US20040072894A1 - Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor - Google Patents

Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor Download PDF

Info

Publication number
US20040072894A1
US20040072894A1 US10655263 US65526303A US2004072894A1 US 20040072894 A1 US20040072894 A1 US 20040072894A1 US 10655263 US10655263 US 10655263 US 65526303 A US65526303 A US 65526303A US 2004072894 A1 US2004072894 A1 US 2004072894A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
pharmaceutical formulation
active substance
solid pharmaceutical
stable solid
ph
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.)
Abandoned
Application number
US10655263
Inventor
Janez Kerc
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LEK Pharmaceuticals dd
Original Assignee
LEK Pharmaceuticals dd
Priority date (The priority date 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 date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, and some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis.
The aforementioned active substances may be destabilised by the environmental factors, their degradation may also be accelerated by interactions with other pharmaceutical ingredients, such as fillers, binders, lubricants, glidants and disintegrating agents, therefore the pharmaceutical ingredients and the process for preparation of the pharmaceutical formulation should be meticulously chosen to avoid the aforementioned undesired interactions and reactions.
The present invention relates to a stable solid pharmaceutical formulation for the treatment of hypercholesterolemia and hyperlipidemia. More precisely, the present invention relates to the new stable solid pharmaceutical formulation containing as an active ingredient a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cerivastatin or pharmaceutically acceptable salts thereof.

Description

    FIELD OF THE INVENTION
  • The present invention relates to a new stable solid pharmaceutical formulation which is particularly suitable for the treatment of hypercholesterolemia and hyperlipidemia. More precisely, the present invention relates to the new stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, such as atorvastatin, pravastatin, fluvastatin and cerivastatin, or pharmaceutically active salts thereof. [0001]
  • BACKGROUND OF THE INVENTION
  • Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin and cerivastatin, derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some are obtained by treating the fermentation products using the methods of chemical synthesis like simvastatin or they are the products of total chemical synthesis like fluvastatin, atorvastatin and cerivastatin. [0002]
  • The purity of the active substance is an important factor for manufacturing a safe and effective pharmaceutical formulation. Maximum possible purity of the product is of particular importance if the pharmaceutical product must be taken on a longer term basis in the treatment or prevention of high cholesterol levels in blood. Accumulation of impurities from drugs of a lower level of purity may cause a variety of side effects during treatment. Besides impurities, that cannot be completely eliminated in the process of preparation of the active substance, degradation products occurring by subjecting the final pharmaceutical formulation to various environmental factors such as temperature, moisture, low pH and light, may also impose a problem. HMG-CoA reductase inhibitors occurring in the form of salts in the final pharmaceutical formulation, such as atorvastatin, pravastatin, fluvastatin and cerivastatin, are particularly sensitive to an acidic environment in which hydroxy acids are degraded into a lactone. [0003]
  • Apart from the fact that the aforementioned active substance may be destabilised by the environmental factors, their degradation may also be accelerated by interactions with other pharmaceutical ingredients, such as fillers, binders, lubricants, glidants and disintegrating agents. Therefore, the pharmaceutical ingredients and the process for preparation of the pharmaceutical formulation should be meticulously chosen to avoid the aforementioned undesired interactions and reactions. [0004]
  • The stability of the active substance in an acidic environment is one of the major problems in the case of statins in the form of salts. One of possible solutions of the aforementioned problem is described in EP 0 336 298, disclosing a stable pharmaceutical formulation for pravastatin. The essence of the formulation is to maintain an alkaline environment so that the aqueous dispersion of the pharmaceutical formulation reaches a pH above 9, preferably about 10. In addition to the active substance pravastatin, the composition of the invention includes a basifying agent, such as magnesium oxide which imparts a pH to an aqueous dispersion of the aforementioned formulation above 9. In view of the stability of the active substance such a formulation is effective. However, the local alkaline environment occurring at the site of dissolution of the pharmaceutical formulation may have a negative impact on the gastric mucosa with its normally acidic environment. This negative impact may be particularly evident for patients with a damaged gastric mucous membrane where the mucosa per se is not able to create a sufficient acidic environment inside the stomach for normal digestive functioning. It is particularly important in chronic therapies as in the case of prophylaxis or treatment with HMG-CoA reductase inhibitors. [0005]
  • SUMMARY OF THE INVENTION
  • It is an object of the present invention to provide a pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor which exerts an excellent stability while avoiding the afore mentioned disadvantages. It is a particular object to provide a stabilized active substance as such where the HMG-CoA reductase inhibitor is precautionary protected from being degraded. [0006]
  • It is a further object to provide a process for the preparation of a stable pharmaceutical formulation which exerts an excellent stability while avoiding the afore mentioned disadvantages. [0007]
  • These and further objects are accomplished by the present invention. [0008]
  • According to the present invention, there is provided a stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, wherein an active substance is contained which is capable of providing a pH in the range from 7 to 11. Within the meaning of the present invention, the term “active substance” denotes a HMG-CoA reductase inhibitor alone or a mixture thereof with a small amount of a buffering agent. Therefore, the present invention also makes available a stabilized pharmaceutically active substance as such, which active substance consists of a HMG-CoA reductase inhibitor and a low amount of a buffering agent. [0009]
  • According to the present invention, there is further provided a stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor, wherein the pharmaceutical formulation is capable of providing a pH below 9. [0010]
  • In addition, according to the present invention, there is provided suitable processes for the preparation of the above specified stable solid pharmaceutical formulation. [0011]
  • According to the present invention, there is further provided a method for the stabilization of a HMG-CoA reductase inhibitor as an active substance in a solid pharmaceutical formulation, wherein an HMG-CoA reductase inhibitor being capable of providing a pH in the range from 7 to 11 is incorporated into a pharmaceutical formulation which is capable of providing a pH below 9.[0012]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1[0013] a is a diagram which shows the growth of weight of a sample of pravastatin in crystal form and a sample of lyophilised pravastatin when exposed to air moisture. FIG. 1b shows the corresponding difference in the starting weight and the weight in time.
  • FIG. 2 is a diagram which shows the occurrence of pravastatin in lactone form when pravastatin was dissolved in different buffers with the pH in a range between 7 and 11 (F=phosphate, C=citrate, B=borate). [0014]
  • FIG. 3 is a diagram which shows the formation of different degradation products (impurities) when pravastatin was dissolved in different buffers with the pH in a range between 7 and 11 (F=phosphate, C=citrate, B=borate).[0015]
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • In the inventor's investigations, it was found that there are three major reasons for instability problems in case of a pharmaceutical formulation containing an active substance and in case of a bulk active substance. [0016]
  • First, the active substance as such is very hygroscopic and it is impossible to remove all water from it. This is illustrated by the following experiment: 111.07 mg of pravastatin in crystal form (prava izh) and 109.8 mg of lyophilized pravastatin (prava lio) were exposed to air moisture. Their weights were measured in different time intervals. The growth of weight of both samples and the difference in the starting weight and the weight in time are illustrated in FIGS. 1[0017] a and 1 b.
  • Another observation was that carbon dioxide from the air can irreversibly bind to the active substance and can cause a drop of pH. This is illustrated by the following experiment: 5 g of pravastatin sodium were dissolved in 30 ml of methanol, the pH was adjusted to 10 with 3% aqueous solution of NaOH. 400 ml of ethylacetate were added and the crystals of pravastatin sodium were formed. Crystals were filtered and dried and then put into three different atmospheres: normal air, nitrogen atmosphere and carbon dioxide atmosphere. In normal air and in the nitrogen atmosphere the pH remained the same during a period of 24 hours (normal air: 9.2, nitrogen: 9.5), but in the carbon dioxide atmosphere the pH dropped in the first two minutes from 9.2 to 6.9. After 12 minutes the pH was 6.6 and after 1 hour the pH was 6.5. After that, the pH remained constant. The third observation is that a sufficient stabilization of the active substance is already obtained at a pH of at least 7.0, but a beneficially high stability is effected at a pH of at least 8.0. We have noticed that at a pH below 8 the formation of lactone has occured and also the amount of other impurities has increased. The presence of humidity in the air and a carbon dioxide-rich atmosphere makes the negative effect of a low pH even stronger. This is illustrated by the following experiment: Pravastatin was dissolved in different buffers with the pH in a range between 7 and 11 (F=phosphate, C=citrate, B=borate). The occurrence of pravastatin in lactone form and the formation of different degradation products (impurities) was measured after 1, 5, 13 and 28 days. The results are shown in FIGS. 2 and 3. [0018]
  • In the present invention, we have surprisingly found that a sufficient stability of the active substance, which is a HMG-CoA reductase inhibitor preferably in the form of salt, can be also obtained by using a pharmaceutical formulation which does not create a marked alkaline environment in an aqueous dispersion. [0019]
  • Further, we have found that for the stability and digestibility of a pharmaceutical formulation both the pH generated by the formulation in an aqueous medium (usually being a dispersion) and the pH of the active substance (HMG-CoA reductase inhibitor) are of great importance. [0020]
  • Another surprising finding was that a sufficient stability of a HMG-CoA reductase inhibitor in the form of a salt in bulk can be obtained by the addition of small amounts of a buffering agent to the pure HMG-CoA reductase inhibitor in the form of salt. Such an addition of small amounts of buffering agents avoids the negative effect of water already present in the bulk substance and of moisture from the air, to avoid the negative effect of low pH caused by other ingredients which will be co-admixed to the pharmaceutical formulation, and to avoid the possible lowering of the pH caused by carbon dioxide. [0021]
  • The active substance and the pharmaceutical formulation according to the present invention were designed to avoid the negative effect of the water present in the bulk substance and in the pharmaceutical formulation, to avoid the negative effect of low pH which can be caused by other ingredients of the pharmaceutical formulation and to avoid possible lowering of the pH caused by carbon dioxide. [0022]
  • The most acceptable stability of the active substance in the formulations is obtained with an active substance which is capable of providing a pH in the range from 7 to 11. The pH value is the one which is obtained when the pH of an aqueous medium containing said active substance would be measured. In the stable pharmaceutical formulation according to the present invention, the basic pH of the active substance has a minimal influence on the pH of the formulation which is lower than 9. By creating locally an environment around the active substance which affords the best stability for the active substance, the potential of negative impact of other ingredients of the composition of the pharmaceutical formulation is reduced, and possible reactions among the active substance and the rest of the ingredients of the composition of the pharmaceutical formulation are also less favoured. Accordingly, the active substance is maintained in a stable form when an active substance which is capable of providing a pH in an aqueous medium in the range from 7 to 11 is added to the pharmaceutical formulation. [0023]
  • The active substance being added to the formulation of the present invention generally is a HMG-CoA reductase inhibitor in the form of a salt. The pH of the active substance may be adjusted within the above specified range in the course of preparing the salt of the HMG-CoA reductase inhibitor from the acid form and an alkaline substance. As an example, the preparation of pravastatin sodium from pravastatin acid and sodium hydroxide may be mentioned. For a preferred adjustment of the pH of the active substance to be incorporated into the formulation within the above specified range of 7 to 11, the active substance is further mixed with an appropriate buffering agent. Accordingly, the active substance may contain small amounts of a buffering agent, preferably less than 1%, more preferably 0.1 to 0.5%, most preferably approximately 0.3%, based on the weight of the active substance added to the formulation. A suitable buffering agent for this purpose is carbonate buffer or phosphate buffer, such as sodium carbonate of sodium phosphate. For example, an amount 0.3% of sodium carbonate in pravastatin results in a pH of pravastatin between 9 and 10. Thus, it is possible to mix pravastatin with other ingredients of the pharmaceutical formulation without fear that a degradation can be caused by the contact of pravastatin with acidic ingredients as a microenvironment of pravastatin is still basic due to the addition of small amounts of a buffering agent. This addition of small amounts of a buffering agent is also important for an easier handling of the pravastatin bulk without special requirements for a carbon dioxide free atmosphere. Preferably, the acidifying effect of carbon dioxide on the final formulation is neutralised by further addition of an appropriate buffering agent to adjust the pH of the formulation in the above specified range, preferably by addition of 20%, more preferably of 10% per weight based on the total weight of the tablet. Any buffering agent capable of adjusting the pH of the total formulation in the desired range is suitable, including sodium or potassium citrate, sodium phosphate, dibasic sodium phosphate, calcium carbonate, hydrogen phosphate, phosphate, sulphate, sodium or magnesium carbonate, sodium ascorbinate, benzoate, sodium or potassium hydrogen carbonate, lauryl sulphate, or mixtures of such buffering agents. Citrate buffer, carbonate buffer and phosphate or hydrogen phosphate buffer may be mentioned as specific examples. [0024]
  • Preferably, an active substance contained in the pharmaceutical formulation according to the present invention is capable of providing a pH in the range from 8 to 10. [0025]
  • Furthermore, the active substance may be selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof. Preferably, the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca). [0026]
  • As mentioned above, it is a further significant aspect of the present invention that the pharmaceutical formulation is capable of providing a pH below 9, preferably below 8.5. The lower limit of the pH generated by the pharmaceutical formulation suitably is 6, preferably 7. [0027]
  • By following the concepts of the present invention, the solid pharmaceutical formulation is stable such that the HMG-CoA reductase inhibitor as the active substance does not tend to be decomposed and essentially retains its activity. Thereby, it is ensured that the active substance in the pharmaceutical formulation according to the present invention shows a sufficient stability while, at the same time, avoiding the negative impact of a high local alkaline environment at the site of dissolution of the pharmaceutical formulation on the gastric mucosa which would occur if the pH of an aqueous dispersion of the pharmaceutical formulation is 9 or more and which results in anormal digestive functioning. [0028]
  • The pharmaceutical formulation of this invention may include, in addition to the HMG-CoA reductase inhibitor which is sensitive to a low pH environment, one or more fillers, such as microcrystalline cellulose, lactose, sugars, starches, modified starch, mannitol, sorbitol and other polyols, dextrin, dextran and maltodextrin, calcium carbonate, calcium phosphate and/or hydrogen phosphate, sulphate, one or more binders, such as lactose, starches, modified starch, dextrin, dextran and maltodextrin, microcrystalline cellulose, sugars, polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone, magnesium aluminium silicate, one or more disintegrating agents such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl starch, starches and microcrystalline cellulose, magnesium aluminium silicate, polyacrylin potassium, one or more different glidants such as magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax, silicon dioxide, one or more buffering agents such as sodium or potassium citrate, sodium phosphate, dibasic sodium phosphate, calcium carbonate, hydrogen phosphate, phosphate, sulphate, sodium or magnesium carbonate, sodium ascorbinate, benzoate, sodium or potassium hydrogen carbonate, lauryl sulphate, or mixtures of such buffering agents. [0029]
  • If required any, the formulation may also include surfactants and other conventional components for solid, pharmaceutical formulations such as colouring agents, lakes, aromas and adsorbents. As surfactants the following may be used: ionic surfactants, such as sodium lauryl sulphate or non-ionic surfactants such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids (such as Span®, manufactured by Atlas Chemie), esters of polyoxyethylenesorbitan and fatty acids (such as Tween®, manufactured by Atlas Chemie), polyoxyethylated hydrogenated castor oil (such as Cremophor®, manufactured by BASF), polyoxyethylene stearates (such as Brij®, manufactured by Atlas Chemie), dimethylpolysiloxane or any combination of the above mentioned surfactants. [0030]
  • If the solid pharmaceutical formulation is in the form of coated tablets, the coating may be prepared from at least one film-former such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, at least from one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others. [0031]
  • The solid pharmaceutical formulations according to the present invention may be prepared as described below: [0032]
  • The mixture of the active substance, filler, binder, buffering agent, disintegrating agent and if required a surfactant and other conventional ingredients for solid pharmaceutical formulations is homogenised employing suitable mixers. Glidants and/or lubricants are added and the mixture is re-homogenised. The resulting mixture is compressed into tablets or filled into capsules. If needed, tablets can be film-coated. [0033]
  • The mixture of the active substance, filler, binder, buffering agent, disintegrating agent and if required a surfactant and other conventional ingredients for solid pharmaceutical formulations is homogenised employing suitable mixers, granulated with a suitable solvent such as water, ethanol, methanol, isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate, isopropyl acetate, methyl acetate, dichloromethane and methanol, and mixtures of these solvents such as ethanol and acetone, methanol and acetone, dichloromethane and methanol, and the mixtures thereof. The resulting granulation is dried in suitable dryers such as standard plate dryers, fluid bed dryers, vacuum and microwave dryers. To the dried granulation, glidants and/or lubricants and if required other conventional ingredients for solid pharmaceutical formulations are added. The resulting mixture is rehomogenised and compressed into tablets or filled into capsules. Optionally, tablets are film-coated. [0034]
  • Moreover, according to the present invention the HMG-CoA reductase inhibitor as an active substance in a solid pharmaceutical formulation can be effectively stabilized by incorporating a HMG-CoA reductase inhibitor, which is capable of providing a pH in the range from 7 to 11, into a pharmaceutical formulation which is capable of providing a pH below 9. The pH generated by the pharmaceutical formulation may be adjusted by the incorporation of appropriate agents such as buffering agents and the like. [0035]
  • The present invention is illustrated but by no means limited by the following examples. [0036]
  • EXAMPLES Example 1
  • The pharmaceutical formulation with the active ingredient pravastatin sodium in the form of tablets was prepared as follows: the hereinunder listed ingredients were homogenised and the resulting mixture was then compressed into tablets each containing 5, 10, 20 or 40 mg of pravastatin sodium. [0037]
  • The pH of the aqueous dispersion of this formulation is 8.3. [0038]
    Ingredients % by weight
    Pravastatin sodium (pH 8.2) 5%
    Lactose 37.5%  
    Microcrystalline cellulose 38% 
    Sodium citrate 10% 
    Magnesium aluminium silicate 2%
    Polyacrylin potassium 3%
    Talc 3%
    Silicon dioxide 0.5%  
    Magnesium stearate 1%
  • Example 2
  • The pharmaceutical formulation with the active ingredient pravastatin sodium in the form of tablets was prepared as follows: the hereinunder listed ingredients were homogenised and the resulting mixture was then compressed into tablets each containing 5, 10, 20, 40 or 80 mg of pravastatin sodium. The pH of the aqueous dispersion of this formulation is 8.0. [0039]
    Ingredients % by weight
    Pravastatin sodium (pH 8.5) 10%
    Lactose 32%
    Microcrystalline cellulose 37%
    Sodium citrate 10%
    Croscarmellose sodium  2%
    Sodium lauryl sulphate 0.5% 
    Polyacrylin potassium  3%
    Talc  3%
    Silicon dioxide 0.5% 
    Calcium stearate  2%
  • Example 3
  • The pharmaceutical formulation with the active ingredient pravastatin sodium in the form of tablets was prepared as follows: the first six hereinunder listed ingredients were homogenised, granulated with water, dried, the remainder of the below listed ingredients were added and homogenised and the resulting mixture was then compressed into tablets each containing 5, 10, 20 or 40 mg of pravastatin sodium. [0040]
  • The pH of the aqueous dispersion of this formulation is 8.2. [0041]
    Ingredients % by weight
    Pravastatin sodium (pH 9)  5%
    Lactose 20%
    Microcrystalline cellulose 20%
    Hydroxypropyl cellulose 1.5% 
    Sodium citrate 10%
    Magnesium aluminium silicate  2%
    Polyacrylin potassium  3%
    Microcrystalline cellulose 35%
    Talc  3%
    Magnesium stearate 0.5% 
  • Example 4
  • The pharmaceutical formulation with the active ingredient pravastatin sodium in the form of tablets was prepared as follows (ingredients are listed in the following table): the mixture of the active substance, filler, buffering agent, disintegrant and surfactant is homogenised employing suitable mixers. Glidants and lubricants are added and the mixture is re-homogenised. The resulting mixture is compressed into tablets. The pH of the aqueous dispersion of this formulation is 8.5. [0042]
    Ingredient % by weight function
    pravastatin sodium* 8.3 active substance
    lactose 58.3 filler
    microcrystalline 14.4 filler
    cellulose
    Na2HPO4 10 buffering agent
    Na lauryl sulphate 0.4 absorption accelerator,
    surfactant
    cross-linked 4 disintegrant
    carboxymethylcellulose
    colloidal silicon 0.5 glidant
    dioxide
    talc 3 glidant, lubricant
    magnesium stearate 1 lubricant
  • Example 5
  • The pharmaceutical formulation with the active ingredient pravastatin sodium in the form of tablets was prepared as in Example 4. The resulting mixture is compressed into tablets. The pH of the aqueous dispersion of this formulation is 8.3. [0043]
    Ingredient % by weight function
    pravastatin sodium* 8.3 active substance
    lactose 58.3 filler
    microcrystalline 16.5 filler
    cellulose
    Na2HPO4 (dried) 7.9 buffering agent
    sodium lauryl sulphate 0.4 absorption accelerator,
    surfactant
    cross-linked 4 disintegrant
    carboxymethylcellulose
    colloidal silicon 0.5 glidant
    dioxide
    talc 3 glidant, lubricant
    magnesium stearate 1 lubricant
  • Example 6
  • The pharmaceutical formulation with the active ingredient atorvastatin calcium in the form of tablets was prepared as in Example 4. The resulting mixture is compressed into tablets. [0044]
    Ingredient weight (mg) function
    Atorvastatin calcium 20.0 active substance
    lactose 140.0 filler
    microcrystalline 34.8 filler
    cellulose
    Na2HPO4 (dried) 24.0 buffering agent
    Na lauryl sulphate 2.0 absorption accelerator,
    surfactant
    cross-linked 9.6 disintegrant
    carboxymethylcellulose
    colloidal silicon 1.2 glidant
    dioxide
    talc 7.2 glidant, lubricant
    magnesium stearate 1.2 lubricant
  • In case of higher or lower dosages of atorvastatin calcium (80, 40, 10 or 5 mg), proportional higher or smaller amounts of other ingredients are used, or proportional bigger or smaller tablets are prepared. [0045]
  • Tablets containing pravastatin or atorvastatin which were formed according to Examples 1 to 6 were subjected to stability studies and it was found that the tablets provide an excellent stability; essentially no degradation products of pravastatin or atorvastatin were observed. [0046]

Claims (38)

  1. 1. A stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor,
    characterized in that
    an active substance is contained which is capable of providing a pH in the range from 7 to 11.
  2. 2. A stable solid pharmaceutical formulation as defined in claim 1,
    characterized in that
    an active substance is contained which is capable of providing a pH in the range from 8 to 10.
  3. 3. A stable solid pharmaceutical formulation as defined in claim 1 or 2, wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt.
  4. 4. A stable solid pharmaceutical formulation as defined in any one of claims 1 to 3, wherein the active substance, which had been incorporated into the formulation, contained a buffering agent.
  5. 5. A stable solid pharmaceutical formulation as defined in claim 4, wherein the active substance, which had been incorporated into the formulation, contained the buffering agent in an amount of less than 1%.
  6. 6. A stable solid pharmaceutical formulation as defined in any one of claims 1 to 5, wherein the active substance is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.
  7. 7. A stable solid pharmaceutical formulation as defined in claim 6, wherein the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).
  8. 8. A stable solid pharmaceutical formulation as defined in claim 1, which further comprises at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent, a glidant, a buffering agent; optionally further comprising at least one constituent selected among colouring agents, lakes, aromas, adsorbents, film formers and plasticizers.
  9. 9. A stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor,
    characterized in that
    the pharmaceutical formulation is capable of providing a pH below 9.
  10. 10. A stable solid pharmaceutical formulation according to claim 9,
    characterized in that
    the pharmaceutical formulation is capable of providing a pH in the range from 6 to 9.
  11. 11. A stable solid pharmaceutical formulation according to claim 9,
    characterized in that
    the pharmaceutical formulation is capable of providing a pH in the range from 7 to 8.5.
  12. 12. A stable solid pharmaceutical formulation according to claim 9,
    characterized in that
    an active substance being capable of providing a pH in the range from 7 to 11 is incorporated into said solid pharmaceutical formulation.
  13. 13. A stable solid pharmaceutical formulation according to claim 9,
    characterized in that
    an active substance being capable of providing a pH in the range from 8 to 10 is incorporated into said solid pharmaceutical formulation.
  14. 14. A stable solid pharmaceutical formulation as defined in claim 12 or 13, wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt.
  15. 15. A stable solid pharmaceutical formulation according to any one of claims 12 to 14, wherein the incorporated active substance contains a buffering agent.
  16. 16. A stable solid pharmaceutical formulation according to claim 15, wherein the buffering agent is contained in an amount of less than 1%.
  17. 17. A stable solid pharmaceutical formulation according to claim 15, wherein additional amounts of a buffering agent are incorporated into said formulation.
  18. 18. A stable solid pharmaceutical formulation according to any one of claims 9 to 17, wherein the active substance is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.
  19. 19. A stable solid pharmaceutical formulation as defined in claim 18, wherein the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).
  20. 20. A stable solid pharmaceutical formulation as defined in claim 9, which further comprises at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent, a glidant, a buffering agent; optionally further comprising at least one constituent selected among colouring agents, lakes, aromas, adsorbents, film formers and plasticizers.
  21. 21. A process for the preparation of a stable solid pharmaceutical formulation according to any of the aforementioned claims, wherein the mixture of the active substance, filler, binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations are homogenised in suitable mixers, glidants and/or lubricants are added, the mixture is then re-homogenised and the resulting mixture is compressed into tablets or filled into capsules; optionally the tablets may be film-coated.
  22. 22. A process for the preparation of a stable solid pharmaceutical formulation according to any of the claims 1 to 20, wherein the mixture of the active substance, filler, binder, buffering agent, disintegrating agent and optionally surfactant and other commonly used ingredients for solid pharmaceutical formulations are homogenised in suitable mixers, granulated with a suitable solvent; the resulting granulation is dried in suitable dryers; to the dried granulations, glidants and/or lubricants are added and optionally other ingredients for solid pharmaceutical formulations and the resulting mixture is re-homogenised and compressed into tablets or filled into capsules; optionally the tablets may be film-coated.
  23. 23. A stabilized pharmaceutically active substance consisting only of a mixture of a HMG-CoA reductase inhibitor and a buffering agent.
  24. 24. A stabilized pharmaceutically active substance according to claim 23, wherein the buffering agent is present in the mixture in an amount of less than 1 wt.—% based on the total weight of the pharmaceutically active substance.
  25. 25. A stabilized pharmaceutically active substance according to claim 23 or 24, wherein the HMG-CoA reductase inhibitor is in the form of a salt.
  26. 26. A stabilized pharmaceutically active substance according to claim 23 or 24, wherein the buffering agent imparts a pH in the range from 7 to 11 to the pharmaceutically active substance.
  27. 27. A stabilized pharmaceutically active substance according to any one of claims 23 to 26, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.
  28. 28. A stabilized pharmaceutically active substance according to claim 27, wherein the HMG-CoA reductase inhibitor is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).
  29. 29. A method for the stabilization of a HMG-CoA reductase inhibitor as an active substance in a solid pharmaceutical formulation, wherein an active substance being capable of providing a pH in the range from 7 to 11 is incorporated into a pharmaceutical formulation which is capable of providing a pH below 9.
  30. 30. The method according to claim 29, wherein the pharmaceutical formulation is capable of providing a pH in the range from 6 to 9.
  31. 31. The method according to claim 29, wherein the pharmaceutical formulation is capable of providing a pH in the range from 7 to 8.5.
  32. 32. The method according to claim 29, wherein the active substance is a HMG-CoA reductase inhibitor in the form of a salt.
  33. 33. The method according to claim 29, wherein the incorporated active substance contains a buffering agent in order to provide a pH for said active substance in the range from 7 to 11.
  34. 34. The method according to claim 33, wherein the incorporated active substance contains less than 1% of a buffering agent.
  35. 35. The method according to claim 33 or 34, wherein additional amounts of a buffering agent are incorporated into the pharmaceutical formulation in order to provide a pH for said pharmaceutical formulation of below 9.
  36. 36. The method according to any one of claims 29 to 35, wherein the active substance is selected from the group consisting of pravastatin, atorvastatin, fluvastatin, cerivastatin and a pharmaceutically acceptable salt thereof.
  37. 37. The method according to claim 36, wherein the active substance is a sodium salt of pravastatin (pravastatin Na) or a calcium salt of atorvastatin (atorvastatin Ca).
  38. 38. The method according to claim 29, wherein said stable solid pharmaceutical formulation further comprises at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent, a glidant, a buffering agent; optionally further comprising at least one constituent selected among colouring agents, lakes, aromas, adsorbents, film formers and plasticizers.
US10655263 1998-12-16 2003-09-04 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor Abandoned US20040072894A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
SIP-9800309 1998-12-16
SI9800309A SI20109A (en) 1998-12-16 1998-12-16 Stable pharmaceutical formulation
US09600436 US6680341B1 (en) 1998-12-16 1999-10-29 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor
US10655263 US20040072894A1 (en) 1998-12-16 2003-09-04 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10655263 US20040072894A1 (en) 1998-12-16 2003-09-04 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor
US12172143 US20090264497A1 (en) 1998-12-16 2008-07-11 Stable pharmaceutical formulation comprising a hmg-coa reductase inhibitor

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB1999/001749 Division WO2000035425A1 (en) 1998-12-16 1999-10-29 STABLE PHARMACEUTICAL FORMULATION COMPRISING A HMG-CoA REDUCTASE INHIBITOR
US09600436 Division US6680341B1 (en) 1998-12-16 1999-10-29 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12172143 Continuation US20090264497A1 (en) 1998-12-16 2008-07-11 Stable pharmaceutical formulation comprising a hmg-coa reductase inhibitor

Publications (1)

Publication Number Publication Date
US20040072894A1 true true US20040072894A1 (en) 2004-04-15

Family

ID=20432372

Family Applications (3)

Application Number Title Priority Date Filing Date
US09600436 Expired - Fee Related US6680341B1 (en) 1998-12-16 1999-10-29 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor
US10655263 Abandoned US20040072894A1 (en) 1998-12-16 2003-09-04 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor
US12172143 Abandoned US20090264497A1 (en) 1998-12-16 2008-07-11 Stable pharmaceutical formulation comprising a hmg-coa reductase inhibitor

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09600436 Expired - Fee Related US6680341B1 (en) 1998-12-16 1999-10-29 Stable pharmaceutical formulation comprising a HMG-CoA reductase inhibitor

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12172143 Abandoned US20090264497A1 (en) 1998-12-16 2008-07-11 Stable pharmaceutical formulation comprising a hmg-coa reductase inhibitor

Country Status (9)

Country Link
US (3) US6680341B1 (en)
EP (2) EP1911445A3 (en)
JP (1) JP2002532409A (en)
CN (1) CN1198597C (en)
CA (1) CA2348988C (en)
DE (1) DE69937691T2 (en)
ES (1) ES2299265T3 (en)
RU (1) RU2227019C2 (en)
WO (1) WO2000035425A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060034815A1 (en) * 2004-08-06 2006-02-16 Hector Guzman Novel statin pharmaceutical compositions and related methods of treatment
WO2008035128A1 (en) * 2006-09-18 2008-03-27 Richter Gedeon Nyrt. Pharmaceutical compositions containing rosuvastatin calcium
WO2009000286A1 (en) * 2007-06-25 2008-12-31 Parmatheen S.A. Improved pharmaceutical formulation containing an hmg-coa reductase inhibitor and method for the preparation thereof
US20090042979A1 (en) * 2004-08-06 2009-02-12 Transform Pharmaceuticals Inc. Novel Statin Pharmaceutical Compositions and Related Methods of Treatment
US20090149533A1 (en) * 2004-08-06 2009-06-11 Transform Pharmaceuticals, Inc. Novel fenofibrate formulations and related methods of treatment
USRE44578E1 (en) 2000-04-10 2013-11-05 Teva Pharmaceutical Industries, Ltd. Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin
US9399064B2 (en) 2011-04-12 2016-07-26 Sawai Pharmaceutical Co., Ltd. Pitavastatin-containing preparation and method for producing same

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060141036A1 (en) * 1997-12-12 2006-06-29 Andrx Labs Llc HMG-CoA reductase inhibitor extended release formulation
GB0001621D0 (en) 2000-01-26 2000-03-15 Astrazeneca Ab Pharmaceutical compositions
EP1296672B2 (en) 2000-06-09 2018-10-24 LEK Pharmaceuticals d.d. Stable pharmaceutical product and formulation
US6806290B2 (en) 2000-06-09 2004-10-19 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
US20050215636A1 (en) * 2000-10-05 2005-09-29 Vilmos Keri Pravastatin sodium substantially free of pravastatin lactone and EPI-pravastatin, and compositions containing same
GB0111077D0 (en) * 2001-05-04 2001-06-27 Biochemie Gmbh Organic compounds
US7229644B2 (en) * 2002-05-23 2007-06-12 Cephalon, Inc. Pharmaceutical formulations of modafinil
CA2449998A1 (en) * 2001-06-21 2003-01-03 Andrx Pharmaceuticals, Inc. Stable controlled release pharmaceutical compositions containing pravastatin
JP2003055217A (en) * 2001-08-10 2003-02-26 Taiyo Yakuhin Kogyo Kk Pharmaceutical composition
EP1905431A1 (en) * 2002-01-11 2008-04-02 Circ Pharma Research and Development Limited Pravastatin pharmaceutical formulations and methods of their use
CA2473106A1 (en) 2002-01-11 2003-07-17 Athpharma Limited Pravastatin pharmaceutical formulations and methods of their use
CA2385529A1 (en) * 2002-05-21 2003-11-21 Bernard Charles Sherman Stable dosage forms comprising atorvastatin calcium
WO2004021973A3 (en) * 2002-09-03 2004-05-21 Biovail Lab Inc Pravastatin pharmaceutical formulations and methods of their use
US20050271717A1 (en) * 2003-06-12 2005-12-08 Alfred Berchielli Pharmaceutical compositions of atorvastatin
US8163797B2 (en) * 2003-12-31 2012-04-24 Actavis Elizabeth Llc Method of treating with stable pravastatin formulation
EP1737449A1 (en) * 2004-03-01 2007-01-03 LEK Pharmaceuticals D.D. Pharmaceutical composition
KR100598326B1 (en) 2004-04-10 2006-07-10 한미약품 주식회사 EXTENDED RELEASE ORAL FORMULATION OF HMG-CoA REDUCTASE INHIBITOR AND METHOD FOR THE PREPARATION THEREOF
WO2006008757A3 (en) * 2004-05-05 2006-04-27 Cadila Healthcare Ltd Stabilized pharmaceutical compositions of pravastatin
CA2588216A1 (en) 2004-11-22 2006-05-26 Dexcel Pharma Technologies Ltd. Stable atorvastatin formulations
US20060229277A1 (en) * 2005-04-08 2006-10-12 Orbus Pharma, Inc. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor
WO2007016757A1 (en) * 2005-08-05 2007-02-15 Orbus Pharma Inc. Stabilized extended release pharmeceutical compositions comprising an hmg-coa reductase inhibitor
US20090247603A1 (en) 2005-12-23 2009-10-01 Orbus Pharma, Inc. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor
EP1810667A1 (en) 2006-01-20 2007-07-25 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical composition comprising amorphous atorvastatin
US20080038332A1 (en) * 2006-08-10 2008-02-14 Cai Gu Huang Stable pharmaceutical formulation comprising atorvastatin calcium
WO2008062476A3 (en) * 2006-10-31 2008-10-16 Glenmark Pharmaceutical Ltd Pharmaceutical composition comprising rosuvastatin or pharmaceutically accepatble salts thereof
GB0713707D0 (en) * 2007-07-13 2007-08-22 Generics Uk Ltd Stable compositions
WO2009024889A3 (en) 2007-08-21 2009-07-09 Vinod Arora Pharmaceutical composition comprising a hmg-coa reductase inhibitor and ezetimibe
DE102007052071A1 (en) 2007-10-30 2009-05-07 Stada Arzneimittel Ag stabilized atorvastatin
WO2011049122A1 (en) * 2009-10-21 2011-04-28 第一三共株式会社 Pravastatin sodium tablet rapidly disintegrating in oral cavity and method for producing same
US8372877B2 (en) * 2010-04-16 2013-02-12 Cumberland Pharmaceuticals Stabilized statin formulations
KR101248804B1 (en) * 2010-05-14 2013-03-29 한미사이언스 주식회사 BILAYERED PHARMACEUTICAL COMPOSITION OF HMG-CoA REDUCTASE INHIBITOR AND IRBESARTAN
JP5829607B2 (en) * 2010-06-30 2015-12-09 持田製薬株式会社 Combination preparation of ω3 fatty acids
WO2012153181A1 (en) * 2011-05-11 2012-11-15 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical composition comprising pitavastatin or its pharmaceutically acceptable salts
RU2014124118A (en) 2011-11-15 2015-12-27 Др. Редди'С Лабораторис Лтд. Pharmaceutical preparations comprising atorvastatin and glimepiride
KR20140030505A (en) * 2012-08-31 2014-03-12 한미약품 주식회사 Pharmaceutical composite capsule formulation comprising irbesartan and hmg-coa reductase inhibitor
KR101597004B1 (en) 2013-07-25 2016-02-23 씨제이헬스케어 주식회사 Pharmaceutical combination comprising sustained-release type metformin and immediate-release type HMG-CoA reductase inhibitor
EP3184103A1 (en) 2015-12-21 2017-06-28 Hexal AG Pharmaceutical composition comprising atorvastatin or a salt thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5030447A (en) * 1988-03-31 1991-07-09 E. R. Squibb & Sons, Inc. Pharmaceutical compositions having good stability
US5180589A (en) * 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
US5798375A (en) * 1995-07-03 1998-08-25 Sankyo Company, Limited Treatment of arteriosclerosis and xanthoma
US6531507B1 (en) * 2000-06-09 2003-03-11 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
US20040077708A1 (en) * 2002-10-11 2004-04-22 Rok Grahek Stablized pharmaceutical composition comprising an amorphous active substance
US6790984B1 (en) * 2003-02-21 2004-09-14 Chunghwa Chemical Synthesis & Biotech Co., Ltd. Process for purifying pravastatin sodium from a fermentation broth

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US579837A (en) * 1897-03-30 Saw-sharpening machine
DK149080C (en) * 1980-06-06 1986-07-28 Sankyo Co Process for the preparation of derivatives of ML236B-carboxylic acid
GB2189699A (en) * 1986-04-30 1987-11-04 Haessle Ab Coated acid-labile medicaments
FI94339C (en) * 1989-07-21 1995-08-25 Warner Lambert Co Method pharmaceutically usable / R- (R *, R *) / - 2- (4-fluorophenyl) - dihydroxy-5- (1-methylethyl) -3-phenyl-4 - / (phenylamino) carbonyl / -1 pyrrole-1-heptanoic acid and pharmaceutically acceptable salts thereof
DE69324504D1 (en) * 1993-01-19 1999-05-20 Warner Lambert Co A stabilized composition comprising orally applicable procedure, the compound ci-981 and
US5298627A (en) * 1993-03-03 1994-03-29 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
FR2751316B1 (en) * 1996-07-19 1998-08-28 Granger Maurice Dispensing apparatus wadding paper webs for towels, toilet paper and the like
US6235311B1 (en) * 1998-03-18 2001-05-22 Bristol-Myers Squibb Company Pharmaceutical composition containing a combination of a statin and aspirin and method

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5030447A (en) * 1988-03-31 1991-07-09 E. R. Squibb & Sons, Inc. Pharmaceutical compositions having good stability
US5180589A (en) * 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
US5798375A (en) * 1995-07-03 1998-08-25 Sankyo Company, Limited Treatment of arteriosclerosis and xanthoma
US6531507B1 (en) * 2000-06-09 2003-03-11 Lek Pharmaceuticals D.D. Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same
US20040077708A1 (en) * 2002-10-11 2004-04-22 Rok Grahek Stablized pharmaceutical composition comprising an amorphous active substance
US6790984B1 (en) * 2003-02-21 2004-09-14 Chunghwa Chemical Synthesis & Biotech Co., Ltd. Process for purifying pravastatin sodium from a fermentation broth

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE44578E1 (en) 2000-04-10 2013-11-05 Teva Pharmaceutical Industries, Ltd. Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
US7642287B2 (en) 2004-08-06 2010-01-05 Transform Pharmaceuticals, Inc. Statin pharmaceutical compositions and related methods of treatment
US20060034815A1 (en) * 2004-08-06 2006-02-16 Hector Guzman Novel statin pharmaceutical compositions and related methods of treatment
US20090042979A1 (en) * 2004-08-06 2009-02-12 Transform Pharmaceuticals Inc. Novel Statin Pharmaceutical Compositions and Related Methods of Treatment
US20090149533A1 (en) * 2004-08-06 2009-06-11 Transform Pharmaceuticals, Inc. Novel fenofibrate formulations and related methods of treatment
US20090297599A1 (en) * 2006-09-18 2009-12-03 Viragh Maria Pharmaceutical compositions containing rosuvastatin calcium
US8221788B2 (en) 2006-09-18 2012-07-17 Richter Gedeon Nyrt. Pharmaceutical compositions containing rosuvastatin calcium
WO2008035128A1 (en) * 2006-09-18 2008-03-27 Richter Gedeon Nyrt. Pharmaceutical compositions containing rosuvastatin calcium
US20100196469A1 (en) * 2007-06-25 2010-08-05 Pharmathen S.A. Pharmaceutical Formulation containing an HMG-COA Reductase Inhibitor and method for the preparation thereof
WO2009000286A1 (en) * 2007-06-25 2008-12-31 Parmatheen S.A. Improved pharmaceutical formulation containing an hmg-coa reductase inhibitor and method for the preparation thereof
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US9399064B2 (en) 2011-04-12 2016-07-26 Sawai Pharmaceutical Co., Ltd. Pitavastatin-containing preparation and method for producing same
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin

Also Published As

Publication number Publication date Type
DE69937691T2 (en) 2008-11-20 grant
CA2348988C (en) 2009-07-21 grant
EP1148872B1 (en) 2007-12-05 grant
US6680341B1 (en) 2004-01-20 grant
EP1148872A1 (en) 2001-10-31 application
EP1911445A2 (en) 2008-04-16 application
JP2002532409A (en) 2002-10-02 application
RU2227019C2 (en) 2004-04-20 grant
EP1911445A3 (en) 2011-04-27 application
WO2000035425A1 (en) 2000-06-22 application
CN1198597C (en) 2005-04-27 grant
US20090264497A1 (en) 2009-10-22 application
CN1330538A (en) 2002-01-09 application
CA2348988A1 (en) 2000-06-22 application
DE69937691D1 (en) 2008-01-17 grant
ES2299265T3 (en) 2008-05-16 grant

Similar Documents

Publication Publication Date Title
US4786505A (en) Pharmaceutical preparation for oral use
US4343789A (en) Sustained release pharmaceutical composition of solid medical material
US5126145A (en) Controlled release tablet containing water soluble medicament
US5442008A (en) Stabilized polymer film coated compounds and stabilized formulations in compressed from using same
US20050096391A1 (en) Compositions comprising fenofibrate and rosuvastatin
US5322698A (en) Process for the preparation of a tablet or dragee composition containing a heat-, light- and moisture-sensitive active ingredient having monoclinic crystal structure
US7022713B2 (en) Hyperlipemia therapeutic agent
US20040126423A1 (en) Pharmaceutical formulation
US5487900A (en) Stabilized vitamin D preparation
US6767558B2 (en) Inhibiting oxidative degradation of pharmaceutical formulations
US20030225124A1 (en) Stable formulations of ACE inhibitors, and methods for preparation thereof
US7030151B2 (en) Atorvastatin calcium in a pharmaceutical form composition thereof and pharmaceutical formulation comprising atorvastatin calcium
US5356896A (en) Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
US5441747A (en) Stabilized solid pharmaceutical composition containing acid addition salts of a basic drug and an alkaline stabilizer
US6242003B1 (en) Organic compounds
US6558659B2 (en) Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids
US5376383A (en) Method for enhancing the lowering of plasma-cholesterol levels
WO2008101723A2 (en) Pharmaceutical composition containing a cholesterol absorption inhibitor
WO2005034908A2 (en) A solid dosage form comprising a fibrate and a statin
EP0342522A1 (en) Peroral preparation of an acid-unstable compound
US20030175338A1 (en) Formulations of atorvastatin stabilized with alkali metal additions
US20050096390A1 (en) Compositions comprising fenofibrate and pravastatin
EP0475482A1 (en) Stabilized solid chemical compositions
EP0465096A1 (en) Plasma cholesterol level lowering composition
EP0882450A2 (en) Cholesterol-lowering composition comprising coenzyme Q

Legal Events

Date Code Title Description
AS Assignment

Owner name: LEK PHARMACEUTICALS D.D., SLOVENIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KERC, JANEZ;REEL/FRAME:014131/0105

Effective date: 20031024