 35% based on the total weight of the pharmaceutical composition.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate wherein the weight of the active agent is greater than 50%.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate comprising microcrystalline cellulose as a pharmaceutically acceptable additive.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate comprising croscarmellose sodium as a pharmaceutically acceptable additive.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, wherein the composition is prepared by wet granulation.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, wherein the composition is prepared by dry granulation.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, wherein the composition is prepared by direct compression.
Another embodiment of the present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, which composition may comprise one or more anti-HIV drugs.
Another embodiment of the present invention is directed to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
The present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate and a process for the preparation thereof. The compositions of the present invention may be administered to a patient in need of a medicament for the treatment of HIV or AIDS.
The term "tenofovir oxalate" herein includes tenofovir oxalate in various forms, such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixtures and all other forms known in the art. Tenofovir oxalate may exist in different physical forms, for example in amorphous form, in one or more crystalline forms (e.g. anhydrous, solvated or hydrated forms), in a mixture of different crystalline forms (e.g. anhydrous, solvated or hydrated forms) or in amorphous mixtures and crystalline forms (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "tenofovir oxalate" as used in the present invention.
The term "pharmaceutically acceptable salt" refers to a salt that is acceptable to a patient, e.g., a mammal (e.g., a salt that is safe for the mammal at a certain dosage). Such salts may be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
The active ingredients, active agents and drugs herein may be used interchangeably.
As used herein, "%" refers to the weight percent of a material relative to the entire composition, unless otherwise specified.
The term "comprising" is synonymous herein with "including," comprising, "or" characterized by.. the term is defined as inclusive or open-ended, and does not exclude additional unrecited elements or method steps, unless the context clearly dictates otherwise.
The present invention relates to a pharmaceutical composition comprising an active agent comprising an effective amount of tenofovir oxalate. The composition may further comprise other additives used in the preparation of the composition.
In another embodiment, the pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate, wherein the active agent is present in an amount greater than 35% based on the total weight of the pharmaceutical composition. The active agent may preferably be present at greater than 40% by weight, most desirably greater than 45% by weight.
In another embodiment, the pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate, the active agent being present in an amount greater than 50%.
In another embodiment, the pharmaceutical composition comprises tenofovir oxalate and a disintegrant. The composition may further comprise a binder and a diluent. Disintegrants are a substance or mixture of substances added to a mixture of ingredients used to prepare a pharmaceutical composition that, when placed in water to form a drug, facilitate disintegration or disintegration of the composition after administration, or disintegration into primary particles (primary particles), a solution that is drinkable by the patient. The pharmaceutically active ingredient must be released from the composition matrix as efficiently as possible to allow dissolution. There are some disintegrants known as superdisintegrants which provide faster disintegration rates. "super disintegrant" is defined as a disintegrant such as corn starch used in small amounts compared to conventional disintegrants to achieve the same effect. Non-limiting examples of super disintegrants are crospovidone, modified starches, especially sodium starch glycolate and carboxymethylcellulose, especially croscarmellose sodium, carboxymethylcellulose calcium. The super-disintegrant can be used in both the wet and dry stages of the granulation process (intragranular and extragranular) and also in direct compression, thus making the best use of the wicking and swelling capabilities of the disintegrant.
The superdisintegrant is present in the composition in an amount of from about 1% to about 20%, desirably from about 1% to about 15%, and most desirably from about 1% to about 10%. It is advantageous to use the following quantitative super-disintegrant, where the weight ratio between tenofovir oxalate and super-disintegrant is 50:1 to 0.5:1, preferably about 20:1 to 0.5: 1. another aspect is 20:1 to 0.5:1, preferably about 10:1 to 0.5: 1.
suitable super-disintegrants for the compositions of the invention are calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), croscarmellose sodium, commercially available, for example with a molecular weight of 90000-
And
crosslinked polyvinylpyrrolidones (PVP) such as crosslinked retinones, e.g.
And Kollidon CL, in particular having a molecular weight of more than 1000000, more in particular a particle size distribution of less than 400 microns or less than 74 microns; modified starches, in particular sodium starch glycolate, e.g.
In particular, the molecular weight is 500000-11000000. The most desirable super disintegrant is croscarmellose sodium.
In another embodiment, the pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate comprising croscarmellose sodium as a pharmaceutically acceptable additive.
In another embodiment, a pharmaceutical composition comprising tenofovir oxalate as an active agent and a diluent, wherein the weight ratio of tenofovir oxalate to diluent is 5:1 to 0.1:1, for example 3:1 to 0.1:1,2:1 to 0.1:1,1:1 to 0.2: 1.
Diluents increase the volume of the solid pharmaceutical composition and may make a pharmaceutical dosage form comprising the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline celluloseFine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrin, dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, methacrylates (e.g., calcium phosphate, calcium sulfate, calcium phosphate, calcium sulfate
) Potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
In another embodiment, the pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate comprising microcrystalline cellulose as a pharmaceutically acceptable additive. Microcrystalline cellulose may possess one or more functions.
In another embodiment, the pharmaceutical composition comprises tenofovir oxalate and a binder, the composition according to the invention may comprise a binder, such as polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, cellulose and cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylhydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc., maltol, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatin, guar gum, starch, pregelatinized starch, partially hydrolyzed starch, alginate, xanthan gum or polymethylmethacrylate, or mixtures thereof. It is preferable to use a binder having good water solubility. In a preferred embodiment of the invention, the excipient comprises at least one binder selected from hydroxypropyl cellulose and povidone.
The binder is present in the composition in an amount of from about 1% to about 25%, preferably from about 1% to about 15%, and most desirably from about 1% to about 10%. The weight ratio of the tenofovir oxalate to the adhesive is 60: 1 to 1:1 (ideally 40: 1:1 to 1: 1), the weight ratio of super disintegrant to binder being 30:1 to 0.1:1 (desirably 5:1 to 0.5: 1).
In one embodiment, a pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate, wherein the active agent is present in an amount greater than 35%, the binder is present in an amount from about 1% to about 25%, and the amount of superdisintegrant is from about 0.01% to about 20% based on the total weight of the composition.
In another embodiment, a pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate, wherein the active agent comprises greater than 40% by total weight, a disintegrant in the range of 0.5-20%, tenofovir oxalate in the range of 1-20% or ideally 40%, a super disintegrant in the range of 1-15% and a binder in the range of 1-15%. Most preferably, tenofovir oxalate is more than 50%, super disintegrant is 1-10% and binder is 1-10%.
In another embodiment, the composition may further comprise 10 to 65% of a diluent, 0 to 10% of a lubricant and additives other than the above additives.
In another embodiment, a pharmaceutical composition comprising the above ingredients, wherein the weight ratio of tenofovir oxalate to super disintegrant is 50:1 to 0.5:1 (ideally 20:1 to 0.5: 1), the weight ratio of tenofovir oxalate to binder is 60: 1-1: 1 (ideally 40:1 to 1: 1), the weight ratio of super disintegrant to binder being 30: 1-0.1: 1 (preferably 5:1 to 0.5: 1).
In another embodiment, the weight ratio of the pharmaceutical composition, e.g. tenofovir oxalate in tablet form, and the super-disintegrant is: e.g., 50:1 to 0.5:1,40:1 to 0.5:1,30:1 to 0.5:1,20:1 to 0.5:1,15:1 to 0.5:1,10:1 to 0.5:1,8:1 to 0.5:1,7.5:1 to 0.5:1,5:1 to 0.5:1,3:1 to 0.5:1,2.5:1 to 0.5:1,2:1 to 0.5:1,1.5:1 to 0.5: 1.
In another embodiment, a pharmaceutical composition comprising tenofovir oxalate as an active agent and a diluent, wherein the weight ratio of tenofovir oxalate to diluent is 5:1 to 0.1:1, for example 3:1 to 0.1:1,2:1 to 0.1:1,1:1 to 0.2: 1.
A typical composition may comprise: contains over 35% tenofovir oxalate, one or more diluents selected from 1 to 20% pregelatinized starch, 1 to 20% lactose, 1 to 20% microcrystalline cellulose, 1 to 20% croscarmellose sodium, 1 to 10% magnesium stearate and 0 to 5% colloidal anhydrous silicon dioxide.
In another embodiment, the pharmaceutical composition comprises an active agent comprising an effective amount of tenofovir oxalate, optionally together with other excipients.
Adjuvants commonly used in Pharmaceutical compositions, such as diluents, lubricants and glidants, may be used, and a number of literature documents relating to suitable substances are cited herein [ see for details the "Handbook of Pharmaceutical Excipients" by Raymond C Rowe, Paul J Sheskey and mean C Owen (2006) ].
Other adjuvants may also be used to prepare the pharmaceutical composition, diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugars, fructose, dextran, other sugars such as mannitol, sorbitol, lactitol, sucrose or mixtures thereof, silicified microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. To reduce the adhesion of the tablets to the equipment of tabletting, we prefer to add silicon dioxide, preferably colloidal or fumed silicon dioxide. In addition, the adjuvant should include at least one diluent selected from the group consisting of microcrystalline cellulose and lactose monohydrate.
The composition according to the invention may also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oils, hydrogenated castor oil, sodium stearyl fumarate, polyethylene glycols or mixtures thereof. The adjuvants should include at least one lubricant selected from stearic acid, magnesium stearate, calcium stearate, and sodium lauryl sulfate, or more desirably from stearic acid, magnesium stearate, and calcium stearate. The composition may also contain a glidant, such as colloidal silicon dioxide (e.g., colloidal silicon dioxide)
) Magnesium trisilicate, powdered cellulose, starch, talc and tricalcium phosphate.
One skilled in the art can select and use one or more of these additives by routine experimentation, given the particular desired properties of the pharmaceutical composition, without any undue influence. The absolute amounts of each additive and the amounts relative to the other additives similarly depend on the desired properties of the pharmaceutical composition and may also be selected by the skilled person by routine experimentation without undue influence.
The core/tablet may be coated using conventional materials for film coating. As described in "drug Coating Technology" by Graham Cole (published 1995). Film coating formulations typically comprise the following ingredients: polymers, plasticizers, colorants/opacifiers, vehicles. In the film coating suspension, small amounts of flavors, surfactants and waxes may be used. Most polymers used for film coating are cellulose derivatives, such as cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol and waxy materials.
Typical cellulose ethers are hydroxyethyl cellulose, hydroxypropyl methylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with various functions. To ensure complete disintegration/dissolution of the overcoat, some of them may be further modified by incorporating materials such as water-soluble cellulose ethers and starches to enhance swelling and permeability.
Commonly used plasticizers can be divided into three categories: polyols (glycerol, propylene glycol and macrocarpol), organic esters (phthalate, dibutyl sebacate, citrate and triacetin) and oils/glycerides (castor oil, acetylated monoglycerides and fractionated coconut oil).
Color-assisting agents/opacifiers are divided into several categories: organic dyes and lakes thereof, inorganic pigments, natural pigments. Combinations of different materials from each group may be combined in defined proportions. The film coating suspension may be purchased as a ready-to-use formulation on the market.
Film coating dispersions can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.
The composition of the coating suspension (calculated as dry material) ideally comprises: 1-99% by weight of a polymer, 1-95% of a polymer; and 1-50% by weight of a plasticizer, desirably 1-40% plasticizer; 0.1-20% of a coloring/opacifying agent, 0.1-10% of a coloring/opacifying agent, all percentages being based on the total weight of the coating.
Tenofovir oxalate is water soluble and therefore the particle size of the API does not have any effect on the dissolution and bioavailability of the compositions of the present invention. Therefore, the average particle size of the drug contained in the pharmaceutical composition of the present invention is not particularly limited. But the use of drug particles having a uniform diameter is advantageous for handling and preparing the composition. In another aspect, the present invention relates to a pharmaceutical composition comprising tenofovir oxalate, characterized in that said tenofovir disoproxil or pharmaceutically acceptable salt thereof is D50It should be less than 1000 μm, preferably less than 200 μm, and more preferably 175 μm.
In one embodiment, the composition may be in the form of tablets, capsules, caplets, powders, pills, beads, microspheres, granules, pills, and the like. Preferred dosage forms are capsules and tablets. The dosage form is preferably suitable for oral administration. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of tenofovir oxalate calculated to produce the desired therapeutic effect, in association with the addition of a suitable pharmaceutical excipient. The pharmaceutical compositions of the present invention may be in the form of tablets, either coated or uncoated. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
The pharmaceutical compositions of the present invention may be in the form of dragees, in which case the compositions are provided with a coating, typically a sugar, shellac or other film coating as is conventional in the art. Note that many known coating methods are employed in the art. For example, by spraying the coating in a perforated pan in a fluidized bed (such as those available from or available from Aeromatic, Glatt Wurster or Huttlin) by the Accela Cota process, or by immersion coating. The sugars used above are among the usual additives and the preparation methods are well known in the art.
The dosage forms may be prepared by known techniques and using well-known and readily available excipients, such as direct compression, dry granulation or wet granulation. In the preparation of tenofovir oxalate compositions, the active ingredient is usually mixed with, diluted with or enclosed in an adjuvant or mixture of adjuvants, such as in the form of capsules, sachets, paper or other containers. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a carrier or vehicle for tenofovir oxalate.
The composition preparation of the present invention can be prepared by compressing a mixture of the drug of the present invention and an auxiliary. For example, a manufacturing method comprising mixing tenofovir oxalate with a manufacturing material by a suitable mixer and directly compressing the mixture into tablets. Other methods include a dry granulation step using a dry granulator or a roller compactor to produce granules for tablets, and a wet granulation step using water, ethanol and a solution containing a binder to prepare granules for tablets.
One of the ideal preparation methods is wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are mixed and then further mixed in the presence of a binding solvent or solution to agglomerate the powder. The granules are suitably sieved, dried, and then sieved and/or milled to the desired particle size by sieving or milling or both. The granules may then be tableted/tableted or other excipients, such as glidants and/or lubricants, may be added prior to tableting.
Likewise, the compositions of the present invention may also be prepared by dry granulation. Mixing the medicine and adjuvants, pressing into block or tablet, and pulverizing into compacted granule of appropriate size. The compacted granules may then be compressed into tablets. The compositions may also be prepared by direct compression, direct compression into compacted dosage forms.
The capsule filling of the present invention may comprise any of the mixtures and granulates described above in relation to tableting. However, they were not subjected to a final tableting step.
In another embodiment, when the dissolution is performed using a paddle apparatus according to ph.eur, at least 75% of the drug is dissolved from the pharmaceutical composition in phosphate buffer at pH 6.2 within 30 minutes. Or apparatus 2 according to USP at a temperature of the dissolution medium of 37. + -. 0.5 ℃ with a paddle rotation speed of 75rpm and a volume of dissolution medium of 900 ml. The drug release rate of the composition of the invention is greater than 70%, greater than 80%, such as 90% (over 30 minutes), and greater than 95% (over 45 minutes) within 15 minutes.
The tenofovir oxalate-containing composition is desirably administered once a day in an amount of 10 to 300 mg. The exact dosage of the active agent and the particular formulation to be administered will depend on a number of factors. Such as the condition being treated, the desired treatment time and the rate of release of the active agent. For example, the amount of active agent required and its release rate can be determined based on known in vitro or in vivo techniques, determining how long a particular active agent concentration in the plasma remains at a therapeutically acceptable level
In one embodiment, the pharmaceutical composition comprises about 10 to about 300mg tenofovir oxalate. In addition, the pharmaceutical composition comprises 40, 80, 120mg, 15mg, 200mg, 250mg or 300mg tenofovir oxalate.
The pharmaceutical compositions of the present invention may be used to incorporate specific active agents for the treatment of known indications, including the treatment of HIV, hepatitis or both. In one embodiment, the present invention relates to a method for treating HIV or hepatitis by administering to a patient in need thereof a pharmaceutical composition comprising tenofovir disoproxil or a pharmaceutically acceptable salt, and a method for preparing a therapeutic agent for treating HIV and hepatitis.
Pharmaceutical compositions comprising an active agent comprising an effective amount of a hot melt extruded tenofovir oxalate may optionally comprise one or more anti-HIV drugs. The additional active ingredient is preferably another anti-HIV agent, such as abacavir, zidovudine, lamivudine, efavirenz, etilatabine, ribavirin, costab, ezetivir and/or gemcitabine.
The pharmaceutical composition comprising an effective amount of tenofovir oxalate of the present invention has a bioavailability comparable to that of a commercial form of tenofovir oxalate or a pharmaceutically acceptable salt thereof. In a desirable embodiment, the pharmaceutical composition comprising tenofovir oxalate is bioequivalent to a commercial form of tenofovir oxalate.
Detailed Description
The following experimental details are set forth to aid in understanding the invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims that follow thereafter.
Example 1:
the preparation process comprises the following steps:
1. API, microcrystalline cellulose, fast flow lactose monohydrate, crospovidone xl10, HPC and Aerosil 200 were sieved using ASTM 40 sieve.
2. The ingredients of step 1 were charged into a Rapid Mixer Granulator (RMG) and mixed for 10 minutes with an impeller at 150rpm, then chopped.
3. The material of step 2 was granulated in a Rapid Mix Granulator (RMG) using water as the granulation liquid.
4. The wet material of step 3 was dried in a flash dryer at 55 c 5 c to reach the desired detection limit.
5. The dried granules were sieved under #20 ASTM.
6. The extragranular material, e.g., croscarmellose sodium, is weighed, microcrystalline cellulose pH101 is sieved using #40, and magnesium stearate is sieved using # 60.
7. The material of step 5 was added to the material of step 6 and mixed with stirring for 5 minutes.
8. The material of step 7 was compressed using a 16.80x 10.30m almond shaped punch.
9. Preparation of coating solution: 15g of Opadry blue (Opadry blue) was added to 85gm of purified water and stirring was continued for 45 minutes.
10. The material of step 9 was coated over the material of step 8 to add 2.5% cumulative weight.
Examples 2 to 4:
the preparation process comprises the following steps:
1. API, microcrystalline cellulose, fast flow lactose monohydrate, crospovidone xl10, HPC and Aerosil 200 were sieved using ASTM 40 sieve.
2. The ingredients of step 1 were charged to a blender and mixed for 10 minutes
3. Magnesium stearate was sieved using a # ASTM 60 screen.
4. Step 3 was added to step 2 and stirred in a blender for 5 minutes.
5. The lubricated mixture of step 4 was compressed using a 16.80X 10.30mm almond shaped punch.
Examples 5 to 10:
the preparation process comprises the following steps:
1. the desired APIS, lactose monohydrate, microcrystalline cellulose pH101, croscarmellose sodium and pregelatinized starch were weighed and sieved using #40 ASTM.
2. The ingredients of step 1 were charged into a Rapid Mixer Granulator (RMG) and mixed for 10 minutes with an impeller at 150rpm, then chopped.
3. The material of step 2 was granulated in a Rapid Mix Granulator (RMG) using water as the granulation liquid.
4. The wet material of step 3 was dried in a flash dryer at 55 c 5 c to reach the desired detection limit.
5. The dried granules were sieved under #20 ASTM.
6. The extragranular material, e.g., croscarmellose sodium, is weighed, microcrystalline cellulose pH101 is sieved using #40, and magnesium stearate is sieved using # 60.
7. Adding the material of step 5 to the material of step 6 and mixing with stirring for 5 minutes
8. The material of step 7 was compressed using a 16.80x 10.30m almond shaped punch.
9. Preparation of coating solution: 15g of Opadry blue (Opadry blue) was added to 85gm of purified water and stirring was continued for 45 minutes.
10. The material of step 9 was coated over the material of step 8 to add 2.5% cumulative weight.
Specific experimental effects
(1) Stability data of tenofovir oxalate tablets of example 1 under accelerated conditions
(2) Stability data of tenofovir oxalate tablets of example 1 under intermediate conditions
(3) Stability data of tenofovir oxalate tablets of example 1 under long term conditions
RRT is the relative retention time.
Those skilled in the art will readily recognize various modifications and changes that may be made without changing the scope of the present invention. Such modifications and variations are included in the scope of the present invention, and these examples in no way limit the scope of the present invention.
Claims (10)
1. A pharmaceutical composition of tenofovir oxalate characterised in that it comprises an active agent comprising an effective amount of tenofovir oxalate, wherein the active agent is present in an amount of more than 35%, preferably more than 40%, 45%, 50% based on the total weight of the pharmaceutical composition.
2. The tenofovir oxalate pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises more than one disintegrant selected from the group consisting of calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, or mixtures thereof, the disintegrant being present in the composition in an amount of from about 1% to about 20%.
3. The tenofovir oxalate pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises one or more diluents, the diluents comprising microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrin, dextrose, dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, methacrylate, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc, or mixtures thereof, the diluents being present in the composition in an amount of about 10-65%.
4. The tenofovir oxalate pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises one or more binding agents, the binding agents including polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, cellulose and cellulose derivatives, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and the like, maltol, sucrose solutions, dextrose solutions, acacia, tragacanth, locust bean gum, gelatin, guar gum, starch, pregelatinized starch, partially hydrolyzed starch, alginates, xanthan gum or polymethylmethacrylate, or mixtures thereof, the binding agents being present in the composition in an amount of about 1% to about 25%.
5. A pharmaceutical composition of tenofovir oxalate according to any of claims 1-4, characterized by containing 0-10% of lubricant and additives other than the above additives.
6. A pharmaceutical composition of tenofovir oxalate according to any of claims 1-4, characterized by containing more than one coating agent.
7. The tenofovir oxalate pharmaceutical composition according to any of claims 1-4, wherein the tenofovir oxalate is prepared by wet granulation, or dry granulation, or direct compression.
8. A pharmaceutical composition of tenofovir oxalate according to any of claims 1-4, characterized in that it contains more than 35% tenofovir oxalate, one or more diluents selected from 1 to 20% pregelatinized starch, 1 to 20% lactose, 1 to 20% microcrystalline cellulose, 1 to 20% croscarmellose sodium, 1 to 10% magnesium stearate and 0 to 5% colloidal anhydrous silicon dioxide.
9. Pharmaceutical composition comprising tenofovir oxalate according to any of claims 1-9, characterised in that it comprises one or more anti-HIV drugs.
10. The pharmaceutical composition according to claim 9, wherein the anti-HIV agent is selected from abacavir, zidovudine, lamivudine, efavirenz, etilatabine, ribivirine, costat, ezetivir and/or gemcitabine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918418A (en) * | 2007-12-12 | 2010-12-15 | 阿尔迪默菲克斯技术有限责任公司 | Solid forms of tenofovir disoproxil |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| WO2015186139A2 (en) * | 2014-06-02 | 2015-12-10 | Laurus Labs Private Limited | Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same |
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2020
- 2020-08-17 CN CN202010826083.5A patent/CN111759850A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918418A (en) * | 2007-12-12 | 2010-12-15 | 阿尔迪默菲克斯技术有限责任公司 | Solid forms of tenofovir disoproxil |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| WO2015186139A2 (en) * | 2014-06-02 | 2015-12-10 | Laurus Labs Private Limited | Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same |
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