JP2005532352A - Nanoparticle formulations comprising HMG-CoA reductase inhibitor derivatives ("statins"), novel combinations thereof, and the manufacture of these pharmaceutical compositions - Google Patents

Abstract

The present invention relates to a nanoparticle composition comprising a statin such as lovastatin or simvastatin comprising a surface stabilizer. The statin particles of the composition have an effective average particle size of less than about 2000 nm. In another aspect of the invention, novel combinations of statins and other cholesterol-lowering agents are described and the use is taught.

Description

  The present invention relates to nanoparticle compositions comprising a combination of statins, preferably lovastatin or simvastatin, and novel statins. The nanoparticulate statin particles preferably have an effective average particle size of less than about 2000 nm. In another aspect, the present invention includes novel combinations of statins with other cholesterol-lowering agents and methods of use thereof.

Background of the Invention
I. Background on nanoparticulate active agent compositions
The nanoparticulate active agent composition first described in US Patent No. 5,145,684 ("'684 patent") is a sparingly soluble therapeutic agent that has adsorbed or bound non-crosslinked surface stabilizer on its surface Or particles made of diagnostic agents. Many factors affect bioavailability, such as drug dosage form, various properties such as dissolution rate. Poor bioavailability is an important problem encountered in the development of pharmaceutical compositions, especially those that contain active ingredients that are poorly soluble in water. By reducing the particle size of the active agent, the surface area of the composition is increased, thus generally increasing bioavailability. The '684 patent does not teach statin nanoparticle compositions.

  For example, US Patent Nos. 5,518,187 and 5,862,999 both describe "Drug substance crushing method", US Patent No. 5,718,388 "Drug substance continuous crushing method", and US Patent No. 5,510,118 describes a “method for producing a therapeutic composition containing nanoparticles”.

Nanoparticulate active agent compositions are also described in US Patent No. 5,298,262, “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization”; 5,302,401, “Method to Reduce Increased Particle Size in Lyophilized Injections” 5,318,767, “X-ray contrast agent compositions useful in medical imaging”; 5,326,552, “New formulation for nanoparticulate X-ray blood pool contrast agent using high molecular weight nonionic surfactant”; 5,328,404, “iodine”; X-ray imaging using fluorinated aromatic propanedioic acid ";5,336,507," Use of charged phospholipids to reduce nanoparticle aggregation ";5,340,564," Olin 10- to prevent particle aggregation and increase stability "Formulations containing G"; 5,346,702, "Use of non-ionic cloud point modifiers to prevent particle aggregation during sterilization"; 5,349,957, "Preparation and magnetic properties of very small magnetic dextran particles"; 5,352,459, "Sterilization" During ~ "Use of purified surface modifiers to prevent particle aggregation"; 5,399,363 and 5,494,683, both "surface modified anticancer nanoparticles"; 5,401,492, "water-insoluble non-magnetic manganese particles as magnetic resonance enhancers"; 5,429,824, ""Use of Tyloxapol as a nanoparticle stabilizer"; 5,447,710, "Method of producing nanoparticle X-ray blood pool contrast agent using high molecular weight nonionic surfactant"; 5,451,393, "X-ray contrast agent useful in medical imaging Composition ";5,466,440," Preparation of X-ray contrast agent for oral gastrointestinal diagnosis in combination with pharmaceutically acceptable clay ";5,470,583," Nanoparticle composition containing charged phospholipids to reduce aggregation " 5,472,683, “Nanoparticle diagnostic mixed carbamic anhydride as an X-ray contrast agent for blood pool and lymphatic imaging”; 5,500,204, “For blood pool and lymphatic imaging” Nanoparticle diagnostic dimer as an X-ray contrast agent ”; 5,518,738,“ Nanoparticle NSAID formulation ”; 5,521,218,“ Nanoparticle iododipamide derivative for use as an X-ray contrast agent ”; 5,525,328,“ blood pool and lymph Diatrizoxyester X-ray contrast medium for nanoparticle diagnosis for system imaging ";5,543,133," Method for producing X-ray contrast medium composition containing nanoparticles ";5,552,160," Surface modified NSAID nanoparticles "; 5,560,931, “Preparation of compounds as nanoparticle dispersants in digestible oils or fatty acids”; 5,565,188, “Polyalkylene block copolymers as surface modifiers for nanoparticles”; 5,569,448, “Stabilizers for nanoparticle compositions” Sulfated nonionic block copolymer surfactants as coatings ";5,571,536," Preparation of compounds as nanoparticle dispersants in digestible oils or fatty acids "; 5,573, 749, “Nanoparticle Diagnostic Mixed Carboxylic Anhydride as X-ray Contrast Agent for Blood Pool and Lymphatic Imaging”; 5,573,750, “Diagnostic Imaging X-Ray Contrast Agent”; 5,573,783, “Redispersion with Protective Overcoat” Nanoparticle membrane matrix ";5,580,579," Site-specific adhesion in the gastrointestinal tract using nanoparticles stabilized by high molecular weight linear poly (ethylene oxide) polymer ";5,585,108," Pharmaceutically acceptable Preparation of Oral Gastrointestinal Therapeutics Combined with Clay ”; 5,587,143,“ Butyl Oxide-Ethylene Oxide Block Copolymer Surfactant as Stabilizer Coating for Nanoparticle Compositions ”; 5,591,456,“ Hydroxy as Dispersion Stabilizer ” Naproxen ground with propylcellulose ”; 5,593,657,“ stable with nonionic and anionic stabilizers 5,622,938, “Nanocrystalline Sugar-Based Surfactant”; 5,628,981, “Improved Preparation of X-ray Contrast Agent for Oral Gastrointestinal Diagnosis and Oral Gastrointestinal Therapeutics”; 5,643,552, “Blood Pool” And mixed carbon dioxide for diagnostics of nanoparticles as X-ray contrast agents for lymphatic imaging ”; 5,718,388,“ Continuous grinding of drug substance ”; 5,718,919,“ Nanoparticles containing the R (-) enantiomer of ibuprofen ” 5,747,001, “aerosol containing beclomethasone nanoparticle dispersion”; 5,834,025, “reduction of physiological side effects induced by intravenous nanoparticle formulation”; 6,045,829, “human immunodeficiency using cellulosic surface stabilizers; Virus crystal (HIV) protease inhibitor nanocrystalline formulation ";6,068,858," Human immunodeficiency virus (HIV) protease using cellulosic surface stabilizers " Preparation of nanocrystalline formulations of inhibitor development "; 6,
153,225, “Nanoparticulate Naproxen Injectable Formulation”; 6,156,506, “New Solid Dosage Form of Nanoparticulate Naproxen”; 6,221,400, “Mammalian Treatment Using Nanocrystalline Formulation of Human Immunodeficiency Virus (HIV) Protease Inhibitor” 6,264,922, “Atomized aerosol containing nanoparticle dispersant”; 6,267,989, “Method to prevent crystal growth and particle aggregation in nanoparticle composition”; 6,270,806, “As surface stabilizer of nanoparticle composition” 6,316,029, “rapidly disintegrating solid oral dosage form”; 6,375,986, “solid dosage nanoparticle composition comprising a synergistic combination of polymeric surface stabilizer and sodium dioctyl sulfosuccinate”; 6,428,814 , “Bioadhesive nanoparticle compositions with cationic surface stabilizers”; 6,431,478, “small scale mill”; and 6,432,381, “top and / or bottom Methods for targeting drug delivery to the gastrointestinal tract, all of which are incorporated herein by reference. In addition, US Patent Application No. 20020012675 A1 (published January 31, 2002) “Controlled Release Nanoparticle Composition” describes a nanoparticle composition, which is incorporated herein by reference. None of these documents describe nanoparticulate statin compositions.

  Amorphous small particle compositions are described, for example, in US Pat. No. 4,783,484, “Particulate Compositions and Their Use as Antimicrobial Agents”; 4,826,689, “Method of Making Uniformly Size Particles from Water Insoluble Organic Compounds”; 4,997,454, "Methods for making particles of uniform size from insoluble compounds"; 5,741,522, "Uniformly sized minimal non-aggregating porous particles and methods for trapping bubbles in"; and 5,776,496, "Ultrasonic backscattering "Small porous particles for enhancement".

II. Background on statins Recently, many new drugs, collectively known as statins or vastatins, have been introduced to lower serum LDL cholesterol levels (a typical example of these drugs is The Merck Index). As detailed in). High LDL cholesterol levels have proven to be an important risk factor for the development of arteriosclerosis and ischemic heart disease. Statins have been shown to reduce serum LDL cholesterol levels in a dose-dependent manner. In addition, these drugs lower serum triglyceride levels, which are other risk factors for heart disease.

  Statins lower serum LDL cholesterol levels by competitive inhibition of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme involved in cholesterol biosynthesis. By tightly binding to the active site of the enzyme, statins prevent the reduction of HMG-CoA, a process necessary for cholesterol biosynthesis. Inhibition of cholesterol biosynthesis by statins reduces LDL cholesterol production and secretion. Furthermore, upregulation of LDL receptors, particularly in the liver, causes removal of LDL from the serum. That is, by reducing LDL cholesterol production and removing LDL cholesterol from the serum, statins effectively reduce overall serum LDL cholesterol levels.

  Two-thirds of total cholesterol in the body is endogenous. The major site of cholesterol biosynthesis is the liver. Such liver-derived cholesterol is a major cause of the development of hypercholesterolemia. In contrast, cholesterol production in non-hepatocytes is necessary for normal cell function. Therefore, selective inhibition of HMG-CoA reductase in the liver is an important requirement for HMG-CoA reductase inhibitors. In this regard, statins typically have high oral availability and high liver extraction during the first pass in the liver. Statins are said to cause strong hepatotoxicity.

  Current HMG-CoA reductase inhibitors are very potent, but there is a need for safer and higher titer HMG-CoA reductase inhibitors. The present invention satisfies these needs.

Means for Solving the Invention

SUMMARY OF THE INVENTION The present invention relates to nanoparticulate active agent compositions comprising at least one statin (eg, lovastatin or simvastatin) and novel statin combinations. The composition preferably comprises at least one statin and at least one surface stabilizer adsorbed on or bound to the surface of the one or more statin particles. The nanoparticulate statin particles preferably have an effective average particle size of less than about 2000 nm.

  Another aspect of the present invention relates to a pharmaceutical composition comprising the nanoparticulate statin composition of the present invention. The pharmaceutical composition preferably comprises at least one statin, at least one surface stabilizer, and at least one pharmaceutically acceptable carrier, and any desired excipients known to those skilled in the art, Formulated to the desired dosage form.

  In another aspect of the invention, a novel combination of a statin and at least one other cholesterol-lowering agent is described and taught how to make it.

  Another aspect of the present invention relates to nanoparticulate statin compositions having improved pharmacokinetic profiles (eg, improved Tmax, Cmax, and AUC parameters) compared to conventional microcrystalline statin formulations.

  One embodiment of the present invention includes a statin composition, where the statin pharmacokinetic profile is preferably according to Cmax and AUC guidelines provided by the US Food and Drug Administration and / or the corresponding European Administration (EMEA). As specified, it is not significantly affected by the dietary or fasted state of the subject taking the composition.

  In yet another embodiment, the invention encompasses a statin composition of the invention, wherein administration of the composition to a fasted subject is in particular administered by the US Food and Drug Administration and / or the corresponding European Administration (EMEA). Is biologically equivalent to administration of the composition to a subject in a dietary state, as defined by the Cmax and AUC guidelines provided.

  Other embodiments of the invention include, but are not limited to, nanoparticulate statin compositions that preferably have one or more of the following properties compared to conventional non-nanoparticulate formulations of the same statin: (1 ) Smaller tablet or other solid dosage form sizes; (2) smaller doses of drug required to achieve the same pharmacological effect; (3) increased bioavailability; (4) disruption of nanoparticulate statin compositions An increase in speed; and (6) a bioadhesive statin composition.

  The present invention further discloses a method for producing the nanoparticulate statin composition of the present invention. Such methods include contacting one or more statins with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate statin composition. The one or more surface stabilizers can be contacted with the statin before, preferably during or after the size reduction of the statin.

  The invention also uses the nanoparticulate statin composition of the invention for conditions such as hypercholesterolemia, hypertriglyceridemia, coronary heart disease, and peripheral vascular disease (including symptomatic carotid artery disease) It relates to treatment. In one embodiment, the composition of the invention comprises LDL-C, total-C, triglycerides, and apo B of adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa and type IIb) It can be used as an adjunct therapy to diet. In another embodiment, the composition can be used as an adjunct therapy to a diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson type IV and type V hyperlipidemia). Significantly elevated serum triglyceride levels (eg> 2000 mg / dL) may increase the risk of developing pancreatitis. Other diseases (eg, restenosis and Alzheimer's disease) that are directly or indirectly associated with elevated levels of uncontrollable cholesterol metabolism are also treated with the compositions of the present invention. Other therapies using the nanoparticulate statin compositions of the present invention are known to those skilled in the art.

  Such a method comprises administering to a subject a therapeutically effective amount of a nanoparticulate statin pharmaceutical composition of the invention.

  The foregoing general description and the following detailed description are exemplary and explanatory and provide further explanation of the claimed invention. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a nanoparticulate active agent composition comprising at least one statin (eg, lovastatin or simvastatin) and a novel statin combination. The composition preferably comprises at least one statin and at least one surface stabilizer adsorbed on or bound to the surface of the statin particles. The nanoparticulate statin particles preferably have an effective average particle size of less than about 2000 nm.

  As taught in the '684 patent, not all combinations of surface stabilizers and active agents provide stable nanoparticle compositions. Surprisingly, it has been discovered that stable nanoparticulate statin formulations can be made.

  Current HMG-CoA reductase inhibitors are very potent, but there is a need for safer and higher titer HMG-CoA reductase inhibitors. Nanoparticulate statin compositions reduce the amount of drug required and the amount that deviates from the liver, which in turn reduces harmful side effects while providing the maximum dose response. Longer plasma half-life is believed to be caused by the nanoparticulate statin compositions of the present invention. In addition, prolonging the action time of HMG-CoA reductase inhibitors is expected to cause even lower serum cholesterol levels and further reduce the dose.

  In general, the dissolution rate of a granular drug can increase with increasing surface area (ie, decreasing particle size). Accordingly, methods for producing miniaturized drugs have been studied and attempts have been made to control the size and size range of drug particles in pharmaceutical compositions. However, nanoparticulate active agent formulations suitable for pharmaceutical administration have prepared active ingredients as colloidal dispersions exhibiting acceptable nanoparticle size ranges, and have stability that maintains such size ranges and does not aggregate. I need. Simply increasing the surface area by reducing the particle size is not guaranteed to succeed. A further challenge is to form a solid dosage form that can be redispersed into a nanoparticulate form upon administration to a patient, maintaining the advantages of nanoparticulate statins over conventional dosage forms.

  The advantages of the nanoparticulate statin formulation of the present invention compared to conventional non-nanoparticulate formulations of the same statin are preferably, but not limited to: (1) Small tablet or other solid dosage form size; (2) Same pharmacology Less drug needed to achieve effect; (3) Improved bioavailability; (4) Substantially similar to nanoparticulate statin composition when administered in a fed state versus a fasted state Pharmacokinetic profile; (5) Improved pharmacokinetic profile; (6) Bioequivalence of nanoparticulate statin composition when administered in a fed state versus fasted state; (7) Nanoparticulate statin composition (8) bioadhesive statin compositions; and (9) nanoparticulate statin compositions can be used with other active agents.

  The present invention also includes a nanoparticulate statin composition with one or more non-toxic pharmaceutically acceptable carriers, adjuvants, or vehicles (collectively referred to as carriers). The composition can be administered parenterally (eg, intravenous, intramuscular, or subcutaneous), orally administered in solid, liquid, or aerosol form, vaginal, intranasal, rectal, intraocular, topical (powder, ointment) Agent or infusion), buccal, intracisternal, intraperitoneal, or topical administration.

  The preferred dosage form of the present invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized. Examples of solid dosage forms include, but are not limited to, tablets, capsules, sachets, troches, powders, pills, or granules. Solid dosage forms can be, for example, fast melt dosage forms, controlled release dosage forms, lyophilized dosage forms, delayed release dosage forms, extended release dosage forms, pulsatile release dosage forms, mixed immediate release and controlled release dosage forms, or A combination of these may also be used. Solid dosage tablets are preferred.

  The present invention is described using several definitions set forth below and throughout the application.

  “About” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which the term is used. Where there is a use of a term that is unknown to those skilled in the art in the context in which it is used, “about” will mean an average of ± 10% of that term.

  “Conventional” or “non-nanoparticulate active agent” means an active agent that is solubilized or has an effective average particle size greater than about 2 microns.

  As used herein, a “water-insoluble drug” has a solubility of less than about 30 mg / ml, preferably less than about 20 mg / ml, or preferably less than about 10 mg / ml, or preferably less than about 1 mg / ml. Means. Such drugs are eliminated from the gastrointestinal tract before being absorbed into the circulation. Furthermore, drugs that are difficult to dissolve in water are not safe for intravenous administration, and they are mainly used with highly water-soluble drugs.

  As used herein, “stable” with respect to stable statin particles includes, but is not limited to, one or more of the following parameters: (1) Statin particles are not strongly aggregated or agglomerated by interparticle attraction, Does not significantly increase particle size over time; (2) The physical structure of statin particles does not change over time, for example, from an amorphous phase to a crystalline phase; (3) Statin particles are chemically And / or (4) In preparing the nanoparticles of the present invention, the statin has not undergone a heating step or treatment at a temperature above the melting point of the statin.

  As used herein, a “therapeutically effective amount” for a drug dose means a dose that provides a specific pharmacological response when the drug is administered to a large number of subjects in need of treatment. A “therapeutically effective amount” when administered to a particular subject in certain cases is not necessarily effective in the treatment of the diseases described herein, even if such a dose is considered a “therapeutically effective amount” by those skilled in the art. I want to emphasize that there are things that are not. It should be further understood that drug dosage is measured as an oral dose in certain instances or relates to drug levels measured in blood.

I. Preferred features of the statin composition of the present invention
A. Increased Bioavailability and Low Dose The statin composition of the present invention preferably exhibits increased bioavailability at the same dose of the same statin as compared to conventional statin formulations of the prior art, and may be in smaller amounts, and Longer plasma half-life.

  In one embodiment of the present invention, the pharmaceutical statin composition has increased bioavailability, thus reducing the statin dose and reducing the toxicity associated with such statins. Surprisingly, it has been discovered in the present invention that stable compositions of nanoparticulate statins can be formed that allow therapeutic levels at preferably low doses.

  The increased bioavailability of the statin compositions of the present invention allows for smaller solid dosage sizes. This is particularly important for patient populations such as the elderly, children and infants.

B. Improved Pharmacokinetic Profile The present invention also preferably provides a statin composition having a desired pharmacokinetic profile when administered to a mammalian subject. Preferred pharmacokinetic profiles of statin compositions preferably include, but are not particularly limited to: (1) The Tmax of statin, preferably measured at the same dose as measured in plasma of a mammalian subject after administration, is conventional Less than the non-nanoparticulate Tmax; (2) the Cmax of the statin is preferably greater than the conventional non-nanoparticulate Cmax administered at the same dose as measured in plasma of the mammalian subject after administration; (3) administration The AUC of the statin is preferably greater than the conventional non-nanoparticulate AUC administered at the same dose, as measured later in the plasma of the mammalian subject.

  A preferred pharmacokinetic profile herein is a pharmacokinetic profile measured after the first administration of a statin. The composition can be produced by any method described below and any method known to those skilled in the art.

  A preferred statin composition of the present invention is about 90% or less, about 80% or less of the Tmax exhibited by a non-nanoparticle formulation of the same statin in a comparative pharmacokinetic study with a non-nanoparticle formulation of the same statin administered at the same dose Hereinafter, Tmax of about 70% or less, about 60% or less, about 50 or less, about 30 or less, about 25 or less, about 20 or less, about 15% or less, or about 10% or less is shown.

  Preferred statin compositions of the present invention are at least about 10%, at least about at least about Cmax exhibited by non-nanoparticle formulations of the same statin in a comparative pharmacokinetic study with non-nanoparticle formulations of the same statin administered at the same dose. A Cmax that is 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% greater.

  Preferred statin compositions of the present invention are at least about 10%, at least about at least about 10% above the AUC exhibited by the same statin non-nanoparticle formulation in a comparative pharmacokinetic study with a non-nanoparticle formulation of the same statin administered at the same dose. AUC that is 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% greater.

  Formulations that provide the desired pharmacokinetic profile are suitable for administration according to the methods of the invention. Examples of formulations that provide such a profile include nanoparticulate statin liquid dispersions, gels, aerosols, ointments, creams, solid dosage forms, and the like.

C. The pharmacokinetic profile of the statin composition of the present invention is not affected by the dietary or fasting state of the subject ingesting the composition. When the present invention is administered to humans, the pharmacokinetic profile of the statin is Included are statin compositions that are substantially unaffected by the dietary or fasting state of the subject taking the composition. This means that there is no substantial difference in the amount of drug absorbed or the rate of drug absorption when the nanoparticulate statin composition is administered in a fed versus a fasted state.

  The invention also encompasses statin compositions where administration of the composition to a fasted subject is bioequivalent to administration of the composition to a subject fed a meal. “Bioequivalence” preferably has a 90% confidence interval (CI) between 0.80 and 1.25 for both Cmax and AUC in the US Food and Drug Administration regulatory guidelines, and 90% CI for AUC in the European EMEA regulatory guidelines from 0.80 to 0.80 A 1.25, and 90% CI for Cmax is established between 0.73 and 1.43 (Tmax is not relevant to bioequivalence determinations in USFDA and EMEA regulatory guidelines).

  The prior art has demonstrated that lovastatin administered in the fasted state gives an average plasma concentration of about two-thirds of the total inhibitor concentration when lovastatin is administered immediately after a standard test meal. . This 33% significant difference in absorption observed with conventional statin formulations is undesirable. The nanoparticulate statin formulations of the present invention alleviate this problem when administered in a fed state as compared to a fasted state, which reduces the difference in absorption levels or preferably does not produce a significant difference. .

  Advantages of a dosage form that substantially eliminates the effects of food may improve subject convenience, thus improving subject compliance and confirming that a subject is being administered with or without a meal There is no need. This is important because of the increasing prevalence of subject compliance in the medical condition for which the drug is prescribed.

  The difference in absorption of the statin compositions of the present invention when administered in a fed state versus a fasted state is preferably less than about 100%, less than about 90%, less than about 80%, less than about 70% Less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or about 3% Is less than.

D. Dissolution Profiles of Statin Compositions of the Invention The statin compositions of the invention preferably have an unexpectedly dramatic dissolution profile. Rapid dissolution of the administered active substance is preferred because fast dissolution generally leads to rapid onset of action and great bioavailability. To improve the dissolution profile and bioavailability of statins, it would be useful to increase the dissolution of the drug so that levels close to 100% can be achieved.

  The statin compositions of the present invention preferably have a dissolution profile that dissolves at least about 20% of the composition within about 5 minutes. In other embodiments of the invention, at least about 30% or about 40% of the statin composition dissolves within about 5 minutes. In yet another embodiment of the invention, preferably at least about 40%, about 50%, about 60%, about 70%, or about 80% of the statin composition dissolves within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, about 80%, about 90%, or about 100% of the statin composition dissolves within about 20 minutes.

  Dissolution is preferably measured in a discriminating medium. Such a dissolution medium gives two very different dissolution curves for two products having very different dissolution profiles in gastric juice, ie the dissolution medium is predictive for in vivo dissolution of the composition. An example of a dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025M. The amount dissolved can be measured spectroscopically. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.

E. Redispersion Profile of the Statin Composition of the Invention An additional feature of the statin composition of the invention is that the composition is preferably reconstituted such that the effective average particle size of the redispersed statin particles is less than about 2 microns. To disperse. If administered, if the nanoparticulate statin composition of the present invention is not substantially dispersed to the nanoparticle size, this dosage form may lose the benefits obtained by manufacturing the statin to the nanoparticle size. So this is important.

  This is because nanoparticulate active agent compositions benefit from the small particle size of the active agent; if the active agent does not redisperse to a small particle size when administered, the extremely high surface of the nanoparticle system Due to free energy and thermodynamic driving force, “lumps” or agglomerated active substance particles are formed, causing an overall reduction in free energy. Due to the formation of such agglomerated particles, the bioavailability of the dosage form may be much lower than that observed with liquid dispersions of nanoparticulate active agents.

  In addition, the nanoparticulate statin compositions of the present invention are preferably reconstituted / redispersed in a biorelevant aqueous medium, as evidenced by an effective average particle size of the redispersed statin particles of about 2 microns, When administered to a mammal (eg, human or animal), it shows dramatic redispersion of nanoparticulate statin particles. Such a biorelevant aqueous medium is any aqueous medium that exhibits the desired ionic strength and pH (which is the basis of the biorelevance of the medium). The desired pH and ionic strength are representative of the physiological conditions of the human body. Such a bioaqueous medium may exhibit the desired pH and ionic strength, for example, in an aqueous electrolyte solution or an aqueous solution of any salt, acid, or base, or combinations thereof.

  Biorelevant pH is known in the art. For example, in the stomach, the pH ranges from slightly less than 2 (but typically greater than 1) to 4 or 5. In the small intestine, the pH is in the range of 4-6, and in the large intestine, it is in the range of 6-8. Biorelevant ionic strength is also known in the art. Fasted state gastric juice has an ionic strength of about 0.1 M, and in the fasted state, small intestinal fluid has an ionic strength of about 0.14. See, for example, Lindahl et al, "Analysis of fluids in male and female stomach and proximal jejunum", Pharm. Res., 14 (4): 497-502 (1997).

  The pH and ionic strength of the test solution are more important than the specific chemical content. That is, suitable pH and ionic strength values are myriad, such as strong acids, strong bases, salts, single or multiple bound acid-base pairs (ie, corresponding salts of weak acids and acids), monoprotic and polyprotic electrolytes, etc. Obtained from the combination.

  Exemplary electrolyte solutions are not particularly limited, and may be about 0.001 to about 0.1 M HCl solution, about 0.001 to about 0.1 M NaCl solution, and mixtures thereof. For example, the electrolyte solution is not particularly limited, but is about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less. About 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01M HCl and / or 0.1M NaCl are most representative of fasting human physiological conditions due to the pH and ionic strength conditions of the proximal gastrointestinal tract.

  The electrolyte concentrations of 0.001M HCl, 0.01M HCl, and 0.1M HCl correspond to pH 3, pH 2, and pH 1, respectively. That is, 0.01M HCl solution simulates the typical acidic conditions of the stomach. 0.1M NaCl provides a reasonable approximation of the ionic strength conditions of the entire body, including gastric juice, but concentrations higher than 0.1M may be used to simulate a dietary condition in the human gastrointestinal tract.

  Examples of salts, acids, bases or combinations thereof that exhibit the desired pH and ionic strength include, but are not limited to, phosphoric acid / phosphate + sodium, potassium and calcium chloride salts, acetic acid / acetate + There are sodium, potassium and calcium salts of chloride, carbonate / carbonate + sodium chloride, potassium and calcium salts, and citric acid / citrate + sodium, potassium and calcium salts of chloride.

  In certain embodiments of the present invention, the redispersed statin particles of the present invention (redispersed in aqueous, biorelevant, or any other suitable medium) can be dispersed by light dispersion, microscopy, or other suitable method. Effective average particle size is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, about <900 nm, <800 nm, <700 nm, <600 nm, <500 nm, <400 nm, <300 nm, <250 nm, <200 nm, <150 nm, <100 nm, <75 nm, <50 nm It is.

  “Effective average particle size of less than about 2000 nm” means that at least 50% of statin particles have a particle size that is smaller than the effective average by weight, ie, about 2000 nm, about 1900 nm, about 1800 nm, etc. Mean small. Preferably, at least about 70%, about 90%, about 95%, or about 99% of the statin particles have a particle size that is smaller than the effective average, ie, less than about 2000 nm, about 1900 nm, about 1800 nm, 1700 nm, and the like.

  Redispersibility can be tested using any suitable method known in the art. See, for example, US Patent No. 6,375,986, column “Solid Dosage Nanoparticle Composition Containing Synergistic Combination of Polymeric Surface Stabilizer and Sodium Dioctyl Sulfosuccinate”.

F. Bioadhesive Statin Composition The bioadhesive statin composition of the present invention comprises at least one cationic surface stabilizer, which is described in detail below. Statin bioadhesive preparations exhibit excellent bioadhesiveness to biological surfaces (eg, mucosa). The term bioadhesive refers to an attractive interaction between two biological surfaces or a biological surface and a synthetic surface. In the case of a bioadhesive nanoparticulate statin composition, the term bioadhesive is used to describe the adhesion between the nanoparticulate statin composition and a biomatrix (ie, gastrointestinal mucin, lung tissue, nasal mucosa, etc.) Is done. See, for example, US Patent No. 6,428,814, “Bioadhesive Nanoparticle Compositions With Cationic Surface Stabilizers,” which is incorporated herein by reference.

  This bioadhesive phenomenon basically involves two mechanisms: mechanical or physical interaction and chemical interaction. Of these, the first mechanical or physical interaction may be sufficient wetting of the bioadhesive surface, swelling of the bioadhesive polymer, penetration of the bioadhesive material into the tear on the tissue surface, or bioadhesive composition It involves the physical linkage or interpenetration of the bioadhesive material and the receptor tissue resulting from the interpenetration of the chain with the bioadhesive composition chain of the mucosa or other such related tissue. A second possible mechanism of bioadhesion incorporates forces such as ionic attraction, bipolar attraction, van der Waals interactions, and hydrogen bonding. It is this type of bioadhesive that is primarily responsible for the bioadhesive properties of the nanoparticulate statin compositions of the present invention. However, physical and mechanical interactions may also play a secondary role in the bioadhesive properties of such nanoparticle compositions.

  The bioadhesive statin composition of the present invention is useful in any situation where it is preferred to apply the composition to a biological surface. The bioadhesive statin composition coats the target surface with a continuous and uniform film that is not visible to the human eye.

  Bioadhesive statin compositions retard composition migration and some statin particles adhere to tissues rather than mucosal cells, thus extending exposure to statins and thus increasing dose absorption and bioavailability .

G. Statin Compositions for Use with Other Active Substances The statin compositions of the present invention may further contain one or more of the following useful compounds: (1) dyslipidemia, high fat Treatment of symptoms including septicemia, hypercholesterolemia, cardiovascular disease, hypertriglyceridemia, coronary heart disease, and peripheral vascular disease (including symptomatic carotid artery disease), or related symptoms; (2) primary Adjunctive therapy to diet for lowering LDL-C, total C, triglycerides, and / or apo B in adult patients with hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa and IIb); (3) Adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson IV and V hyperlipidemia); (4) treatment of pancreatitis; (5) treatment of restenosis; and / or (6 ) Treatment of Alzheimer's disease.

  Examples of non-statin compositions useful in the claimed invention include, but are not limited to, cholesterol-lowering agents, policosanols, alkanoyl L-carnitines, antihypertensive agents, sterols and / or stanols.

  Useful cholesterol-lowering agents are known to those skilled in the art and include, but are not limited to, ACE inhibitors, nicotinic acid, niacin, bile acid sequestering agents, fibrates, vitamins, fatty acid derivatives (eg fish oil), long chain plant extract alcohols ( For example, polycosinol), ezetimibe, and cellulose.

  Useful policosanols include, but are not limited to, triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, tetracontanol, or natural products or products containing such compounds There is an extract of

  Useful alkanoyl L-carnitines include, but are not limited to, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine, and isovaleryl L-carnitine, or their pharmaceutically acceptable There is salt.

  Examples of antihypertensive agents include, but are not limited to, diuretics (“drugs”), beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, angiotensin. There is a receptor blocker (formally known as the angiotensin-2-receptor antagonist, known as “sartans” for short).

  Examples of sterols and stanols include, but are not limited to, plant sterols, plant sterol esters, fish oil, sitosterol, sitostanol, phytosterol, campestanol, stigmasterol, coprostanol, cholestanol, beta-sitosterol and the like.

  Such additional compounds have a conventional non-nanoparticle size, i.e., an effective average particle size greater than about 2 microns, or such additional compounds have a nanoparticle size, i.e., an effective average particle less than about 2 microns. Can be formulated into size. If such one or more non-statin compounds have a nanoparticle size, preferably such non-statin compounds are insoluble in at least one liquid medium (as insoluble in the “Definition” section above), It has at least one surface stabilizer adsorbed on or associated with the surface of the non-statin compound. The one or more surface stabilizers used in the composition of the non-statin compound may be the same or different from the one or more surface stabilizers used in the statin composition. Surface stabilizers useful in the present invention are described below.

II. Compositions The present invention relates to nanoparticulate active agent compositions comprising a combination of at least one statin (eg, lovastatin or simvastatin) and a novel statin. The composition preferably comprises at least one statin and at least one surface stabilizer adsorbed on or bound to the surface of the statin. The nanoparticulate statin particles preferably have an effective average particle size of less than about 2000 nm. In another aspect of the invention, novel combinations of statins with other cholesterol-lowering agents are described and their use is taught.

  The present invention also includes a nanoparticulate statin composition with one or more non-toxic pharmaceutically acceptable carriers, adjuvants, or vehicles (collectively referred to as carriers). The composition is not particularly limited but is orally administered in oral, rectal, intraocular, parenteral injection (eg, intravenous, intramuscular or subcutaneous), solid (preferred route), liquid or aerosol type. It can be formulated for a variety of administration routes including intravaginal, intranasal, topical (powder, ointment or infusion), buccal, intracisternal, intraperitoneal, or topical administration.

A. Statin particles As used herein, “statin” preferably has a solubility in water of lovastatin or simvastatin, ie, less than about 30 mg / ml, less than about 20 mg / ml, less than about 10 mg / ml, or more preferably in water. Means any HMG-CoA reductase inhibitor (including analogs thereof), or salts thereof, having a solubility of less than about 1 mg / ml.

  The one or more statin particles or salts thereof may be in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.

  Such statin compositions include, but are not limited to, atorvastatin (Lipitor®) (US Patent No. 4,681,893), and other 6- [2- (substituted pyrroles) disclosed in US Patent No. 4,647,576. 1-yl) alkyl] pyran-2-one and derivatives; fluvastatin (Lescol®) (US Patent No. 5,354,772); lovastatin (US Patent No. 4,231,938); pravastatin (US Patent No. 4,346,227); Simvastatin (US Patent No. 4,444,784); verostatin; fluindostatin (Sandoz XU-62-320); pyrazole analogs of mevalonolactone derivatives disclosed in PCT application WO86 / 03488; rivastatin and others disclosed in European Patent 491226A Pyridyldihydroxyheptenoic acid; Seale's SC-45355 (3-substituted pentanedioic acid derivative); dichloroacetate; imvalazo of mevalonolactone disclosed in PCT application WO86 / 07054 Analogs; 3-carboxy-2-hydroxy-propane-phosphate derivatives disclosed in French Patent 2,596,393; 2,3-disubstituted pyrroles, furans, and thiophenes disclosed in European Patent Application No. 0221025 Derivatives; naphthyl analogues of mevalonolactone disclosed in US Pat. No. 4,686,237; octahydronaphthalenes as disclosed in US Pat. No. 4,499,289; keto of mevinolin (lovastatin) disclosed in European Patent Application No. 0,142,146A2 There are analogs; phosphinic acid compounds; as well as other HMG-CoA reductase inhibitors.

  Lovastatin is one of the most important known cholesterol lowering agents. Lovastatin (CAS Registry No. 75330-75-5), also known herein as mevinolin or monocolin K, is chemically beta, beta-dihydroxy-7- [ 1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-8- (2-methyl-butyryloxy) -1-naphthalen-1-yl] -heptanoic acid beta lactone is known. Lovastatin is one of a class of compounds commonly referred to as statins and is known to exist in ring-opening hydroxy acid and lactone forms.

  Lovastatin and its analogs inhibit HMG-CoA reductase. Lovastatin is particularly effective because, as a result of its application, biosynthetic intermediates with a toxic steroid skeleton formed late in biosynthesis do not accumulate. Lovastatin also increases the number of LDL receptors on the cell membrane surface, which removes LDL cholesterol circulating in the blood, thus inducing a decrease in plasma cholesterol levels.

  Lovastatin is routinely produced by fermentation and is a white, non-hygroscopic crystalline powder that is insoluble in water and slightly soluble in ethanol, methanol and acetonitrile.

  Lovastatin tablets are marketed as 10 mg, 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lovastatin, each tablet contains cellulose, lactose, magnesium stearate and starch. Butylated hydroxyanisole (BHA) is added as a preservative.

  Lovastatin is known in the art and is readily recognized by those skilled in the art. High LDL cholesterol is usually treated with exercise, weight loss in obese people, and diets low in cholesterol and saturated fat. If these methods do not work, a cholesterol-lowering agent (eg lovastatin) is added. The National Cholesterol Education Program (NCEP) has published treatment guidelines for the use of statins such as lovastatin. These treatment guidelines take into account LDL cholesterol levels, as well as other risk factors such as diabetes, hypertension, smoking, low HDL cholesterol levels, and family history of early coronary heart disease. The effectiveness of statin medications in lowering cholesterol is dose related. Blood cholesterol measurements are taken periodically during treatment to allow dose adjustment. A decrease in LDL cholesterol levels is seen 2 weeks after starting treatment with statins.

B. Surface Stabilizers Surface stabilizers that are particularly useful herein physically adhere to or bind to the surface of the nanoparticulate statin but do not chemically react with the statin particle or itself. Preferably, the individual molecules of the surface stabilizer are essentially free of intermolecular crosslinks.

  The selection of a surface stabilizer for statins is not a minor problem and extensive experimentation was required to achieve a favorable formulation of the desired therapeutic effect of the active ingredient. For example, the effectiveness of using a particular stabilizer with an active ingredient is unpredictable because stabilizers affect the dissolution and pharmacokinetic profile of statins, among other factors. The present invention therefore relates to the surprising discovery that stable and therapeutically effective nanoparticulate statin compositions can be produced.

  A combination of two or more surface stabilizers can preferably be used in the present invention. Useful natural surface stabilizers used in the present invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Suitable surface stabilizers include nonionic, anionic, cationic, and zwitterionic surfactants.

Representative examples of surface stabilizers include hydroxypropyl methylcellulose (anionic), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinic acid (anionic), gelatin, casein, lecithin (phosphatide), dextran, Gum arabic, cholesterol, tragacanth, stearate, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (eg, cetomacrotol 1000 Macrogol ether), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (eg commercially available tweens such as tweens) 20 (registered trademark) and Tween 80 (registered trademark) (ICI Specialty Chemicals)); polyethylene glycol (for example, Carbowax 3550 (registered trademark) and 934 (registered trademark) (Union Carbide)), polyoxyethylene stearate, colloid Silicon dioxide, phosphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), ethylene oxide and formaldehyde 4- (1,1,3,3-tetramethylbutyl) -phenolic polymer (also known as tyloxapol, superion and triton), poloxamer (eg For example, Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide), poloxamines (eg, Tetronic908®, poloxamine 908®) This is a tetrafunctional block copolymer obtained by continuously adding propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), Triton X-200®, which is an alkylaryl polyether sulfonate (Dow Chemical); Crodestas F-110®, which contains sucrose stearate and sucrose distearate. (Croda Inc.); p-isononylphenoxypoly- (glycidol), Ol also known as in-IOG® or surfactant 10-G® (Olin Chemicals, Stamford, Conn.); Crodetas SL-40® (Croda Inc.); and SA9OHCO, This is C ₁₈ H ₃₇ CH ₂ (CON (CH ₃ ) —CH ₂ (CHOH) ₄ (CH ₂ OH) ₂ (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl β-D-glucopyranoside; Octyl β-D-thioglucopyranoside; PEG-derivatized phospholipids; PEG-derivatized cholesterol PEG-derivatized cholesterol derivatives, PEG-derivatized vitamin A, PEG-derivatized vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, etc., eg Plasdone with a 60:40 ratio of pyrrolidone and vinyl acetate (registered) Trademark) S630.

  Additional examples of useful surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulose derivatives, alginate, phospholipids, and non-polymeric compounds such as zwitterionic stabilizers, poly-n-methylpyridinium, Anthrylpyridinium chloride, cationic phospholipid, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammonium bromide bromide (PMMTMABr), hexadecyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate There is dimethyl sulfate.

Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, Coconut trimethylammonium chloride or bromide, coconut methyl dihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or bromide, C _12-15 dimethylhydroxyethylammonium chloride or bromide, coconut dimethylhydroxyethylammonium chloride or bromide , Myristyltrimethylammonium methyl sulfate, lauryldimethylbenzylamine Niumukurorido or bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride or bromide, N- alkyl (C _12-18) dimethyl benzyl ammonium chloride, N- alkyl (C _14-18) dimethyl benzyl ammonium chloride, N- tetradecylcarbamoyl chloride methyl Benzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium and dialkyldimethylammonium salts, lauryltrimethylammonium chloride, Ethoxylated alkylamidoalkyldialkylammonium salts and / or ethoxylated trialkylammonium salts, dialkylbenzenedialkylammonium salts Lido, N- didecyl dimethyl ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, N- alkyl (C _12-14) dimethyl 1-naphthylmethyl ammonium chloride, and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium _{bromide, C 12, C 15, C} 17 trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - dialkyl dimethyl chloride (DADMAC), dimethyl ammonium Chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethyl Ruammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT336 (registered trademark)), POLYQUAT10 (registered trademark), tetrabutylammonium bromide , Benzyltrimethylammonium bromide, choline ester (eg choline ester of fatty acid), benzalkonium chloride, stearalkonium chloride compound (eg stearyltrimonium chloride and distearyldimonium chloride), cetylpyridinium bromide or chloride, quaternary polyoxy Halide salt of ethyl alkylamine, MIRAPOL® and ALKAQUAT® (Al karil Chemical Company), alkylpyridinium salts; amines such as alkylamines, dialkylamines, alkanolamines, polyethylene polyamines, NN-dialkylaminoalkyl acrylates, and vinylpyridines, amine salts such as laurylamine acetate, stearylamine acetate, alkylpyridinium salts , Alkyl imidazolium salts, and amine oxides; imidoazolinium salts; protonated quaternary acrylamides; methylated quaternary polymers such as poly [diallyldimethylammonium chloride], and poly [N-methylvinylpyridinium chloride]; and positive There is ionic guar.

  Examples of such cationic surface stabilizers and other useful cationic surface stabilizers are J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D Rubing (eds.), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry (Marcel Dekker, 1990).

The non-polymeric surface stabilizer is any non-polymeric compound such as benzalkonium chloride, carbonium compound, phosphonium compound, oxonium compound, halonium compound, cationic organometallic compound, quaternary phosphorus compound, pyridinium compound, There are anilinium compounds, ammonium compounds, hydroxylammonium compounds, _primary ammonium compounds of the formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ , secondary ammonium compounds, tertiary ammonium compounds, and quaternary ammonium compounds. For compounds of formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ :
(i) none of R _{1 to} R ₄ is CH ₃ ;
(ii) _{one of} R _{1 to} R ₄ is CH ₃ ;
(iii) three of R _{1 to} R ₄ are CH ₃ ;
(iv) R _{1 to} R ₄ are all CH ₃ ;
(v) Two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ is an alkyl chain of 7 or less carbon atoms. is there;
(vi) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ is an alkyl chain of 19 or more carbon atoms Is
(vii) two of R _{1 to} R ₄ are CH ₃ and one of R _{1 to} R _{4 is} a group C ₆ H ₅ (CH ₂ ) _n , where n>1;
(viii) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ contains at least one heteroatom;
(ix) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ contains at least one halogen;
(x) two of R _{1 to} R ₄ are CH ₃ , one of R _{1 to} R ₄ is C ₆ H ₅ CH ₂ , and one of R _{1 to} R ₄ includes at least one cyclic fragment;
(xi) two of R _{1 to} R ₄ are CH ₃ and one of R _{1 to} R ₄ is a phenyl ring;
(xii) Two of R _{1 to} R ₄ are CH ₃ and one of R _{1 to} R ₄ is a purely aliphatic fragment.

  Examples of such compounds include, but are not limited to, behairluconium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride, Chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyldimethylethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylamino Dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oleyl ether phosphate, diethanolammonium POE (3) oleyl ether phosphate, tallowalkonium chloride, dimethyldio Tadecylammonium bentonite, stearalkonium chloride, domifene bromide, denatonium benzoate, myristalkonium chloride, raurtrimonium chloride, ethylenediaminedihydrochloride, guanidine hydrochloride, pyridoxine HCl, isophetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, bromide Myritrimonium, oleyltrimonium chloride, polycaternium-1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkonium hectonite, stearyltrihydroxyethylpropylenediaminedihydrofluoride, tallowtrimonium chloride, and hexa There is decyltrimethylammonium bromide.

  Most of these surface stabilizers are known pharmaceutical excipients, jointly published by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000) The Handbook of Pharmaceutical Excipients, which is incorporated herein by reference.

  Surface stabilizers are commercially available and / or can be prepared by techniques known in the art.

C. Other Pharmaceutical Excipients The pharmaceutical composition of the present invention may also include one or more binders, fillers, lubricants, suspending agents, sweetening agents, flavoring agents, preservatives, buffering agents, wetting agents. , Disintegrants, foaming agents, and other excipients depending on the route of administration and the desired dosage form. Such excipients are known in the art.

  Examples of fillers are lactose monohydrate, anhydrous lactose, and various starches; examples of binders are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose such as Avicel® PH101 and Avicel® Trademarks PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC®).

  Suitable lubricants (including substances that affect the flowability of the powder to be tableted) are colloidal silicon dioxide, such as Aerosil® 200, talc, stearate, magnesium stearate, calcium stearate, and silica gel. is there.

  Examples of sweeteners are natural or artificial sweeteners such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and axulfame. Examples of flavoring agents are Magnasweet® (registered trademark of MAFCO), bubble gum flavor, fruit flavor and the like.

  Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid (eg butylparaben), alcohols (eg ethanol or benzyl alcohol), phenolic compounds ( For example, phenol) or a quaternary compound (for example, benzalkonium chloride).

  Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, calcium hydrogen phosphate, sugar, and / or any mixture thereof. Examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; lactose, such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; calcium hydrogen phosphate, For example, Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.

  Suitable disintegrants include lightly cross-linked polyvinyl pyrrolidone, corn starch, potato starch, corn starch, and modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof.

  Examples of blowing agents are organic acids and foamable combinations such as carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid and alginic acid, and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the foamable couple may be present.

D. Nanoparticle Statin Particle Size The compositions of the present invention contain nanoparticles, such as lovastatin or simvastatin nanoparticles, which have an effective average particle size of less than about 2000 nm (ie, 2 microns). In preferred embodiments of the invention, the statin nanoparticles have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, as measured by light dispersion, microscopy, or other suitable method. Less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, about 300 nm Less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm.

  “Effective average particle size of less than about 2000 nm” means that at least 50% of statin particles have a particle size that is smaller than the effective average by weight, ie, about 2000 nm, about 1900 nm, about 1800 nm, etc. Mean small. Preferably, at least about 70%, about 90%, about 95%, or about 99% of statin particles have a particle size that is smaller than the effective average, ie, less than about 2000 nm, about 1900 nm, about 1800 nm, and the like.

  In the present invention, the value for D50 of the nanoparticulate statin composition is the particle size under which 50% by weight of statin particles fall. Similarly, D90 is the particle size under which 90% by weight of statin particles are placed.

E. Concentration of nanoparticulate statin and surface stabilizer The relative amounts of at least one statin and one or more surface stabilizers vary widely. Optimal amounts of the individual components are, for example, the particular statin selected and one or more physical and chemical properties of the selected surface stabilizer (eg, hydrophilic / lipophilic balance (HLB) of an aqueous solution of the stabilizer, Melting point, surface tension, etc.).

  Preferably, the concentration of at least one statin is about 99.5% to about 0.001% by weight, preferably about about 1%, based on the combined weight of statin and at least one surface stabilizer (excluding other excipients). It may vary from 95% to about 0.1%, preferably from about 90% to about 0.5%. Higher concentrations of active ingredient are generally preferred from a dose and cost efficiency standpoint.

  Preferably, the concentration of at least one surface stabilizer is from about 0.5% to about 99.999% by weight, based on the total combined dry weight of statin and at least one surface stabilizer (without other excipients), Preferably it may vary from about 5.0% to about 99.9%, preferably from about 10% to about 99.5%.

  Examples of useful ratios of active ingredient to stabilizer are by weight, preferably about 1: 1, based on the total combined dry weight of statin and at least one surface stabilizer (without other excipients). Preferably about 2: 1, preferably about 3: 1, preferably about 4: 1, preferably about 5: 1, preferably about 6: 1, preferably about 7: 1, preferably about 8: 1, and Preferably it is about 10: 1.

III. Methods for Producing Nanoparticulate Statin Composition Nanoparticulate statin compositions can be produced using any suitable method known in the art, for example, grinding, homogenizing, or precipitation methods. A method for making nanoparticle compositions is described in the '684 patent. Methods for producing nanoparticle compositions are also described in US Patent No. 5,518,187, “Method of Grinding Drug Substance”, US Patent No. 5,718,388, “Continuous Grinding Method of Drug Substance”, and 5,862,999, “Method of Grinding Drug Substance”. , US Patent No. 5,665,331, “simultaneous microprecipitation of nanoparticulate drug with crystal growth modifier”, US Patent No. 5,662,883, “simultaneous microprecipitation of nanoparticulate drug with crystal growth modifier”, US Patent No. 5,560,932 , "Microprecipitation of nanoparticulate drugs", US Patent No. 5,543,133, "Method for producing X-ray contrast agent composition containing nanoparticles", US Patent No. 5,534,270, "Method for producing stable drug nanoparticles", US Patent No. 5,510,118, “Method for producing therapeutic composition containing nanoparticles”, and US Patent No. 5,470,583, “Method for producing nanoparticle composition containing charged phospholipids to reduce aggregation” Has been described.

  The resulting nanoparticulate statin composition or dispersion is a solid or liquid dosage form such as a liquid dispersion, gel, aerosol, ointment, cream, controlled release formulation, fast melt formulation, lyophilized formulation, tablet, capsule. Can be used in agents, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations. A solid dosage form of the dispersion of the novel statin formulation of the present invention can be prepared as described in US Patent No. 6,375,986.

A. Grinding to obtain a nanoparticulate statin dispersion Statin grinding to obtain a nanoparticulate statin dispersion involves dispersing statin particles in a liquid dispersion medium in which the statin is difficult to dissolve, and then in the presence of the grinding medium. Reducing the particle size of the statin to a desired effective average particle size using conventional means. The dispersion medium may be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.

  The statin particles can be reduced in size, preferably in the presence of at least one surface stabilizer. Alternatively, the statin particles can be contacted with one or more surface stabilizers after abrasion. Other compounds, such as diluents, may be added to the statin / surface stabilizer during the size reduction process. The dispersion can be produced continuously or batchwise.

B. Precipitation to obtain a nanoparticulate statin composition Another method of producing the desired nanoparticulate statin composition is by microprecipitation. This is a stable dispersion of an active substance that is difficult to dissolve in the presence of one or more surface stabilizers and one or more colloidal stability-enhancing surface active substances that do not contain trace amounts of toxic solvents or solubilized heavy metal impurities. It is a method of preparing. Such methods include, for example: (1) dissolving the statin in a suitable solvent; (2) adding the formulation from step (1) to a solution containing at least one surface stabilizer; (3) Precipitate the formulation from step (2) using a suitable non-solvent. Following this process, the salt formed, if present, is removed by dialysis or diafiltration, and the dispersion is concentrated by conventional methods.

C. Homogenization to obtain statin nanoparticle compositions Examples of homogenization methods for preparing active substance nanoparticle compositions are disclosed in US Patent No. 5,510,118, "Method for Producing Nanoparticle-Containing Treatment Composition" It is described in. Such a method disperses statin particles in a liquid dispersion medium in which the statin is difficult to dissolve, and then homogenizes the dispersion to reduce the statin particle size to the desired effective average particle size. The statin particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the statin particles may be contacted with one or more surface stabilizers before or after grinding. Other compounds, such as a diluent, may be added to the statin / surface stabilizer composition before, during or after the size reduction process. Dispersions can be produced continuously or batchwise.

IV. Uses of Statin Formulations of the Present Invention The statin compositions of the present invention can be prepared using any conventional method, including but not limited to, preferably oral, rectal, intraocular, parenteral (eg, intravenous, intramuscular, or It can be administered to a subject by subcutaneous), intracisternally, intrapulmonary, intravaginally, intraperitoneally, topically (including powders, ointments or drops) or buccal or nasal sprays. As used herein, “subject” is used to mean an animal, preferably a mammal (including a human or non-human). The terms patient and subject are used interchangeably.

  The present invention provides a method of prolonging plasma levels of a subject's statins while achieving a desired therapeutic effect. In one embodiment, such a method comprises orally administering to a subject an effective amount of a composition of the invention comprising a statin.

  In one embodiment, the compositions of the invention are useful for treating conditions directly or indirectly associated with elevated and / or uncontrolled cholesterol metabolism as described herein and known to those skilled in the art.

  Compositions suitable for parenteral injection contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Also good. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (polyethylene glycol, propylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (eg olive oil), and injections Organic esters such as ethyl oleate. The correct fluidity can be maintained, for example, using a coating such as lecithin, maintaining the required particle size in the case of dispersion, and using a surfactant.

  Nanoparticulate statin compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth is ensured by various antibiotics and antifungal agents (eg, parabens, chlorobutanol, phenol, sorbic acid, etc.). It may also contain isotonic substances such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form is brought about by the use of substances that delay absorption, for example, aluminum monostearate and gelatin.

  Solid dosage forms for oral administration are preferred and include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms the active substance (ie the composition of the invention) is admixed with at least one of the following: (a) one or more inert excipients (or carriers) such as (B) fillers or fillers such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (c) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, Sugar and gum arabic; (d) humectants such as glycerol; (e) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some complex silicates, and sodium carbonate; (f) Dissolution-retarding substances such as paraffin; (g) absorption-accelerating substances such as quaternary ammonium compounds; (h) wetting agents Cetyl alcohol and glycerol monostearate; (i) adsorbents such as kaolin and bentonite; and (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof . For capsules, tablets, and pills, the dosage forms may also contain buffering agents.

  Liquid dosage forms for oral administration include pharmaceutically acceptable dispersions, emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active substance, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Examples of emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (eg cottonseed oil, peanut oil, corn germ oil, Olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

  In addition to such inert diluents, the composition may also contain adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.

  Effective amounts of the statin compositions of the present invention are determined empirically and are used in pure form or, if such forms exist, pharmaceutically acceptable salt, ester or prodrug forms Can be used in The actual dosage level of statins in the nanoparticle compositions of the invention will vary to obtain an effective amount of statins to obtain the desired therapeutic response for the particular composition and method of administration and condition being treated. May be. The selected dose level will therefore depend on the desired therapeutic effect, the route of administration, the potency of the administered statin, the desired duration of treatment, and other factors.

  A unit dosage composition may contain a fraction of that to make a daily dose. However, the specific dosage level for a particular patient will depend on various factors: the type and extent of the cellular or physiological response achieved; the activity of the specific substance or composition used. The specific substance or composition used; the patient's age, weight, general health, sex, and diet; administration time, route of administration, and excretion rate of the substance; treatment period; in combination with the specific substance or Drugs used together; similar factors known in the medical field.

V. Statin Combinations The statin compositions of the present invention are also particularly useful when administered in accordance with the methods of the present invention with a therapeutically effective amount of at least one other active agent that is useful in the following: Treatment of symptoms including lipemia, hyperlipidemia, hypercholesterolemia, cardiovascular disease, hypertriglyceridemia, coronary heart disease, and peripheral vascular disease (including symptomatic carotid artery disease), or related symptoms ; (2) Adjunctive therapy to diet for lowering LDL-C, total C, triglycerides, and / or apo B in adult patients (Fredrickson IIa and IIb) with hypercholesterolemia or mixed dyslipidemia (3) Adjunct therapy to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson IV and V hyperlipidemia); (4) Treatment of pancreatitis; (5) Treatment of restenosis; / Or (6) a Treatment of Tsuhaima disease.

  Examples of non-statin compositions useful in the claimed invention include, but are not limited to, cholesterol-lowering agents, policosanols, alkanoyl L-carnitines, antihypertensive agents, sterols and / or stanols.

  Useful cholesterol-lowering agents are known to those skilled in the art and include, but are not limited to, ACE inhibitors, nicotinic acid, niacin, bile acid sequestering agents, fibrates, vitamins, fatty acid derivatives (eg fish oil), long chain plant extract alcohols ( For example, polycosinol), ezetimibe, and cellulose.

  Useful policosanols include, but are not limited to, triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, tetracontanol, or natural products or products containing such compounds There is an extract of

  Useful alkanoyl L-carnitines include, but are not limited to, acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine, and isovaleryl L-carnitine, or their pharmaceutically acceptable There is salt.

  Examples of antihypertensive agents include, but are not limited to, diuretics (“drugs”), β blockers, α blockers, α-β blockers, sympathetic nerve inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, angiotensin. There is a receptor blocker (formally known as the angiotensin-2-receptor antagonist, known as “sartans” for short).

  Examples of sterols and stanols include, but are not limited to, plant sterols, plant sterol esters, fish oil, sitosterol, sitostanol, phytosterol, campestanol, stigmasterol, coprostanol, cholestanol, β-sitosterol and the like.

  As used herein, “stanol” includes plant stanol esters, which are food ingredients that help lower LDL cholesterol. Plant stanols are obtained from naturally occurring substances in plants by methods known to those skilled in the art. Stanols are often combined with small amounts of canola to produce stanol esters, producing ingredients that are used in a variety of foods and in combination with the compositions of the present invention.

  The following examples are intended to illustrate the present invention. However, it should be understood that the invention is not limited to the specific conditions or details described in these examples. Throughout this specification, all documents and publicly available documents, including US patents, are incorporated herein by reference.

  In the following examples, particle size was measured using a Horiba LA-910 laser dispersed particle size distribution analyzer (Horiba Instruments, Irvine, CA). The particle average and D90 (which is the size under which 90% of the distribution is present) are obtained from the weight distribution. Furthermore, all formulations are given in weight% (w / w).

  Some formulations in the following examples were also tested using a light microscope.

  The purpose of this example is to prepare a nanoparticulate dispersion of lovastatin and test the prepared composition for stability at various temperatures.

  The lovastatin formulation, as shown in Table 1, under high energy grinding conditions with DYNO®-Mill KDL (Willy A. Bachofen AG, Maschinenfabrik, Basle, Switzerland) until the desired particle size is achieved, The compound of the composition was ground for 2-3 hours.

  Formulation 1 is 5% (w / w) lovastatin, 1.25% (w / w) hydroxypropylcellulose, ultra-low viscosity grade (HPC-SL), and 0.05% (w / w) dioctyl sodium sulfosuccinate (DOSS) Contained.

  Formulation 2 contained 5% (w / w) lovastatin, 1.25% (w / w) hydroxypropylmethylcellulose (HPMC), and 0.05% (w / w) dioctyl sodium sulfosuccinate (DOSS).

  Formulation 3 consists of 5% (w / w) lovastatin, 1.25% (w / w) povidone USP, Plasdon® K29 / 52 (PVPK29 / 32), and 0.05% (w / w) dioctyl sodium sulfosuccinate (DOSS) was contained.

  Formulation 4 contained 5% (w / w) lovastatin, 1.25% (w / w) Plasdon® S630 (S630), and 0.05% (w / w) dioctyl sodium sulfosuccinate (DOSS).

The particle size of the resulting composition was measured using a Horiba LA-910 laser dispersed particle size distribution analyzer (Horiba Instruments, Irvine, CA).

  The results of this experiment indicate that all formulations or compositions were stable.

  As described in the literature (Pharmazie, Volume 56, September 2001, P738-740), lovastatin has the potential for oxidative degradation. To examine which formulation showed the least degradation product, the composition prepared in Example 1 was subjected to HPLC analysis.

  This method is a reverse phase HPLC method based on the existing assay method in the literature (Pharmazie, Vol. 56, September 2001, P738-740). The experimental results of these samples were compared to an active drug ingredient (API) (commercially available lovastatin) standard to determine which ground sample had the least oxidation.

  Analysis was performed after 4-5 weeks of storage. Four different samples were compared to API standards. For this comparison, these factors were used to determine which formulation was optimal: (1) percent lovastatin, (2) overall appearance of impurity profile, and (3) peak area at RRT 0.87 percent. This peak was chosen because it had the largest peak for all impurities and appeared to increase as the area of lovastatin decreased.

  Formulation # 2 containing HPMC was most consistent with the API standard. All had similar impurities, percent lovastatin, and peak areas comparable to RRT 0.87. The sample containing PVP K29 / 32 had the highest impurities and lowest lovastatin, and the highest peak area at RRT 0.87.

  The results of this experiment showed that the formulation containing HPMC gave the best impurity profile. No significant difference from the lovastatin API profile was observed, indicating that oxidative degradation that occurred during grinding or subsequent storage was minimal.

  The purpose of this example is to evaluate the effect of the nanoparticulate lovastatin composition.

  New Zealand white rabbits were fed a diet enriched with 1% cholesterol for 4 weeks. At 4 weeks, the animals were maintained on a high cholesterol diet, but with a suspension of 6 mg / kg dose of Formulation # 2 (Example 1) or Formulation # 2 daily for 4 additional weeks (with food). Commercially available lovastatin (Mevacor®) tablets mixed in a mortar into a crude suspension containing the same amounts of HPMC and DOSS were administered.

Blood samples for total cholesterol analysis were taken at -2, 0, 2, and 4 weeks after administration. The total change in cholesterol in each group was as follows:
1. Mevacor® mortar mixed tablets administered as liquid suspension: -17.8% (N = 6)
2. Formulation # 2 administered as a liquid suspension: -23.2% (N = 8)
3. Placebo administered as a liquid suspension: -12.3 (N = 4)
4. Meal enriched with 1% cholesterol (not administered): +0.10 (N = 4)
Blood samples for liver activity (37.8 U ALAT liver enzyme activity) showed the following percentage of rabbits that were 3 × higher than normal levels as follows:
1. Mevacor® mortar mixed tablets administered as liquid: 20% (N = 6)
2. Formulation # 2 administered as a liquid suspension: 7.6% (N = 8)
3. Placebo administered as a liquid: 0 (N = 4)
The results show that formulation # 2 shows a greater effect and a lower tendency to hepatotoxicity than the other two groups measured.

  It will be apparent to those skilled in the art that various modifications and variations can be made to the method and composition of the present invention without departing from the spirit or scope of the invention. The present invention includes modifications and variations of the present invention within the scope of the appended claims and their equivalents.

Claims (108)

A statin composition comprising:
(a) particles of at least one statin or salt thereof having an effective average particle size of less than about 2000 nm; and
(b) at least one surface stabilizer.   2. The composition of claim 1, wherein the statin is atorvastatin; 6- [2- (substituted pyrrol-1-yl) alkyl] pyran-2-one and derivatives other than atorvastatin; lovastatin; keto analog of mevinolin other than lovastatin Body: pravastatin; simvastatin; verostatin; fluindostatin; pyrazole analog of mevalonolactone derivative; rivastatin; pyridyldihydroxyheptenoic acid other than rivastatin; SC-45355; dichloroacetate; imidazole analog of mevalonolactone; -Propane-phosphate derivatives; 2,3-disubstituted pyrrole derivatives; 2,3-disubstituted furan derivatives; 2,3-disubstituted thiophene derivatives; naphthyl analogues of mevalonolactone; octahydronaphthalenes; phosphinic acid compounds The above composition selected from the group.   The composition of claim 1 or claim 2, wherein the statin is lovastatin or simvastatin.   4. The composition of any one of claims 1-3, wherein the statin is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.   5. The composition of any one of claims 1-4, wherein the effective average particle size of the statin particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, Less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, about 200 nm Less than, less than about 150 nm, less than about 100 nm, less than about 75 nm, less than about 50 nm.   6. The composition of any one of claims 1-5, comprising oral, pulmonary, rectal, intraocular, colon, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, intranasal and The composition described above, formulated for administration selected from the group consisting of topical administration.   A composition according to any one of claims 1 to 6, comprising a liquid dispersion, an oral suspension, a gel, an aerosol, an ointment, a cream, a controlled release formulation, a fast melt formulation, a lyophilized formulation, The above composition formulated into a dosage form selected from the group consisting of tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release reaction mixtures and controlled release formulations.   8. The composition of any one of claims 1-7, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or combinations thereof.   9. The composition of any one of claims 1 to 8, wherein the at least one statin or salt thereof is a total combination of the statin or salt thereof and at least one surface stabilizer (without other excipients). The composition of claim 1, wherein the composition is present in an amount selected from the group consisting of about 99.5% to about 0.001%, about 95% to about 0.1%, and about 90% to about 0.5% by weight.   10. The composition of any one of claims 1-9, wherein the at least one surface stabilizer is based on the total combined dry weight of statin and at least one surface stabilizer (excluding other excipients). Wherein the composition is present in an amount selected from the group consisting of about 0.5% to about 99.999%, about 5.0% to about 99.9%, and about 10% to about 99.5% by weight.   11. A composition according to any one of the preceding claims comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.   The surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. Item composition.   13. The composition of claim 12, wherein the at least one surface stabilizer is cetylpyridinium chloride, gelatin, casein, phosphatide, dextran, gum arabic, cholesterol, tragacanth, stearate, benzalkonium chloride, calcium stearate, monostearin Acid glycerol, cetostearyl alcohol, cetomacrogol emulsified wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, Colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypro Cellulose, hypromellose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4- (1,1 of ethylene oxide and formaldehyde , 3,3-tetramethylbutyl) -phenol polymer, poloxamer; poloxamine; charged phospholipid, dioctylsulfosuccinate, dialkyl ester of sodium sulfosuccinate, sodium lauryl sulfate, alkylaryl polyether sulfonate, sucrose stearate and distearic acid Mixture with sucrose, p-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glu Copyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl β-D-glucopyranoside; n-heptyl β -D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl β-D-glucopyranoside; octyl The above composition selected from the group consisting of β-D-thioglucopyranoside; lysozyme; PEG-phospholipid; PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, and a random copolymer of vinyl acetate and vinylpyrrolidone.   13. The composition of claim 12, wherein the at least one cationic surface stabilizer is selected from the group consisting of polymers, biopolymers, polysaccharides, cellulose derivatives, alginate, non-polymeric compounds, and phospholipids. 13. The composition of claim 12, wherein the surface stabilizer is a cationic lipid, polymethyl methacrylate trimethyl ammonium bromide, sulfonium compound, polyvinyl pyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyl trimethyl ammonium bromide, phosphonium compound. Quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyl dihydroxyethylammonium chloride, coconut methyl dihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxy Ethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium Um chloride bromide, C _12-15 dimethylhydroxyethylammonium chloride, C _12-15 dimethylhydroxyethylammonium chloride bromide, coconut dimethylhydroxyethylammonium chloride, coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammonium methyl sulfate, lauryldimethylbenzylammonium chloride , Lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N-alkyl (C _12-18 ) dimethyl benzyl ammonium chloride, N-alkyl (C _14-18 ) dimethyl benzyl Ammonium chloride, N-tetradecylidomethylbenzylammonium chloride monohydrate, dimethyl Decyl ammonium chloride, N- alkyl and (C _12-14) dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl trimethyl ammonium salt, dialkyl dimethyl ammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkylamine ammonium salts, Ethoxylated trialkylammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride, monohydrate, N-alkyl (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride , Dodecyldimethylbenzylammonium chloride, dialkylbenzene alkylammonium chloride, lauryltrimethylammonium Chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide ,, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - dialkyl dimethyl chloride (DADMAC), dimethyl Ammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT10 (registered trademark), tetrabutylammonium bromide, benzyltrimethyl Ammonium bromide Amide, choline ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, cetylpyridinium chloride, quaternary polyoxyethylalkylamine halide salt, MIRAPOL (registered trademark), ALKAQUAT (registered trademark), alkylpyridinium salt Said composition selected from the group consisting of amines, amine salts, amine oxides, imidoazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guars.   16. A composition according to any of claims 12, 14, or 15, wherein the composition is bioadhesive.   The composition of any one of claims 1 to 16, comprising hydroxypropylmethylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers.   18. The composition of any one of claims 1 to 17, wherein the Tmax of the statin is less than the conventional non-nanoparticulate Tmax of the same statin administered at the same dose as measured in the plasma of the mammalian subject after administration.   20. The composition of claim 18, wherein the Tmax is about 90% or less, about 80% or less, about 70% or less, about 60% or less of the Tmax exhibited by the same statin non-nanoparticle formulation administered at the same dose. , About 50% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, and about 10% or less.   20. The composition of any one of claims 1-19, wherein the Cmax of the statin is greater than the conventional non-nanoparticulate Cmax of the same statin administered at the same dose as measured in plasma of the mammalian subject after administration.   21. The composition of claim 20, wherein the Cmax is at least about 10%, at least about 20%, at least about 30%, at least about 40 than the Cmax exhibited by a non-nanoparticle formulation of the same statin administered at the same dose. %, At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100%.   22. The composition of any one of claims 1-21, wherein the AUC of the statin is greater than the conventional non-nanoparticulate AUC of the same statin administered at the same dose as measured in the plasma of the mammalian subject after administration. The above composition.   23. The composition of claim 22, wherein the AUC is at least about 10%, at least about 20%, at least about 30%, at least about 40% than the AUC exhibited by a non-nanoparticulate formulation of the same statin administered at the same dose. At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100%.   24. The composition of any one of claims 1 to 23, wherein the composition does not produce significantly different absorption levels when administered in a fed state compared to a fasted state.   25. The composition of claim 24, wherein when administered in a fed state to a fasted state, the difference in absorption of the statin composition of the present invention is less than about 100%, less than about 90%, about Less than 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, about The above composition selected from the group consisting of less than 5% and less than about 3%.   26. The administration of a composition according to any one of claims 1 to 25, wherein when administered to a human, the administration of the composition to a fasted subject is bioequivalent to the administration of the composition to a dieted subject. Composition.   27. The composition of claim 26, wherein "bioequivalence" is established by a 90% confidence interval (CI) between 0.80 and 1.25 for both Cmax and AUC when administered to a human.   27. The composition of claim 26, wherein when administered to a human, "bioequivalence" is established with a 90% confidence interval of 0.80 to 1.25 for AUC and a 90% confidence interval of 0.70 to 1.43 for Cmax.   29. The composition of any one of claims 1-28, wherein at least about 20% of the composition dissolves within about 5 minutes, the dissolution is measured in a discriminating medium, and the dissolution is measured. The above composition, wherein the rotating blade method (European Pharmacopoeia) is used.   30. The composition of claim 29, wherein at least about 30% or at least about 40% of the composition dissolves within about 5 minutes.   30. The composition of claim 29, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns.   32. The composition of any one of claims 1-31, wherein at least about 40% of the composition dissolves within about 10 minutes, the dissolution is measured in a discriminating medium, and the dissolution is measured. The above composition, wherein the rotating blade method (European Pharmacopoeia) is used.   35. The composition of claim 32, wherein at least about 50%, about 60%, about 70%, or about 80% of the composition dissolves within about 10 minutes.   35. The composition of claim 32, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns.   35. The composition of any one of claims 1-34, wherein at least about 70% of the composition dissolves within about 20 minutes, the dissolution is measured in a discriminating medium, and the dissolution is measured. The above composition, wherein the rotating blade method (European Pharmacopoeia) is used.   36. The composition of claim 35, wherein at least about 80%, about 90%, or about 100% of the composition dissolves within about 20 minutes.   36. The composition of claim 35, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns. 38. The composition of any one of claims 1-37, further comprising one or more non-statin active substances selected from the group consisting of:
(a) an active substance useful for treating dyslipidemia;
(b) an active substance useful for treating hyperlipidemia;
(c) an active substance useful for treating hypercholesterolemia;
(d) an active substance useful for treating cardiovascular disease;
(e) an active substance useful for treating hypertriglyceridemia;
(f) an active substance useful for treating coronary heart disease;
(g) an active substance useful for treating peripheral vascular disease;
(h) Adjunct to diet for lowering LDL-C, total C, triglycerides, and / or apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa and IIb) Active substances useful as therapy;
(i) an active substance useful as an adjunct to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson IV and V hyperlipidemia);
(j) an active substance useful for treating pancreatitis;
(k) an active substance useful for treating restenosis; and
(l) An active substance useful for treating Alzheimer's disease.   39. Any one of the non-statin active substances selected from the group consisting of cholesterol lowering agents, policosanols, alkanoyl L-carnitines, antihypertensive agents, sterols and / or stanols. Item composition.   40. The composition of claim 39, wherein the cholesterol-lowering agent is selected from the group consisting of ACE inhibitors, nicotinic acid, niacin, bile acid sequestering agents, fibrates, vitamins, fatty acid derivatives, long chain plant extract alcohols, ezetimibe, and cellulose. Stuff.   Policosanol consists of (1) triacontanol, (2) hexacontanol, (3) ecocosanol, (4) hexacosanol, (5) tetracosanol, (6) dotriacontanol, (7) tetracontanol, (8) natural products including triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, tetracontanol; and (9) triacontanol, hexacontanol, ecocosanol, hexacosanol, 40. The composition of claim 39, selected from the group consisting of tetracosanol, dotriacontanol, an extract from a natural product comprising tetracontanol.   The antihypertensive agent is selected from the group consisting of diuretics, beta blockers, alpha blockers, alpha-beta blockers, sympathetic inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin receptor blockers. 39 compositions.   40. The composition of claim 39, wherein the sterol is selected from the group consisting of plant sterols, plant sterol esters, sitosterol, sitostanol, fish oil, phytosterols, campestanol, stigmasterol, coprostanol, cholestanol, β-sitosterol.   44. The composition of any one of claims 39-43, wherein the at least one non-statin compound has an effective average particle size greater than about 2 microns.   44. The composition of any one of claims 39 to 43, wherein the at least one non-statin compound has an effective average particle size of less than about 2 microns.   46. The composition of any one of claims 1-45, wherein upon administration, the composition redisperses and the statin particles are less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, Less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, about 300 nm Less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and having an effective average particle size selected from the group consisting of less than about 50 nm.   46. The composition of any one of claims 1-45, wherein the composition is redispersed in a biorelevant medium so that the statin particles are less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, Less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, about 400 nm Less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and having an effective average particle size selected from the group consisting of less than about 50 nm .   Contacting the particles of at least one statin or salt thereof with at least one surface stabilizer for a time and under conditions sufficient to provide a statin composition having an effective average particle size of less than about 2000 nm. A method for producing the composition.   49. The method of claim 48, wherein the contacting comprises grinding.   50. The method of claim 49, wherein the contacting comprises wet grinding.   49. The method of claim 48, wherein the contacting comprises homogenization. 49. The method of claim 48, wherein the contacting comprises:
(a) dissolving particles of a statin or a salt thereof in a solvent;
(b) adding the resulting statin solution to a solution comprising at least one surface stabilizer; and
(c) Precipitating solubilized statin having at least one surface stabilizer adsorbed on its surface by adding a non-solvent thereto.   53. The method of any one of claims 48 to 52, wherein the statin is atorvastatin; 6- [2- (substituted pyrrol-1-yl) alkyl] pyran-2-one and derivatives other than atorvastatin; lovastatin; lovastatin Kevin analog of mevinolin other than pravastatin; simvastatin; verostatin; fluindostatin; pyrazole analog of mevalonolactone derivative; rivastatin; pyridyl dihydroxyheptenoic acid other than rivastatin; SC-45355; dichloroacetate; imidazole analog of mevalonolactone -Carboxy-2-hydroxy-propane-phosphate derivatives; 2,3-disubstituted pyrrole derivatives; 2,3-disubstituted furan derivatives; 2,3-disubstituted thiophene derivatives; naphthyl analogues of mevalonolactone; octahydronaphthalenes Selected from the group consisting of phosphinic acid compounds; The above method.   54. The method of any one of claims 48 to 53, wherein the statin is lovastatin or simvastatin.   55. The method of any one of claims 48 to 54, wherein the statin or salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.   56. The method of any one of claims 48-55, wherein the effective average particle size of the statin particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, about Less than 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm , Less than about 150 nm, less than about 100 nm, less than about 75 nm, less than about 50 nm.   57. The method of any one of claims 48 to 56, comprising oral, pulmonary, rectal, intraocular, colon, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, intranasal and topical. A method as described above, wherein the method is formulated for administration selected from the group consisting of clinical administration.   58. The method of any one of claims 48-57, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or combinations thereof.   59. The method of any one of claims 48 to 58, wherein the statin or salt thereof is based on the total combined weight of the statin or salt thereof and at least one surface stabilizer (excluding other excipients). Wherein the method is present in an amount selected from the group consisting of about 99.5% to about 0.001% by weight, about 95% to about 0.1%, and about 90% to about 0.5%.   60. The method of any one of claims 48-59, wherein the at least one surface stabilizer is a combined dry weight of a statin or salt thereof and at least one surface stabilizer (without other excipients). Wherein the method is present in an amount selected from the group consisting of about 0.5% to about 99.999%, about 5.0% to about 99.9%, and about 10% to about 99.5% by weight.   61. The method of any one of claims 48-60, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.   62. The surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. Section method.   63. The method of claim 62, wherein the at least one surface stabilizer is cetylpyridinium chloride, gelatin, casein, phosphatide, dextran, gum arabic, cholesterol, tragacanth, stearate, benzalkonium chloride, calcium stearate, monostearic acid Glycerol, cetostearyl alcohol, cetomacrogol emulsified wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloid Silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropy Cellulose, hypromellose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde 4- (1,1, 3,3-tetramethylbutyl) -phenol polymer, poloxamer; poloxamine; charged phospholipid, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinate, sodium lauryl sulfate, alkylaryl polyether sulfonate, stearate sucrose and distearate sucrose Mixture with sugar, p-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-gluco N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl β-D-glucopyranoside; n-heptyl β -D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl β-D-glucopyranoside; octyl The above method, selected from the group consisting of β-D-thioglucopyranoside; lysozyme; PEG-phospholipid; PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, and a random copolymer of vinyl acetate and vinylpyrrolidone.   64. The method of claim 62, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulose derivative, an alginate, a non-polymeric compound, and a phospholipid. The method of claim 62, wherein the surface stabilizer is a cationic lipid, polymethylmethacrylate trimethylammonium bromide, sulfonium compound, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethylammonium bromide, phosphonium compound, Quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyldihydroxyethylammonium chloride, coconut methyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethyl Ammonium chloride, decyldimethylhydroxyethyl ammonium Muclide bromide, C _12-15 dimethylhydroxyethylammonium chloride, C _12-15 dimethylhydroxyethylammonium chloride bromide, coconut dimethylhydroxyethylammonium chloride, coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammonium methyl sulfate, lauryldimethylbenzylammonium chloride , Lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N-alkyl (C _12-18 ) dimethyl benzyl ammonium chloride, N-alkyl (C _14-18 ) dimethyl benzyl Ammonium chloride, N-tetradecylide methylbenzylammonium chloride monohydrate, dimethyldi Sill ammonium chloride, N- alkyl and (C _12-14) dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl trimethyl ammonium salt, dialkyl dimethyl ammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkylamine ammonium salts, Ethoxylated trialkylammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride, monohydrate, N-alkyl (C _12-14 ) dimethyl 1-naphthylmethylammonium chloride , Dodecyldimethylbenzylammonium chloride, dialkylbenzene alkylammonium chloride, lauryltrimethylammonium chloride Rorido, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide ,, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - dialkyl dimethyl chloride (DADMAC), dimethyl Ammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT10 (registered trademark), tetrabutylammonium bromide, benzyltrimethyl Ammonium bromi , Choline ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, cetylpyridinium chloride, quaternary polyoxyethylalkylamine halide salt, MIRAPOL (registered trademark), ALKAQUAT (registered trademark), alkylpyridinium salt A process as described above, selected from the group consisting of amines, amine salts, amine oxides, imidoazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar;   66. The method of any of claims 62, 64, or 65, wherein the composition is bioadhesive.   67. A method according to any one of claims 48 to 66, comprising hydroxypropylmethylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers. A method of treating a subject in need, comprising administering to the subject an effective amount of a composition comprising:
(a) statins particles having an effective average particle size of less than about 2000 nm, statins or salts thereof; and
(b) at least one surface stabilizer bound to the surface of the statin particles.   69. The method of claim 68, wherein the statin is atorvastatin; 6- [2- (substituted pyrrol-1-yl) alkyl] pyran-2-one and derivatives other than atorvastatin; lovastatin; keto analogs of mevinolin other than lovastatin Simvastatin; verostatin; fluindostatin; pyrazole analogues of mevalonolactone derivatives; rivastatin; pyridyldihydroxyheptenoic acid other than rivastatin; SC-45355; dichloroacetate; imidazole analogue of mevalonolactone; 3-carboxy-2-hydroxy -Propane-phosphate derivatives; 2,3-disubstituted pyrrole derivatives; 2,3-disubstituted furan derivatives; 2,3-disubstituted thiophene derivatives; naphthyl analogues of mevalonolactone; octahydronaphthalenes; phosphinic acid compounds The method described above, selected from the group.   70. The method of claim 68 or claim 69, wherein the statin is lovastatin or simvastatin.   71. The method of any one of claims 68-70, wherein the statin or salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.   72. The method of any one of claims 68-71, wherein the effective average particle size of the statin particles is less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, about Less than 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm , Less than about 150 nm, less than about 100 nm, less than about 75 nm, less than about 50 nm.   75. The method of any one of claims 68-72, comprising oral, pulmonary, rectal, intraocular, non-colon, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, intranasal and A method as described above, formulated for administration selected from the group consisting of topical administration.   74. The method of any one of claims 68 to 73, wherein the composition comprises a liquid dispersion, oral suspension, gel, aerosol, ointment, cream, controlled release formulation, fast melt formulation, freezing. The method as described above, which is a dosage form selected from the group consisting of dry formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release reaction mixtures and controlled release formulations.   75. The method of any one of claims 68-74, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or combinations thereof.   76. The method of any one of claims 68-75, wherein the statin or salt thereof is based on the total combined weight of the statin or salt thereof and at least one surface stabilizer (excluding other excipients). Wherein the method is present in an amount selected from the group consisting of about 99.5% to about 0.001% by weight, about 95% to about 0.1%, and about 90% to about 0.5%.   77. The method of any one of claims 68-76, wherein the at least one surface stabilizer is a combined dry weight of a statin or salt thereof and at least one surface stabilizer (without other excipients). Wherein the method is present in an amount selected from the group consisting of about 0.5% to about 99.999%, about 5.0% to about 99.9%, and about 10% to about 99.5% by weight.   78. The method of any one of claims 68-77, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.   79. The surface stabilizer is any one of claims 68 to 78 selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. Section method.   80. The method of claim 79, wherein the at least one surface stabilizer is cetylpyridinium chloride, gelatin, casein, phosphatide, dextran, gum arabic, cholesterol, tragacanth, stearate, benzalkonium chloride, calcium stearate, monostearic acid Glycerol, cetostearyl alcohol, cetomacrogol emulsified wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloid Silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropy Cellulose, hypromellose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde 4- (1,1, 3,3-tetramethylbutyl) -phenol polymer, poloxamer; poloxamine; charged phospholipid, dioctyl sulfosuccinate, dialkyl ester of sodium sulfosuccinate, sodium lauryl sulfate, alkylaryl polyether sulfonate, stearate sucrose and distearate sucrose Mixture with sugar, p-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl β-D-gluco N-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl β-D-glucopyranoside; n-heptyl β -D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl β-D-glucopyranoside; octyl The above method, selected from the group consisting of β-D-thioglucopyranoside; lysozyme; PEG-phospholipid; PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, and a random copolymer of vinyl acetate and vinylpyrrolidone.   80. The method of claim 79, wherein the at least one cationic surface stabilizer is selected from the group consisting of polymers, biopolymers, polysaccharides, cellulose derivatives, alginate, non-polymeric compounds, and phospholipids. 80. The method of claim 79, wherein the surface stabilizer is benzalkonium chloride, cationic lipid, polymethyl methacrylate trimethyl ammonium bromide, polyvinyl pyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyl trimethyl ammonium bromide, positive Ionic lipids, sulfonium compounds, phosphonium compounds, quaternary ammonium compounds, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride, coconut trimethylammonium bromide, coconut methyl dihydroxyethylammonium chloride, coconut methyl dihydroxyethylammonium bromide Decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride, Sildimethylhydroxyethylammonium chloride bromide, C _12-15 dimethylhydroxyethylammonium chloride, C _12-15 dimethylhydroxyethylammonium chloride bromide, coconut dimethylhydroxyethylammonium chloride, coconut dimethylhydroxyethylammonium bromide, myristyltrimethylammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) ₄ ammonium chloride, lauryl dimethyl (ethenoxy) ₄ ammonium bromide, N- alkyl (C _12-18) dimethyl benzyl ammonium chloride, N- alkyl (C _{14- 18)} dimethyl benzyl ammonium chloride, N- tetradecylcarbamoyl chloride methylbenzyl Nmo chloride monohydrate, dimethyl didecyl ammonium chloride, N- alkyl and (C _12-14) dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl trimethyl ammonium salt, dialkyl dimethyl ammonium salts, lauryl trimethyl ammonium chloride, ethoxylated Alkylamide alkyldialkylammonium salt, ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride, monohydrate chloride, N-alkyl (C _12-14 ) Dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylbenzene alkylammonium chloride Chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C ₁₂ trimethyl ammonium bromide ,, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecyl benzyl triethyl ammonium chloride, poly - dialkyl dimethyl ammonium chloride (DADMAC), dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT10 (registered trademark), tetrabutyl Ammonium bromide , Benzyltrimethylammonium bromide, choline ester, benzalkonium chloride, stearalkonium chloride compound, cetylpyridinium bromide, cetylpyridinium chloride, quaternary polyoxyethylalkylamine halide salt, MIRAPOL (registered trademark), ALKAQUAT (registered trademark) An alkylpyridinium salt; an amine, an amine salt, an amine oxide, an imidoazolinium salt, a protonated quaternary acrylamide, a methylated quaternary polymer, and a cationic guar.   83. The method of any one of claims 79, 81, or 82, wherein the composition is bioadhesive.   84. A method according to any one of claims 68 to 83, comprising hydroxypropylmethylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers.   85. The method of any one of claims 68-84, wherein when administered to a human, administration of the statin composition does not produce significantly different absorption levels when administered in a fed state compared to a fasted state. Method.   86. The method of claim 85, wherein when administered in a fed state to a fasted state, the difference in absorption of the statin composition of the present invention is less than about 100%, less than about 90%, about 80 %, Less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, about 5 %, And selected from the group consisting of less than about 3%.   87. The administration of any one of claims 68-86, wherein when administered to a human, administration of the composition to a fasted subject is bioequivalent to administration of the composition to a fed subject. Method.   90. The method of claim 87, wherein "bioequivalence" is established by a 90% confidence interval (CI) between 0.80 and 1.25 for both Cmax and AUC when administered to a human.   88. The method of claim 87, wherein when administered to a human, "bioequivalence" is established with a 90% confidence interval of 0.80 to 1.25 for AUC and a 90% confidence interval of 0.70 to 1.43 for Cmax.   90. The method of any one of claims 68-89, wherein the Tmax of the statin is less than the conventional non-nanoparticulate Tmax of the same statin administered at the same dose as measured in plasma of the mammalian subject after administration.   90. The method of claim 90, wherein Tmax is about 90% or less, about 80% or less, about 70% or less, about 60% or less of Tmax exhibited by a non-nanoparticle formulation of the same statin administered at the same dose, The above method, selected from the group consisting of about 50% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, and about 10% or less.   92. The method of any one of claims 68-91, wherein the Cmax of the statin is greater than the conventional non-nanoparticulate Cmax of the same statin administered at the same dose as measured in the plasma of the mammalian subject after administration.   94. The method of claim 92, wherein Cmax is at least about 10%, at least about 20%, at least about 30%, at least about 40% greater than Cmax exhibited by a non-nanoparticle formulation of the same statin administered at the same dose. At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100%.   94. The method of any one of claims 68-93, wherein the AUC of the statin is greater than the conventional non-nanoparticulate AUC of the same statin administered at the same dose as measured in the plasma of the mammalian subject after administration. , The above method.   95. The method of claim 94, wherein the AUC is at least about 10%, at least about 20%, at least about 30%, at least about 40% greater than the AUC exhibited by a non-nanoparticle formulation of the same statin administered at the same dose, The method described above, selected from the group consisting of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100%. 96. The method of any one of claims 68-95, further comprising one or more non-statin active substances selected from the group consisting of:
(a) an active substance useful for treating dyslipidemia;
(b) an active substance useful for treating hyperlipidemia;
(c) an active substance useful for treating hypercholesterolemia;
(d) an active substance useful for treating cardiovascular disease;
(e) an active substance useful for treating hypertriglyceridemia;
(f) an active substance useful for treating coronary heart disease;
(g) an active substance useful for treating peripheral vascular disease;
(h) Adjunct to diet for lowering LDL-C, total C, triglycerides, and / or apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson type IIa and IIb) Active substances useful as therapy;
(i) an active substance useful as an adjunct to diet for the treatment of adult patients with hypertriglyceridemia (Fredrickson IV and V hyperlipidemia);
(j) an active substance useful for treating pancreatitis;
(k) an active substance useful for treating restenosis; and
(l) An active substance useful for treating Alzheimer's disease.   96. Any one of claims 68-96, further comprising one or more non-sterol active substances selected from the group consisting of cholesterol lowering agents, policosanols, alkanoyl L-carnitines, antihypertensive agents, sterols and / or stanols. Section method.   98. The method of claim 97, wherein the cholesterol-lowering agent is selected from the group consisting of ACE inhibitors, nicotinic acid, niacin, bile acid sequestering agents, fibrates, vitamins, fatty acid derivatives, long chain plant extract alcohols, ezetimibe, and cellulose. .   Policosanol consists of (1) triacontanol, (2) hexacontanol, (3) ecocosanol, (4) hexacosanol, (5) tetracosanol, (6) dotriacontanol, (7) tetracontanol, (8) natural products including triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, tetracontanol; and (9) triacontanol, hexacontanol, ecocosanol, hexacosanol, 98. The method of claim 97, selected from the group consisting of extracts from natural products comprising tetracosanol, dotriacontanol, tetracontanol.   The antihypertensive agent is selected from the group consisting of diuretics, beta blockers, alpha blockers, alpha-beta blockers, sympathetic inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin receptor blockers. 97 ways.   98. The sterol and / or stanol is selected from the group consisting of plant sterol, plant sterol ester, sitosterol, sitostanol, fish oil, phytosterol, campestanol, stigmasterol, coprostanol, cholestanol, beta-sitosterol. Method.   102. The method of any one of claims 68-101, wherein the subject is a human.   105. Any one of claims 68-102 used for treating a condition selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, coronary heart disease, cardiovascular disease, and peripheral vascular disease. the method of.   105. Used as an adjunct therapy to diet for lowering LDL-C, total C, triglycerides, or apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia Any one of the methods.   105. The method of any one of claims 68 to 102, wherein the method is used as an adjunct therapy to a diet therapy for an adult patient having hypertriglyceridemia.   105. The method of any one of claims 68-102, used to reduce the risk of pancreatitis.   105. The method of any one of claims 68-102, used to reduce or treat the risk of Alzheimer's disease.   105. The method of any one of claims 68-102, wherein the method is used to treat an indication that typically uses a lipid control agent.