JP2009533341A - Nanostructured compositions having antibacterial, antifungal, antiyeast, and / or antiviral properties - Google Patents

Abstract

  The present invention provides nanostructured compositions having antibacterial, antifungal, antiyeast, and / or antiviral properties. The present compositions are useful as drug delivery carriers for one or more active agents, or in the absence of active agents, such compositions are useful in methods where desirable.

Description

The present invention relates to nanostructured compositions having antibacterial, antifungal, antiyeast, and / or antiviral properties. The present compositions are useful as drug delivery carriers for one or more active agents, or in the absence of active agents, are useful in methods where such compositions are desired.

(A. Background on the use of antibacterial drugs in drug dosage forms and consumer products)
Microbial preservatives are added to a non-sterile dosage form to protect the dosage form from microbial growth or microorganisms that are inadvertently introduced during or subsequent to the manufacturing process. In the case of sterile articles used in multi-dose containers, antimicrobial preservatives are added to prevent the growth of microorganisms that can be incorporated by repeatedly removing individual doses.

  All useful antimicrobial agents are toxic substances. See USP 26, General Chapters, Section 51, "Antimicrobial Effectiveness Testing". For maximum patient protection, the concentration of preservatives shown to be effective in the finished prepared packaged product should be below a level that can be toxic to humans.

  U.S. Food and Drug Administration guidelines apply to all antimicrobial effects packaged in multi-dose containers, whether they are product specific (ie for antibiotics) or occur due to the addition of antimicrobials Requires that it be demonstrated for other infusions or other antimicrobial preservative-containing products. Antibacterial effects must be demonstrated for multi-dose topical and oral dosage forms, as well as other dosage forms such as eye drops, ear drops, nasal drops, irrigation solutions, and dialysate. See USP 26, General Chapters, Section 51, "Antimicrobial Effectiveness Testing".

  The addition of antimicrobial agents to therapeutic dosage forms may be undesirable because such compounds may be toxic and may have undesirable interactions with the active agent that is to be delivered in nature. . Furthermore, the use of microbicides can promote the development of drug resistant bacteria, drug resistant yeasts, drug resistant fungi and the like. This has been observed in the use of popular antibacterial lotions, soaps, detergent products and the like.

  Antibiotic resistance among bacteria has increased in recent years, and there is increasing concern that exposure to antibiotics or biocides may cause cross resistance in bacteria or other microorganisms. Rutala, WA, "APIC Guideline for Selection and Use of Disinfectants," American J., 24: 313-342 (1996); Russell et al., "Do Antiseptics and Disinfectants Select for Antibiotic Resistance?" J. of Medicinal Microbiology, 48: 613-615 (1999). More effective disinfectants are extremely irritating and toxic, resulting in health problems such as contact dermatitis and mucosal irritation in workers. Hansen, KS, "Occupational Dermatoses in Hospital Cleaning Women," Contact Dermatitis, 9: 343-351 (1983); Beauchamp et al., "A Critical Review of the Toxicology of Glutaraldehyde, Critical Reviews in Toxicology, 22: 143-174 (1992) Therefore, there is a continuing need for effective and safe biocidal agents in terms of local and surface disinfection, microbial changes, and the development of resistant bacteria.

(B. Background on opportunistic fungi, bacteria, yeast and viral opportunistic bacteria)
USP kills E. coli, P. aeruginosa, and S. aureus to determine the antibacterial effect of the dosage form, plus C. aureus. C. albicans and A.I. Define tests for efficacy in controlling and limiting the growth of A. niger. See USP 26, Section 51, General Chapters, "Antimicrobial Effectiveness Testing". These particular microorganisms are representative of the most problematic and troublesome bacteria, fungi, and yeast.

  Aspergillus niger is a fungus and is one of the most common species of the genus Aspergillus. It causes black mold on certain types of fruits and vegetables and is a common food contaminant.

  C. C. albicans is an important fungal pathogen in humans. Infectious diseases are localized, such as vaginal infections and oral infections, which cause a significant degree of discomfort. In some patient groups (premature babies, leukemia and burn patients) whose defense system is severely compromised, yeast can be a lethal pathogen, causing systemic infections, resulting in Up to 50% die. The incidence of such infections is increasing rapidly, especially in hospitalized patients. In New Zealand, such infections are now 10 times more frequent than 15 years ago. Furthermore, the host of anti-Candida drugs is very limited, and these drugs can have severe side effects.

  E. coli is a ubiquitous bacterium and there are many known strains. E. coli O157: H7, a particularly troublesome E. coli strain, is a member of the EHEC-enterohemorrhagic E. coli group. Enterohemorrhagic means an intestinal related organism that causes bleeding and thus blood loss. E. coli O157: H7 produces a toxin called Shiga toxin-like toxin (SLT) or verotoxin. Toxins are proteins that cause severe damage to intestinal epithelial cells. This condition is particularly dangerous and fatal for small children because children are too small to withstand large amounts of blood and fluid loss. In some cases, another syndrome called hemolytic uremic syndrome (HUS) characterized by renal failure and red blood cell loss is involved. Approximately 5% to 10% of children progress to this stage of the disease. In severe cases, the disease causes permanent kidney damage. The presence of this bacterium is also very dangerous for the elderly or weak. There may be a combination of HUS and other factors that involve the blood system and are fatal in 50% of cases for the elderly. There is evidence that E. coli O157: H7 is increasingly prevalent.

  Pseudomonas aeruginosa is a Gram-negative bacterium known for its environmental flexibility, its ability to cause disease in particularly susceptible individuals, and its antibiotic resistance. The most serious complication of cystic fibrosis is respiratory tract infection due to the ubiquitous bacterium Pseudomonas aeruginosa. Cancer and burn patients also generally suffer from serious infections with this organism, as are certain other individuals with immune system deficiencies. Unlike many environmentally derived bacteria, P. aeruginosa has a significant ability to cause disease in susceptible hosts. It has the ability to adapt and reproduce in many ecological positions ranging from water and soil to plant and animal tissues. Bacteria have an exceptional ability to colonize ecological status where nutrients are limited because a wide range of organic compounds can be used as food sources. P. aeruginosa not only causes massive tissue damage, but can also produce a number of toxic proteins that interfere with the defense mechanisms of the human immune system. These proteins range from powerful toxins that enter and kill host cells at or near the site of colonization, and degradable enzymes that permanently destroy cell membranes and connective tissue in various organs.

  Staphylococcus aureus is a major cause of soft tissue infections as well as toxic shock syndrome (TSS) and burn-like skin syndrome. The pathogenic effects of S. aureus are primarily associated with the toxins it produces. Many of these toxins are produced at stationary phase in the bacterial growth curve. In fact, it is not uncommon for the site of infection to contain no live S. aureus cells. S. aureus enterotoxin causes rapidly onset food poisoning that can result in abdominal pain and severe vomiting. Infectious diseases can result in contaminated meat that has not been fully cooked. These microorganisms also secrete leukocidin, a toxin that destroys white blood cells leading to the formation of pus and acne. In particular, S. aureus has been found to be a causative agent in diseases such as pneumonia, meningitis, pimples, arthritis and osteomyelitis (chronic bone infection). Most S. aureus are resistant to penicillin, but vancomycin and nafcillin are known to be effective drugs against most species.

  Molds such as Aspergillus fumigatus are filamentous fungi. They grow and spread especially on non-living organic matter in the soil. They spread their asexual spores, called conidia, in the air. Most Aspergillus are harmless to humans. A. fumigatus is harmless, especially for humans whose immune system has not been compromised by disease, drug therapy or genetic conditions. A. Exposure to A. fumigatus can cause allergic reactions in sensitive individuals. More importantly, A.I. A. fumigatus is an opportunistic pathogen of bone marrow tissue transplant patients, AIDS patients, and other immunocompromised people.

  Aspergillus fumigatus is the most common mold causing infections worldwide. Aspergilloma, the first infection described in humans, was reported in Edinburgh in 1842, and numerous cases of invasive disease in non-immune deficient patients have been reported. These cases and more recent epidemiological data are described in A. Emphasize that A. fumigatus is a rare but major human pathogen. Allergic disease caused by Aspergillus was first described in London in 1952, and the first invasive (and fatal) infection in immunocompromised patients was reported in 1953 by the British Medical Journal, Gloucester. (Gloucester) reported on a patient.

  The incidence of invasive disease has increased approximately 14-fold over the 12 years up to 1992, with post-mortem determination in arbitrarily selected anatomy. Invasive aspergillosis has replaced candidiasis as the most frequent fungal pathogen detected postmortem in tertiary care hospitals in Europe. Therefore, 4% of all patients who died had invasive aspergillosis compared to approximately 2% due to invasive candidiasis. Patients at risk based on disease frequency include patients with chronic granulomatous disease (25-40%), lung tissue transplant patients (17-26%), allogeneic bone marrow transplant patients (4-30%), leukemia There are neutropenic patients (5-25%), heart tissue transplant patients (2-13%), pancreatic tissue transplant patients (1-4%), Europe and the United States (about 1%) and India (about 10%) %) Kidney tissue transplant patients and patients with AIDS, multiple myeloma and severe combined immunodeficiency (about 4%). More than 500,000 tissue transplants are performed worldwide every year. Acute leukemia affects about 3 / 100,000 of the population, and on average each patient receives 3 cycles of chemotherapy, each cycle characterizing a significant risk period. Similar incidence is observed for patients with high-grade lymphoma who are at high risk for invasive aspergillosis. In developed countries alone, these treatment protocols generate about 250,000 critical risk periods each year. AIDS cases are expected to exceed 40 million at the end of 2000, which will result in about 1.4 million cases of invasive aspergillosis, but most patients in developing countries are afflicted with this disease. I don't live long.

  The crude mortality rate from invasive aspergillosis is about 85% and drops to about 50% when treated. New drugs under study (such as voriconazole) may reduce mortality slightly (about 10%), but test patients tend to be better than patients being treated in clinical practice. In addition to invasive diseases, Aspergillus causes a number of other diseases in humans. These include aspergilloma ("colonization" of the existing lung cavity), normal sinusitis, allergic bronchopulmonary and sinus infections, keratitis (usually leading to blindness in the eyes, Common), and postoperative infections in patients who remain immune. Due to the increased incidence of tuberculosis, the number of aspergillomas is heading for a dramatic rise, and such aspergilloma cases are notoriously difficult to treat. A cavity 2 cm or more after tuberculosis subsequently develops aspergilloma in 15-20% of patients (UK). The 5-year survival rate for patients with aspergilloma is approximately 40%. Allergic bronchopulmonary aspergillosis occurs in cystic fibrosis and asthmatic patients (increased) and usually causes pulmonary fibrosis and death within 10 years of diagnosis.

  Aspergillus flavus is a pathogen in a wide range of infections, including aflatoxins-induced mycotoxins, hypersensitivity pneumonia, otitis, sinusitis, and invasive disease. Some reports suggest that the disease course may be enhanced by aflatoxins, especially in immunodeficient / neutropenic hosts. The organism is extremely vascular invasive, resulting in necrosis and infarction.

(C. Prior art drug delivery (drug delivery) technology)
Ease of active drug delivery is an important challenge facing pharmaceutical companies developing and commercializing therapeutic agents. For example, an active agent that is readily soluble in water is not difficult to formulate into a suitable dosage form.

  However, formulating a poorly water-soluble active agent into an appropriate dosage form poses a major challenge. This is because the human body is an aqueous system, and therefore the drug must dissolve after administration as a condition that provides therapeutic activity.

  Some poorly water-soluble active agents have not been commercialized because they cannot be solubilized effectively and therefore cannot exhibit in vivo therapeutic activity that meets the conditions. As an alternative, given the poor water solubility of the drug, the amount of poorly water-soluble active drug that must be administered to achieve an acceptable level of therapeutic activity may result in unacceptable toxicity . Even if the active agent is solubilized in a solvent and the active agent is formulated into a liquid, such dosage forms sometimes do not function optimally. For example, such dosage forms may have unpredictable properties or induce undesirable side effects.

  There are prior art methods for increasing the solubility of active agents. For example, reducing the particle size of the active agent, thereby increasing the exposed surface area of the active agent, resulting in improved dissolution rates and greater water solubility. One prior method for reducing particle size is wet grinding. This method involves the active agent with beads made of hard glass, ceramic, porcelain, zirconium oxide, zirconium silicate, polymer resin, or other suitable material in a medium in which the active agent is sparingly soluble, such as water. Requires grinding. The active agent is physically converted into even smaller particles that remain suspended in the grinding media. The resulting micron or nanometer sized active agent particles are then isolated from the grinding media by methods such as filtration or centrifugation and formulated into a suitable dosage form. See U.S. Pat. No. 5,145,684, U.S. Pat. No. 5,518,187, U.S. Pat. No. 5,862,999, and U.S. Pat. No. 5,718,388. I want to be. The medium in which the active agent is ground typically contains one or more compounds that function as surface stabilizers for the active agent. The surface stabilizer is adsorbed on the surface of the active agent and plays a role in sterically hindering the increase in the particle size of the active agent.

  Thus, conventional wet grinding techniques produce a “two-phase” system in which the stabilized active agent nanoparticles are suspended in an aqueous medium. Nanoparticulate drugs marketed under the trade name NanoCrystal® technology by Elan Drug Delivery of King of Prussia, PA and under the trade name Insoluble Drug Delivery (IDD®) technology by SkyePharma, plc The delivery technique illustrates such a wet grinding technique. However, wet milling of the active agent has the main disadvantage of processing costs. It can be said that the additional cost of formulating poorly water-soluble active agents into nanoparticulate compositions using wet grinding is very high. Furthermore, amorphous compounds are not suitable for wet grinding techniques.

  Other known methods of making nanoparticulate active agent compositions include precipitation, homogenization, and supercritical fluid methods. Microprecipitation is a method for preparing stable dispersions of poorly soluble active agents. Such a method involves dissolving the active agent in a solvent followed by precipitating the active agent from solution. Homogenization is a technique that does not use grinding or grinding media. The active agent in the liquid medium constitutes a process stream propelled in a processing zone called the interaction chamber in Microfluidizer® (Microfluidics, Inc.). The shape of the interaction chamber results in strong shear forces, fits, and cavitation, which leads to particle size reduction. US Pat. No. 5,510,118 refers to a two-phase process using Microfluidizer® which results in nanoparticulate active agent particles. Finally, a supercritical fluid method for making a nanoparticulate active agent composition includes dissolving the active agent in solution. Next, the solution and the supercritical fluid are simultaneously introduced into the particle formation vessel. Temperature and pressure are controlled so that vehicle dispersion and extraction occur substantially simultaneously by the action of the supercritical fluid. Examples of known supercritical methods for making nanoparticles include WO 97/144407 and US Pat. No. 6,406,718.

  There is a need in the art for drug delivery dosage forms having unique antibacterial, anti-yeast, antifungal, and / or antiviral properties. Furthermore, there is a need for compositions that have such inherent antibacterial, anti-yeast, antifungal, and / or antiviral properties and can be used in the absence of active agents. The present invention satisfies these requirements.

(wrap up)
The present invention relates to nanostructured compositions having antibacterial, antifungal, antiyeast, and / or antiviral properties. The composition includes at least one oil, at least one surfactant, at least one solvent, and water. In addition, the composition can include an active agent. The active agent can be useful, for example, as a pharmaceutical, diagnostic, or cosmetic.

  Another aspect of the present invention includes a nanostructure composition according to the present invention and one or more desired pharmaceutically acceptable carriers, and / or viscosity modifiers, colorants, flavoring agents, perfumes and the like. It relates to a pharmaceutical composition comprising the desired excipients. One aspect of the present invention includes (1) a micelle component, (2) a hydroalcoholic component, ie, a mixture of water and a water-miscible solvent, (3) an oil-in-water emulsion droplet component, and optionally ( 4) relates to a unique nanostructured formulation of active pharmaceutical ingredients, including solid particle constituents of the active drug. Any or all of these components may comprise the desired active pharmaceutical agent, diagnostic agent, or cosmetic, or other active ingredient. Thus, the active agent may be in solution as shown in components 1-3, or it may be in the form of a precipitated suspension, as in component 4.

  In one embodiment, when the composition is applied to the skin, the solubilized dosage form moves through the skin and into deeper skin layers, such as in the dermis. Other components such as micelles, oil fractions, and / or particulate drugs may typically be placed in the stratum corneum of the skin layer. Depending on various physical and chemical properties, certain compounds may be placed in different layers of the epidermis and dermis, while others may penetrate directly across the skin.

  This combined formulation avoids having to incorporate chemical permeation enhancers that are otherwise necessary to induce transdermal penetration of the active pharmaceutical ingredient.

  Another aspect of the invention is the step of (a) mixing at least one oil, at least one solvent, and at least one surfactant (also referred to as a surface stabilizer) to form an emulsion base. And (b) adding water to the emulsion base and (c) homogenizing or vigorously stirring the mixture. When utilizing an active agent in the composition, an exemplary method of making the composition is: (a) adding the active agent to a mixture of oil, solvent, and surfactant or stabilizer to form an emulsion base. Forming step; (b) adding water to the emulsion base; and (c) homogenizing or stirring vigorously the mixture, the active agent being soluble in one or both of the oil and solvent. But it is not water soluble.

  Finally, methods of using the compositions of the present invention as broad spectrum antimicrobial compositions for treating problematic subjects or for topical or surface disinfection are also encompassed by the present invention.

  Both the foregoing general description and the following brief description of the drawings and detailed description are exemplary and explanatory and are intended to 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 (A. Summary of the Invention)
The present invention surprisingly relates to nanostructured compositions having antibacterial, antifungal, antiyeast, and / or antiviral properties. The nanostructure composition of the present invention includes at least one solvent, at least one oil, at least one surface stabilizer (also referred to as a surfactant), and an aqueous medium. The composition may further comprise one or more active agents that can be dissolved or dispersed in any one of oil, solvent, or water. The active agent can be useful, for example, as a pharmaceutical or cosmetic product. It is not necessary to add external antibacterial agents or preservatives to impart antibacterial, anti-yeast, antifungal, and / or antiviral properties to the compositions of the present invention.

  The compositions of the present invention meet the “Antimicrobial Effectiveness Testing” criteria as described in the USP-General Chapters, Section 51. This is demonstrated by the test described in Example 4 below in which various microorganisms were cultured in the presence of the composition according to the invention (E. coli (ATCC 8739), Pseudomonas aeruginosa (P. aeruginosa (ATCC 9027), S. aureus (ATCC 6538), C. albicans (ATCC 10231), A. niger (ATCC 16404), Pseudomonas aeruginosa ( P. aeruginosa (ATCC 13388), P. aeruginosa (ATCC 25619), A. flavus, and A. fumigatus). The test results are shown in FIG. Here, the dramatic antibacterial properties of the composition of the invention are shown graphically.

  Standard USP tests include Aspergillus niger (ATCC 16404), Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027) And assessment in five microorganisms of Staphylococcus aureus (ATCC 6538). Additional strains were used to produce A. flavus, A. flavus. Antimicrobial efficacy in A. fumigatus, P. aeruginosa (ATCC 25619), and P. aeruginosa (ATCC 13388) was confirmed. As shown in the graph of FIG. 2 which shows the results of this test, the antimicrobial effect in these additional strains undoubtedly proves that the composition vehicle itself is antimicrobial.

  Furthermore, the incorporation of the active agent does not impair the antimicrobial effect of the composition of the present invention. Specifically, as shown in Examples 3 and 4, the compositions of the present invention comprising estradiol and testosterone also exhibited significant antibacterial effects and met USP test requirements for demonstration of fungal activity. See also FIGS. 3 and 4.

  In addition to the pharmacological properties of the active agent in such compositions, the compositions of the present invention can be used for topical therapies such as infections, wound healing because the vehicle itself acts as a microbicide. It is particularly useful in manufactured products. Such a composition probably induces synergy and reduces the likelihood of drug-resistant microorganisms being generated. Furthermore, such compositions may allow the use of low doses of active agent.

  Currently, various types of cosmetic and pharmaceutical compositions require the addition of antimicrobial agents to retard microbial growth. Choosing the right antibacterial agent is difficult because of the potential interaction between the active agent and the antibacterial agent. In addition, antibacterial agents can be toxic, which can induce adverse reactions in patients.

  In one embodiment of the invention, the composition comprises an active agent, and the active agent is selected from the group consisting of, but not limited to, fenofibrate, estradiol, alendronate, acyclovir, paclitaxel, and cyclosporine. Is done.

  In another embodiment, the oil is, but is not limited to, almond oil (sweet tonsil), apricot oil, borage oil, canola oil, coconut oil, corn oil, cottonseed oil, fish oil, jojoba bean oil, lard oil , Flaxseed oil (boiling), macadamia nut oil, medium chain triglyceride, mineral oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, squalene, sunflower seed oil, tricaprylin (1,2,3-trioctanoylglycerol ), And wheat germ oil.

  In one embodiment, the solvent is selected from the group consisting of, but not limited to, isopropyl myristate, triacetin, N-methylpyrrolidinone, aliphatic and aromatic alcohols, polyethylene glycol, and propylene glycol. Examples of other useful solvents are long chain alcohols. Ethyl alcohol and benzyl alcohol are yet another example of alcohols that may be used in the present invention.

  In yet another embodiment, the stabilizer or surfactant may be, but is not limited to, sorbitan ester, glycerol ester, polyethylene glycol ester, block polymer, acrylic polymer (such as Pemulen®), ethoxyl. Group consisting of oxyfatty acid esters (such as Cremophor® RH-40), ethoxylated alcohols (such as Brij®), ethoxylated fatty acids (such as Tween 20), monoglycerides, silicon-based surfactants, and polysorbates Selected from. In a further embodiment, the sorbitan ester stabilizer is Span® or Arlacel®, the glycerol ester is glyceryl monostearate, the polyethylene glycol ester is polyethylene glycol stearate, and the block polymer is Pluronic ( The acrylic polymer is Pemulen®, the ethoxylated fatty acid ester is Cremophor® RH-40, the ethoxylated alcohol is Brij®, and the ethoxylated fatty acid is Tween. (Registered trademark) 20, or a combination thereof.

  In another embodiment, the homogenizing step is performed through a high pressure system of 1,000 to 40,000 psi.

  In one embodiment, the active agent particles, droplets containing the active agent, or combinations thereof have an average particle size of less than about 10 μm. In another embodiment of the invention, the active agent particles, droplets containing the active agent, or combinations thereof are less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, about Less than 3 μm, less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, less than about 2500 nm, less than about 2400 nm, less than about 2300 nm, less than about 2200 nm, less than about 2100 nm, 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, about <500nm Less than about 400 nm, less than about 300 nm, less than about 200 nm, or less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, or Having an average particle size of less than about 10 nm. In one embodiment, the active agent particles, droplets containing the active agent, or combinations thereof have an average particle size of less than about 3 μm in diameter.

  Three methods of making the composition of the present invention are described. The first method does not require the presence of an active agent. In this method, at least one oil, at least one solvent, and at least one surfactant are combined to form an emulsion base, and water is added to the emulsion base to (c) homogenize the mixture. Or stir vigorously.

  When an active agent is utilized in the composition, an exemplary method of making the composition includes: (a) adding the active agent to an oil, solvent, and a mixture of surfactants or stabilizers to add the emulsion base. Forming step; (b) adding water to the emulsion base; and (c) homogenizing or stirring vigorously the mixture, wherein the active agent is soluble in one or both of the oil and solvent. But it is not water soluble.

  Two specific methods of making the active agent composition of the present invention are described. In the first method ("Route I"), the active agent is ground in an emulsion base (ie, homogenized or vigorously stirred to reduce the active agent particle size). This method requires that the active agent be sparingly soluble or insoluble in all phases of the oil phase / lipophilic phase and water or buffer. In the second method ("Route II"), active agent attrition (ie homogenization or vigorous stirring to reduce active agent particle size) and precipitation in the emulsion base is observed. . The second method is that the active agent is soluble or partially soluble in one or more phases of the emulsion base, i.e. the active agent is soluble in oil, solvent, or water or buffer. You need to be.

  One advantage of the method of making the compositions of the present invention compared to prior art methods such as wet grinding is that the method is applicable to water soluble active agents as well as poorly water soluble active agents. Another advantage of the method of the present invention is that they do not require grinding media, or special grinding steps, or equipment. The use of such grinding media can add cost and complexity to the process of reducing the particle size of the active agent. Yet another advantage of the method of the present invention is that it can be used to process amorphous drugs.

  In Route I, the active agent is first suspended in a mixture of oil, solvent, and immiscible liquid such as water or buffer to form an emulsion base, and the emulsion base is homogenized or activated. Followed by continuous stirring. Nanoparticles can be generated by reciprocating syringe devices, continuous flow devices, or high speed mixing equipment. High speed homogenization or vigorous stirring that produces high shear and cavitation forces is preferred. High shear processing is preferred because low shear processing can result in larger particle sizes of the active agent. The resulting composition comprises an active agent suspended in emulsion droplets (nano-emulsion fraction) and a sterically stabilized microcrystalline and / or nanocrystalline active agent in a medium. It is a complex mixture. This three-phase system includes particulate drug, oil, and water or buffer. The resulting micro / nano-particulate active agent has an effective average particle size of less than about 3 μm. Smaller particulate active agents can also be obtained as described below.

  The active agent can be precipitated from the oil droplets by adding more immiscible liquid. The precipitated active agent typically has an effective average particle size of less than about 3 μm. If desired, surfactants or emulsifiers or “surface stabilizers” can be incorporated to prevent the active agent particles from agglomerating or clumping together.

  Route II is utilized for active agents that are soluble in at least a portion of an emulsion base such as a solvent. In route II, the active agent is dissolved in a mixture of oil, solvent, and stabilizer to form an emulsion premix. If water or buffer is not added to the mixture, the active agent remains in a soluble form. Upon addition of water or buffer and application of shear force, the active agent precipitates into micro / nanoparticles having an effective average particle size of less than about 3 μm. Nanoparticles can be generated by reciprocating syringe devices, continuous flow devices, or high speed mixing equipment. High energy input through high speed homogenization or vigorous stirring is a preferred process. High energy processing reduces emulsion droplet size, thereby exposing large surface areas to the surrounding aqueous environment. High shearing is preferred because low shearing can result in larger particle sizes of the active agent. This is followed by precipitation of the nanoparticulate active agent pre-embedded in the emulsion base. The final product contains the active agent in solution and microparticle suspension, both distributed between solvent, oil, and water or buffer. In one embodiment, the nanoparticulate active agent has at least one surface stabilizer associated with its surface.

  Examples of active agents that are poorly soluble in water but soluble in another liquid include estradiol that is soluble in ethanol, and 1-methyl-2-pyrrolidone or N-methyl-pyrrolidinone. Mention may be made of fenofibrate, which is easily soluble in [NMP], slightly soluble in oils and stabilizers and insoluble in water.

  If desired, water-miscible oil droplets and active agent nanoparticles prepared using Route I or Route II can be filtered through either 0.2 or 0.45 μm filters. Larger oil droplets and / or active agent particles can be created by simply increasing the water content, decreasing the oil-stabilizer-solvent content, or changing the shear in the formation of oil droplets.

  For emulsion bases used as antimicrobial compositions or used in Route I or Route II as drug delivery vehicles, the preferred ratio of oil: stabilizer: solvent is about 23: about 5: weight to weight, respectively. About 4. A preferred ratio of oil-containing phase to water or buffer is about 2: 1: 1, respectively. In another embodiment of the invention, the oil may be present from about 5% to about 50% (w / w) and the solvent may be present from about 0.5% to about 10% (w / w). The stabilizer or surfactant may be present from about 0.5% to about 10% (w / w) and the water is present from about 20% to about 80% (w / w) or any combination thereof. Also good.

(B. Composition of the present invention)
The method of the present invention can produce several different types of compositions. The first composition comprises (1) at least one oil, (2) at least one solvent, (3) at least one surfactant or surface stabilizer, and (4) water. This composition exhibits a wide range of antibacterial activity and can therefore be used as a general purpose disinfectant.

  Another type of composition according to the invention comprises at least one active agent. For example, the second composition comprises (1) a nanoparticulate active agent having at least one surface stabilizer associated with its surface, (2) water or buffer, (3) at least one oil and optionally at least It may contain an emulsion premix or oil phase or lipophilic phase containing one solvent and optionally (4) a microparticulate active agent. The microparticulate active agent can be the same or different from the nanoparticulate active agent. The particulate active agent can be present in water or buffer, oil, solvent, or combinations thereof. Such compositions are made using Route I.

  The third composition comprises (1) a nanoparticulate active agent having at least one surface stabilizer associated with its surface, (2) water or buffer, and (3) at least one oil, optionally at least 1 One emulsion and an emulsion premix or oil phase or lipophilic phase containing the solubilized active agent. The composition may further comprise a microparticulate active agent. The solubilized active agent can be present in water or buffer, oil, solvent, or a combination thereof. In addition, the nanoparticulate active agent can be present in water or buffer, oil, solvent, or combinations thereof. Such a composition is made using Route II. In a further embodiment of the invention, the solubilized active agent can be precipitated from the emulsion droplets. The precipitated active agent preferably has an effective average particle size of less than about 3 μm.

  The three-phase composition of the present invention is beneficial for several reasons. First, the formulation resulting from the route II method includes both solid and solubilized forms of the same active agent. The resulting pharmaceutical formulation allows for the provision of both rapid and controlled release of the constituent active agent and provides a rapid onset of activity in combination with the long-term activity of the active agent.

  In addition, when formulated for topical application to the skin, for example in a cream or lotion, the solubilized active agent in the emulsion base crosses the skin / cell barrier and allows the active agent to enter body tissue. However, solid active agent nanoparticles can provide an immediate local therapeutic effect on the skin surface. That is, the solubilized active agent passes quickly through the skin and penetrates deeper layers, while the solid portion does not penetrate deeper skin layers, but as a local reservoir and supplies drugs to deeper layers Acts as a reservoir. Thus, formulations comprising both active agent nanoparticles and solubilized active agent can provide local and systemic therapeutic effects, which are particularly beneficial for transdermal dosage forms.

  The different components of the two types of compositions described above are separable and can be used separately if desired.

  The present invention allows many different types of active agents to be formulated into emulsion-based formulations. Examples of such active agents include, but are not limited to, acyclovir, cyclosporine, estradiol, fenofibrate, ceterizine, nicotine, naltrexone, and alendronic acid.

(1. Active drug nanoparticles)
Solid active agent nanoparticles can be separated from the aqueous suspension medium and / or emulsion globules, for example, by filtration or centrifugation. This provides a convenient way to obtain nanoparticles of poorly water soluble or water insoluble active agents. In addition, when a surface stabilizer is included in the process of reducing the particle size, it prevents the active agent nanoparticles from aggregating, and thus the active agent nanoparticles are stabilized at the nanoparticulate size. If desired, the active agent nanoparticles can then be formulated into any suitable dosage form. Active agent nanoparticles can be made using food grade, USP or NF grade materials suitable for human use.

  Exemplary dosage forms include, but are not limited to, liquid dispersions, oral suspensions, tablets, gels, fumes, ointments, creams, capsules, dry powders, multiparticulates, sprinkles, sachets, Examples include lozenges and syrups. Furthermore, the dosage forms of the present invention include solid dosage forms, liquid dosage forms, semi-liquid dosage forms, immediate release formulations, modified release formulations, controlled release formulations, immediate dissolution formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulse It may be a release formulation, an immediate and controlled release mixed formulation, or any combination thereof. The compositions of the invention can be administered parenterally (i.e. intravenously, intramuscularly or subcutaneously), orally administered in solid, liquid, or aerosol form, vaginal, nasal, rectal, intraocular, intraocular, It may be formulated for delivery by any suitable method, such as for topical (powder, ointment or drops), buccal, cisterna, intraperitoneal, or topical administration.

  Because the active agent nanoparticles have an effective average particle size of less than about 3 μm, the particles typically can more easily cross absorption barriers such as the skin compared to microcrystalline active agents. Similarly, the small particle size of the active agent allows passage through the blood / tissue and blood / tumor barrier of various organs.

(2. Emulsion globules containing active agent nanoparticles and / or solubilized active agent)
Also, emulsion globules containing solubilized active agent, active agent nanoparticles, or combinations thereof can be isolated from the surrounding aqueous or buffer phase and used in therapeutic dosage forms, if desired. is there. Emulsion globules can be made using food grade, USP or NF grade materials suitable for human use. For nanoparticulate oil globules containing solubilized active agents and methods for making the materials, see US Pat. No. 5,629,021, incorporated herein by reference (“the '021 patent”). It is stated in. The emulsion globules of the present invention typically comprise (1) at least one oil, (2) at least one solvent, (3) at least one surface stabilizer or surfactant, and optionally (4) solubilized. Active agents, particulate active agents, or combinations thereof. Emulsion globules containing solubilized active agent, particulate active agent, or combinations thereof can be isolated if desired, for example, by filtration. Emulsion globules containing solubilized active agents are particularly suitable vehicles for transporting active agents across the skin barrier and into the blood. Thus, globules containing solubilized active agent provide a systematic way of administering the active agent to an individual.

  In general, emulsion globules containing solubilized active agent, active agent nanoparticles, or combinations thereof have a diameter of about 10 to about 1000 nm, contain a large amount of active agent, and preferably have an average diameter of less than about 1 μm. The smallest globules can be filtered through a 0.2 μm filter as typically used in microbiological purification. The range of active agent concentration in the globules is about 1% to about 50%. Emulsion globules can be stored between about 20 and about 40 ° C. In one embodiment of the invention, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the globules in the formulation are less than about 1 μm, less than about 900 nm, about It has a diameter of less than 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 200 nm, or less than about 100 nm.

  By varying different parameters of Path I and Path II, the size and concentration of such globules can be varied. Thus, the stability of the globules containing the dissolved active agent can be altered so that the active agent can be released as either a solution or a precipitate. This is a microreservoir dissolution control system where drug solids act as a reservoir and when the solubilized fraction is depleted, more drug is withdrawn from the microparticle reservoir into solution. Thus, emulsion globules containing solubilized active agent allow controlled release of active agent over time.

  The small size of emulsion globules containing solubilized active agents, active agent nanoparticles, or combinations thereof, and their histocompatibility make them applicable for a number of applications. For example, emulsion globules are useful as topical drug delivery vehicles because they allow rapid transdermal penetration. The globules are also exceptionally flexible and the active agent utilized therein can be any active agent that can be suspended or dissolved in either water or buffer, oil, or solvent. . These properties allow the system to be used with active agents that are difficult to formulate for use in other delivery systems.

  In addition, emulsion globules containing solubilized active agent, active agent nanoparticles, or combinations thereof can be diluted with an aqueous solution without compromising stability. This allows the use of products with a high concentration, ie up to about 30% active agent concentration, which can be diluted for use as needed. However, the active agent concentration depends on the actual drug solubility and the amount of solvent used to dissolve it.

  In one embodiment of the invention, the emulsion globules contain estradiol, acyclovir, or testosterone as the active agent and are formulated into a dosage form for transdermal delivery.

(C. Components of the method and composition of the present invention)
(1. Active pharmaceutical ingredient)
(A. Characteristics)
Any suitable active agent may be used in the compositions and methods of the invention. For active agents utilized in Route I methods, the active agents are sparingly soluble in all phases of the grinding (ie homogenization or vigorous stirring) system, including the water and solvents and oils used in the method. Must be insoluble. In the active agent utilized in the route II method, the active agent is sparingly soluble or insoluble in water, but soluble in at least one phase of an emulsion base such as an oil or solvent and a stabilizer or stabilizer solution. Must-have.

  “Poorly water soluble” or “water insoluble” means that the active agent is less than about 20 mg / mL, less than about 10 mg / mL, less than about 1 mg / mL, less than about 0.1 mg / mL at ambient temperature and pressure and about pH 7. Having a solubility in water of less than about 0.01 mg / mL, or less than about 0.001 mg / mL.

  The active agent used in the method of the invention and present in the composition of the invention can be amorphous, semi-amorphous, crystalline, semi-crystalline, or a mixture thereof.

(B. Active agent particle size)
As used herein, the particle size of the active agent will be measured by conventional techniques well known to those skilled in the art such as sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction, or disk centrifugation. Further, it is determined based on the weight average particle size.

  As used herein, “nanoparticulate active agent” refers to an active agent having an effective average particle size of less than about 3 μm, and “microcrystalline active agent” is an activity having an effective average particle size of greater than about 3 μm. Refers to a drug.

  As used herein, an “effective average particle size” for an active agent is a size that allows approximately 50% of the active agent particle to fit within. Thus, if the effective average particle size is less than about 3 μm, at least 50% of the active agent particles have a composition size of less than about 3 μm. In another embodiment of the invention, the effective average particle size of the active agent particles in the composition of the invention is less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, less than about 2500 nm, less than about 2400 nm, Less than about 2300 nm, less than about 2200 nm, less than about 2100 nm, 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, 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 200 nm, or less than about 100 nm.

  In another embodiment of the invention, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the active agent particles are below the effective average, i.e. The size is less than about 3 μm, less than about 2900 nm, less than about 2800 nm, and the like.

(C. Exemplary Active Agent)
Any suitable active agent may be used in the methods and compositions of the invention. Examples of types of useful active agents include, but are not limited to, therapeutic and diagnostic agents, pigments, paints, inks, dyes, photographic materials, cosmetic ingredients, and the like.

  An amphiphile type active agent may be incorporated into the formulation. That is, drugs or therapeutic compounds that can be ionized and are soluble in polar or non-polar solvents may be incorporated into the formulations of the present invention. Such compounds are therefore soluble in both oily and aqueous environments (amphiphiles). Examples of such compounds include nicotine and ceterizine.

  Hydrophilic active agents may also be incorporated into the formulations of the present invention. Such compounds include, but are not limited to, naltrexone hydrochloride, alendronic acid, and ceterizine dihydrochloride.

  The active agent may be a hormone such as testosterone, progesterone, and estrogen. Examples of other hormones include (1) catecholamine, adrenaline (or epinephrine), dopamine, noradrenaline (or norepinephrine), tryptophan derivative, melatonin (N-acetyl-5-methoxytryptamine), serotonin (5-HT), tyrosine derivative, Amine-derived hormones such as thyroxine (T4), triiodothyronine (T3), (2) anti-Muellerian hormone (AMH, Muller tube inhibitor or hormone), adiponectin (also Acrp30), adrenocorticotropic hormone (ACTH, Corticotropin), angiotensinogen and angiotensin, antidiuretic hormone (ADH, vasopressin, arginine vasopressin, AVP), atrial natriuretic peptide (ANP, atri) Peptin), calcitonin, cholecystokinin (CCK), corticotropin releasing hormone (CRH), erythropoietin (EPO), follicle stimulating hormone (FSH), gastrin, glucagon, gonadotropin releasing hormone (GnRH), growth hormone Release hormone (GHRH), human chorionic gonadotropin (hCG), growth hormone (GH or hGH), insulin, insulin-like growth factor (IGF, somatomedin), leptin, luteinizing hormone (LH), melanocyte stimulating hormone (MSH) Or α-MSH), neuropeptide Y, oxytocin, parathyroid hormone (PTH), prolactin (PRL), relaxin, rennin, secretin, somatostatin, thrombopoietin, thyroid stimulating hormone (TSH), instep Peptide hormones such as gonadotropin releasing hormone (TRH), (3) glucocorticoid, cortisol, mineralocorticoid, aldosterone, sex steroid, androgen, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate ( Steroid hormones such as (DHEAS), androstenedione, dihydrotestosterone (DHT), estrogen, estradiol, progestagen, progesterone, progestin, (4) sterol hormones such as vitamin D derivatives and calcitriol, (5) prostaglandins, Examples include lipids and phospholipid hormones (eicosanoids) such as leukotrienes, prostacyclins, and thromboxanes.

  Thus, in one embodiment of the invention, the active agent is estradiol, fenofibrate, acyclovir, alendronate, or testosterone. Specific examples of active agents that may be utilized in the methods of the present invention include, but are not limited to, insulin, calcitonin, calcitonin gene regulatory protein, atrial natriuretic protein, betaserori, erythropoietin , Alpha interferon, beta interferon, gamma interferon, somatropin, somatotropin, somatostatin, insulin-like growth factor, luteinizing hormone-releasing hormone, factor VIII, interleukin, interleukin analogue, blood agonist, anticoagulant, hematopoietic, Hemostatic agent, thrombolytic agent, endocrine agent, antidiabetic agent, antithyroid agent, β-adrenergic receptor blocking agent, growth hormone, growth hormone releasing hormone, sex hormone, thyroid agonist, parathyroid calcitonin, bisphosphonate, child Active agents, cardiovascular agents, antiarrhythmic agents, antianginal agents, antihypertensive agents, vasodilators, drugs used in the treatment of cardiac disorders, cardiotonic agents, renal agents, genitourinary agents, antidiuretics Drugs, respiratory drugs, antihistamines, cough medicines, parasympathomimetic drugs, sympathomimetic drugs, xanthines, central nervous system drugs, analgesics, anesthetics, antiemetics, appetite suppressants, antidepressants, fragments Headache, antiepileptic, dopaminergic, anticholinergic, antiparkinsonian, muscle relaxant, narcotic antagonist, sedative, stimulant, attention deficit disorder, methylphenidate, fluvoxamine Bisolperol, tacrolimus, sacrolimus, cyclosporine, gastrointestinal agonists, systemic antiinfectives, drugs used in the treatment of AIDS, anthelmintics, antimycobacterials, Epidermis, vaccines, hormones, anti-inflammatory drugs and elastase inhibitors and other skin preparations, antimuscarinic drugs, lipid regulators, blood products, blood substitutes, leuprolide acetate, chemotherapeutics and tumor treatment Antineoplastic agent, nutrient, nutrient, chelating agent, interleukin-2, IL-1ra, heparin, hirudin, colony stimulating factor, tissue plasminogen activator, oxytocin, nitroglycerin, diltiazem, clonidine, nifedipine, Verapamil, isosorbide-5-mononitrate, organic nitrate, diuretic, desmopressin, vasopressin, expectorant, mucolytic, fentanyl, sufentanil, butorphanol, buprenorphine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, Re Docaine, bupivacaine, diclofenac, naproxen, paverine, scopolamine, ondansetron, domperidone, metoclopramide, sumatriptan, ergot alkaloids, benzodiazepines, phenothiazines (phenothiozines), prostaglandin antibiotics, antivirals, antifungals, immunosuppression Agents, antiallergic agents, astringents, corticosteroids, fluorouracil, bleomycin, vincristine, or desferrioxamine. The active agent may be useful in wound-healing procedures.

(2. Oil)
Any suitable oil can be used for both the Route I and Route II methods and the compositions of the present invention. Exemplary oils that can be used include, for example, vegetable oil, nut oil, fish oil, lard oil, mineral oil, squalane, tricaprylin, and mixtures thereof. Specific examples of oils that may be used include, but are not limited to, almond oil (sweet tonsil), apricot oil, borage oil, canola oil, coconut oil, corn oil, cottonseed oil, fish oil, jojoba bean oil , Lard oil, linseed oil (boiling), macadamia nut oil, medium chain triglyceride, mineral oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, squalene, sunflower seed oil, tricaprylin (1,2,3-trio Kutanoylglycerol), wheat germ oil, and mixtures thereof.

(3. Surface stabilizer or surfactant)
The composition of the present invention also includes at least one surface stabilizer or surfactant. When the composition further comprises a nanoparticulate active agent, the surface stabilizer used in the methods and compositions of the present invention is associated or adsorbed to the surface of the nanoparticulate active agent, but the active agent and the covalent bond are not. do not do. The surface stabilizer is preferably soluble in water. One or more surface stabilizers may be used in the compositions and methods of the present invention. As used herein, the terms “stabilizer”, “surface stabilizer”, and “surfactant” are used interchangeably.

  Any suitable nonionic or ionic surfactant may be utilized in the compositions of the present invention, including anionic, cationic, and zwitterionic surfactants. Exemplary stabilizers or surfactants that may be used in the compositions of the present invention that lack active agents and in the active agents that make up the compositions of the present invention are not limited thereto. Are surfactants of the Tween® (polyoxyethylene derivatives of sorbitan fatty acid esters) family (ie Tween® 20, Tween® 60, and Tween® 80), non-phenols Polyethylene glycol ether, sorbitan ester (such as Span (registered trademark) and Arlacel (registered trademark)), glycerol ester (such as glyceryl monostearate), polyethylene glycol ester (such as polyethylene glycol stearic acid), block polymer (Pluronics (registered trademark)) ), Acrylic polymers (e.g. Pemulen (R)), Toxylated fatty acid esters (such as Cremophor® RH-40), ethoxylated alcohols (such as Brij®), ethoxylated fatty acids, monoglycerides, silicon-based surfactants, polysorbates, and Tergitol® NP- 40 (poly (oxy-1,2-ethanediyl), α- (4-nonylphenol) -ω-hydroxy, branched [molecular weight average 1980]), and Tergitol® NP-70 (mixed surfactant-AQ Non-phospholipid surfactants such as 70%).

(4. Solvent)
Any suitable solvent can be used in the methods and compositions of the present invention. Exemplary solvents include, but are not limited to, long chains such as isopropyl myristate, triacetin, N-methylpyrrolidinone, long chain alcohols, polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, and ethanol and A short chain alcohol is mentioned. Other short chain alcohols and / or amides and aliphatic and aromatic alcohols such as benzyl alcohol may also be used. Solvent mixtures can also be used in the compositions and methods of the present invention.

(5. Water or buffer)
When the method and / or composition of the present invention uses or includes water or a buffer, the aqueous solution is preferably a physiologically compatible solution such as water or phosphate buffered saline.

(6. Other ingredients)
Some other materials may be added to the compositions of the present invention, volatile oils such as volatile flavor oils can be used in place of some oils, or can be added in addition to the main oil. Exemplary volatile oils or fragrances that can be utilized in the present invention include, but are not limited to, balm oil, bay oil, bergamot oil, cedar oil, cherry oil, cinnamon oil, clove oil, and Majorana oil. , And peppermint oil. Colorants such as food colorants can also be used. Exemplary food pigments that can be utilized in the compositions of the present invention include, but are not limited to, green, yellow, red, and blue. The food dye utilized is food grade material (McCormick), but may be replaced with material from other sources. In addition, flavored extracts can be used in the methods and compositions of the present invention. Exemplary flavored extracts include, but are not limited to, pure anise extract (73% alcohol), imitation banana extract (40% ethanol), imitation cherry extract (24% ethanol), Chocolate extract (23% ethanol), pure lemon extract (84% ethanol), pure orange extract (80% ethanol), pure peppermint extract (89% ethanol), imitation pineapple extract (42% ethanol), imitation Examples include lamb extract (35% ethanol), imitation strawberry extract (30% ethanol), and pure or imitation vanilla extract (35% ethanol). The extract typically utilized is food grade material (McCormick), but can be replaced with material from other sources.

(D. Method of using the composition of the present invention)
The compositions of the present invention are useful as a broad range of antimicrobial agents. They can be used, for example, for local or surface disinfection of biological and non-biological surfaces. The composition can be used to disinfect suspected surfaces that have been exposed to microorganisms, such as cooking surfaces, meal surfaces, any surface in the hospital, and areas accessible to children. Biological surfaces include skin, hair, mucous membranes, wound surfaces, insect bites, etc.

  The composition can also be used as a delivery vehicle for active agents such as drugs or cosmetics. The composition eliminates the need to add antimicrobial agents to retard microbial growth. When formulated into a dosage form for administration to a mammal, such as a human, the compositions of the invention can be administered to the subject through any conventional means. The composition can be useful in the formulation of active agents intended to treat wounds and would surfaces. Some of these active agents are not compatible with typical antimicrobial agents. Thus, a vehicle that is essentially an antimicrobial agent would be an ideal delivery system.

  As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably. Furthermore, the composition of the present invention can be applied to any suitable agent such as liquid dispersions, oral suspensions, tablets, gels, mists, ointments, creams, capsules, dry powders, multiparticulates, sprinkles, sachets, lozenges and syrups. Can be formulated into a shape. Furthermore, the dosage forms of the present invention include solid dosage forms, liquid dosage forms, semi-liquid dosage forms, immediate release formulations, modified release formulations, controlled release formulations, immediate dissolution formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulse It can be a release formulation, a mixture of immediate release and sustained release formulations, or any combination thereof.

  The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and pre-formulations. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption such as aluminum monostearate and gelatin.

  Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent, the liquid dosage form may contain inert diluents commonly used in the art such as water or other solvents, solubilizers, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, cottonseed oil, peanut oil, corn germ oil, olive oil and castor. Oils such as 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 compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

  “Therapeutically effective amount” as used herein for an active agent dosage refers to a specific pharmacological response in many subjects in need of such treatment to which an active agent is administered. It shall mean the dosage given. It should be emphasized that a “therapeutically effective amount” administered to a subject in a particular case may not be effective for 100% of patients treated for a disease. Such dosages are not always effective in treating the diseases described herein, even if they are considered “therapeutically effective amounts” by those skilled in the art.

  One skilled in the art will recognize that an effective amount of the active agent can be determined empirically and can be used in pure form or, if such form is present, in a pharmaceutically acceptable salt, ester, or prodrug form. You will understand. The actual dosage level of the active agent in the compositions of the invention may be varied to obtain an amount of active agent that is effective to obtain the desired therapeutic response for the particular composition and method of administration. The dosage level selected will thus depend on the desired therapeutic effect, the route of administration, the potency of the active agent administered, the desired duration of treatment, and other factors.

  A dosage unit composition may contain an amount of that dosage unit that may be used to make up a daily dose. However, it will be appreciated that the particular dose level for any particular patient will depend on a variety of factors such as: The type and degree of cellular or physiological response to be achieved, the activity of the specific drug or composition used, the specific drug or composition used, the patient's age and weight, overall health and sex, diet, time of administration and administration Route and drug excretion rate, duration of treatment, drugs used in combination or at the same time with specific drugs, and similar factors well known in the medical field.

  The following examples are given 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 the specification, all and all references to publicly available literature, including US patents, are specifically incorporated by reference.

(Example 1)
The purpose of this example was to describe the preparation of an exemplary nanostructure composition according to the present invention.

  Ethyl alcohol, soybean oil, and polysorbate 80 were mixed together. Water was then added to the mixture and the resulting composition was mixed well using a vertical stirrer. The amount of each component is shown in Table 1 below.

  The composition was then fed into a high pressure homogenizer (APV Invensys, model APV-1000) to a pressure of 10,000 psi. The mixture was passed twice through a homogenizer.

  Alternatively, water can be added to the ethyl alcohol, oil, and polysorbate 80 mixture under high speed stirring using a rotor stator assembly attached to a Silverson mixer (10,000 rpm, 15 minutes).

  The resulting composition can be used directly as a topical lotion or cream having antibacterial, antiviral, antifungal, and / or anti-yeast properties, or the composition can be formulated into another suitable dosage form. it can.

(Example 2)
The purpose of this example was to describe the preparation of an exemplary nanostructure composition according to the present invention comprising the active agent estradiol.

である。エストラジオールの分子量は２７２．３９である。 Estradiol is chemically described as estra-1,3,5 (10) -triene-3,17β-diol. The molecular formula of estradiol is C ₁₈ H ₂₄ O ₂ and the structural formula is

It is. The molecular weight of estradiol is 272.39.

  Current US Food and Drug Administration (FDA) approved estradiol products include oral pills (Estinyl (R), Estrace (R), Gynodiol (R), Ovcon 35 (R)), transdermal patches (Climara ( (Registered trademark), Vivelle (registered trademark), Estraderm (registered trademark)), vaginal ring (Estring (registered trademark)), and topical emulsion (Estrasorb (registered trademark)). The drug is used to treat moderate to severe symptoms of hot flashes and night sweats associated with menopause, and in hormone replacement therapy to prevent pregnancy.

  Estradiol was dissolved in ethanol. Oil and polysorbate 80 were added to the estradiol solution, water was added to the estradiol / ethyl alcohol / oil / polysorbate 80 mixture, and the resulting composition was mixed well using a vertical stirrer. The amount of each component is shown in Table 2A below.

  The composition was fed into a high pressure homogenizer (APV Invensys, model APV-1000) and the pressure was 10,000 psi. The mixture was passed twice through a homogenizer. The particle size of the composition is detailed in Table 2B below and is further illustrated in FIG.

  Alternatively, estradiol can be dissolved in ethyl alcohol, oil and water can be added to the estradiol solution, and water can be added to the resulting composition under high speed stirring using a rotor stator assembly attached to a Silverson mixer (10,000 rpm, 15 minutes).

  The particle size of the composition according to the Silverson method is detailed in Table 2C below and is further illustrated in FIG.

  When the resulting composition has antibacterial, antiviral, antifungal, and / or anti-yeast properties, it can be used directly as an estradiol topical lotion or cream, or the composition can be formulated into another suitable dosage form. can do.

(Example 3)
The purpose of this example was to describe the preparation of an exemplary nanostructured composition according to the present invention comprising the active agent testosterone.

これは化学式Ｃ_１９Ｈ_２８Ｏ_２および分子量２８８．４２を有する。テストステロンは、例えば注射用剤形、経皮ゲル（AndroGel（登録商標）、Testim（登録商標））、経皮送達装置（Androderm（登録商標）、Testoderm（登録商標））、およびバッカル薬物送達系（Striant（登録商標））で市販される。テストステロンは、例えばホルモン代替療法で使用される。 Testosterone USP is a white to almost white crystalline powder that is chemically described as 17-β hydroxyandroste-4-en-3-one.

It has the chemical formula C ₁₉ H ₂₈ O ₂ and a molecular weight of 288.42. Testosterone can be used in, for example, injectable dosage forms, transdermal gels (AndroGel®, Testim®), transdermal delivery devices (Androderm®, Testoderm®), and buccal drug delivery systems ( Striant®). Testosterone is used, for example, in hormone replacement therapy.

  Testosterone was dissolved in ethyl alcohol. Oil and polysorbate 80 were added to the testosterone solution and water was added to the resulting composition. The resulting composition was mixed well using a vertical stirrer. The amount of each component is shown in Table 3A below.

  The testosterone / ethyl alcohol / oil / polysorbate 80 / water composition was fed into a high pressure homogenizer (APV Invensys, model APV-1000) and the pressure was 10,000 psi. The mixture was passed twice through a homogenizer. The particle size of the composition is detailed in Table 3B below and is further illustrated in FIG.

  Alternatively, testosterone can be dissolved in ethyl alcohol and oil and polysorbate 80 can be added to the testosterone solution. Water can be added to the testosterone / ethyl alcohol / oil / polysorbate 80 composition under high speed stirring using a rotor stator assembly attached to a Silverson mixer (10,000 rpm, 15 minutes).

  The resulting composition can be used directly as a testosterone topical lotion or cream with antibacterial, antiviral, antifungal, and / or anti-yeast properties, or the composition can be formulated into another suitable dosage form Can do.

(Example 4)
This example aimed to determine the effect of excipient concentration on the antimicrobial properties of the formulation. The composition described in Example 1 was diluted 10 times with water and tested for antimicrobial effect.

  The amount of each component is shown in Table 4 below.

  This formulation did not meet the stated criteria when tested according to the USP Antibacterial Effect Test Criteria. The resulting composition cannot be used directly as a topical lotion or cream having antibacterial, antiviral, antifungal, and / or anti-yeast properties, and may be formulated with another composition to provide antimicrobial properties. It cannot be made into an appropriate dosage form.

(Example 5)
The purpose of this example was as yet another example to determine the effect of excipient concentration on the antimicrobial properties of the formulation. The composition of Example 1 was diluted 50 times with water and tested for antimicrobial properties.

  The amount of each component is shown in Table 4 below.

  This formulation did not meet the stated criteria when tested according to the USP Antibacterial Effect Test Criteria. The resulting composition cannot be used directly as a topical lotion or cream having antibacterial, antiviral, antifungal, and / or anti-yeast properties, and may be formulated with another composition to provide antimicrobial properties. It cannot be made into an appropriate dosage form.

(Example 6)
The purpose of this example was to describe the preparation of an exemplary nanostructure composition according to the present invention.

  Ethyl alcohol, soybean oil, and Pluronic F-68 were mixed together. Water was then added to the mixture and the resulting composition was mixed well using a vertical stirrer. The amount of each component is shown in Table 6 below.

  The composition was then fed into a high pressure homogenizer (APV Invensys, model APV-1000) and the pressure was 10,000 psi. The mixture was passed twice through a homogenizer.

  Alternatively, water can be added to the ethyl alcohol, oil, and Pluronic F-68 mixture under high speed stirring using a rotor stator assembly attached to a Silverson mixer (15 minutes at 10,000 rpm).

  The resulting composition can be used directly as a topical lotion or cream having antibacterial, antiviral, antifungal, and / or anti-yeast properties, or the composition can be formulated into another suitable dosage form. it can.

(Example 7)
The purpose of this example was to describe the preparation of an exemplary nanostructure composition according to the present invention.

  Ethyl alcohol, benzyl alcohol, isopropyl myristate, light oil, and Pluronic F-68 were mixed together. Water was then added to the mixture and the resulting composition was mixed well using a vertical stirrer. The amount of each component is shown in Table 7 below.

  The composition was then fed into a high pressure homogenizer (APV Invensys, model APV-1000) and the pressure was 10,000 psi. The mixture was passed twice through a homogenizer.

  Alternatively, water can be added to the ethyl alcohol, oil, and Pluronic F-68 mixture under high speed stirring using a rotor stator assembly attached to a Silverson mixer (10,000 rpm, 15 minutes).

  The resulting composition can be used directly as a topical lotion or cream with antibacterial, antiviral, antifungal, and / or anti-yeast properties, or the composition can be formulated into another suitable dosage form Can do.

(Example 8)
The purpose of this example was to describe the preparation of nanostructured compositions containing propofol, which is a model active pharmaceutical ingredient and does not meet USP antimicrobial efficacy testing criteria.

  Propofol, ethyl alcohol, soybean oil, and polysorbate 80 were mixed together. Next, brine was added to the mixture and the resulting composition was mixed well using a vertical stirrer. The amount of each component is shown in Table 8 below.

  The composition was then fed into a high pressure homogenizer (APV Invensys, model APV-1000) to a pressure of 10,000 psi. The mixture was passed twice through a homogenizer.

  This formulation did not meet the stated criteria when tested according to the USP Antimicrobial Effect Test Criteria.

Example 9
The purpose of this example was to determine the antibacterial effect of the composition prepared as described in Example 1.

  Antibacterial tests were performed according to USP 25, <51>, pages 1869-1871. An aliquot of the composition prepared as described in Example 1 was exposed to the following various bacteria, yeasts or fungi. Aspergillus niger (fungi), Candida albicans (yeast), Escherichia coli (bacteria), Pseudomonas aeruginosa (bacteria), Staphylococcus aureus (Staphylococcus aureus) Bacteria), Aspergillus fumigatus (fungus), and Aspergillus flavus (fungus).

  Prior to testing, the surface of an appropriate volume of solid agar was inoculated with a stock culture reactivated recently for each organism shown in Table 4 below. The amount of inoculum for each test of the composition prepared as in Example 1 is shown in Table 4 below. The amount of bacteria, fungi, or yeast was measured at day 7, day 14, and day 28 at the time of inoculation. The culture conditions followed USP25, <51>, pages 1869-1871. The test results are shown in Table 4. The results are further illustrated in FIGS.

  The results dramatically demonstrate the surprising effectiveness of the compositions of the present invention as antibacterial, antifungal and anti-yeast drugs. Except for one organism tested (A. niger), all organisms were eradicated after 7 days. In A. niger, the growth of the organism dramatically declined and only 70 cfu / g was measured on the 28th day. The results further demonstrate that the composition meets the requirements of USP 25 Antimicrobial Effectiveness Test.

(Example 10)
This example determines the antibacterial effect of the composition prepared as described in Example 2, and the addition of an active agent such as estradiol is an antibacterial, anti-yeast, antifungal, And / or aimed to determine whether it affects antiviral properties. This example also evaluates the effect of varying amounts of alcohol present in the compositions of the present invention on antimicrobial activity.

  The antibacterial test was performed according to USP 25, <51>, pages 1869-1871. An aliquot of the composition prepared as described in Example 2 was exposed to the following various bacteria, yeasts or fungi. Aspergillus niger (fungi), Candida albicans (yeast), Escherichia coli (bacteria), Pseudomonas aeruginosa (bacteria), and Staphylococcus aureus (Bacteria).

  Prior to testing, the surface of an appropriate volume of solid agar was inoculated with stock cultures reactivated recently for each organism shown in Table 5 below. The amount of inoculum for each test of the composition prepared as described in Example 2 is shown in Table 5 below. The amount of bacteria, fungi, or yeast was measured at the time of inoculation on day 14 (Table 5) and day 28 (Table 6). The culture conditions followed USP25, <51>, pages 1869-1871. The test results are shown in Tables 5 and 6. The results are further illustrated in FIG.

Example 11
This example determines the antibacterial effect of a composition prepared as described in Example 3, and the addition of an active agent such as testosterone is an antibacterial, anti-yeast, antifungal, And / or aimed to determine whether it affects antiviral properties.

  The antibacterial test was performed according to USP 25, <51>, pages 1869-1871. An aliquot of the composition prepared as described in Example 2 was exposed to the following various bacteria, yeasts or fungi. Aspergillus niger (fungi), Candida albicans (yeast), Escherichia coli (bacteria), Pseudomonas aeruginosa (bacteria), and Staphylococcus aureus (Bacteria).

  Prior to testing, the surface of an appropriate volume of solid agar medium was A. niger, C.I. Inoculated with recently reactivated stock cultures of C. albicans, E. coli, P. aeruginosa, and S. aureus organisms. The amount of bacteria, fungi, or yeast was measured at day 7, day 14, and day 28 at the time of inoculation. The culture conditions followed USP25, <51>, pages 1869-1871. The test results shown in Table 4 dramatically demonstrate the surprising effectiveness of the compositions of the present invention as antibacterial, antifungal, and anti-yeast drugs when the compositions are used as drug delivery vehicles. Yes. Surprisingly, the presence of the active agent does not abrogate the antimicrobial effect of the composition of the present invention. The results further demonstrate that the composition meets the requirements of USP 25 Antimicrobial Effectiveness Test.

  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. Thus, it is intended that the present invention cover various modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

FIG. 1 shows the results of an antibacterial effect test of a placebo composition of the present invention (ie, lacking an active agent) performed according to the protocol defined in USP 25, <51>, pages 1869-1871 (E. coli (E E. coli (ATCC 8739), P. aeruginosa (ATCC 9027), S. aureus (ATCC 6538), C. albicans (ATCC 10231), and A. coli. Test with A. niger (ATCC 16404). FIG. 2 was performed according to the protocol defined in USP 25, <51>, pages 1869-1871, but with microorganisms (P. aeruginosa ATCC 13388), P. aeruginosa (ATCC 25619). ) A. flavus, and A. flavus Figure 3 shows the results of an antibacterial effect test of a placebo composition of the present invention (i.e. lacking active agent) with the addition of A. fumigatus. FIG. 3 shows the results of the antibacterial effect test of the estradiol composition of the present invention carried out according to the protocol defined in USP 25, <51>, pages 1869-1871 (E. coli (ATCC 8739)). P. aeruginosa (ATCC 9027), S. aureus (ATCC 6538), C. albicans (ATCC 10231), and A. niger ( Test in ATCC 16404)). FIG. 4 shows the results of an antibacterial effect test of the testosterone composition of the present invention, performed according to the protocol defined in USP 25, <51>, pages 1869-1871 (E. coli (ATCC 8739)). P. aeruginosa (ATCC 9027), S. aureus (ATCC 6538), C. albicans (ATCC 10231), and A. niger ( Test in ATCC 16404)). FIG. 5 shows the particle size of estradiol within the nanostructure composition after homogenization. FIG. 6 shows the particle size of estradiol in the nanostructure composition after the Silverson method. FIG. 7 shows the particle size of testosterone in the nanostructure composition after homogenization.

Claims (19)

(A) at least one solvent,
(B) at least one surfactant;
An antimicrobial composition comprising (c) at least one oil, and (d) an emulsion of water,
An antimicrobial composition that meets US Pharmacopeia (USP) testing requirements for antimicrobial efficacy.   E. coli (ATCC 8739), P. aeruginosa (ATCC 9027), S. aureus (ATCC 6538), C.I. C. albicans (ATCC 10231); The composition of claim 1 having an antimicrobial effect against one or more of A. niger (ATCC 16404).   P. aeruginosa (ATCC 13388), P. aeruginosa (ATCC 25619), A. flavus, and A. aeruginosa. 3. The composition of claim 2, having an antibacterial effect against one or more of A. fumigatus.   2. The composition of claim 1 comprising oil: stabilizer: solvent in a ratio of about 23: about 5: about 4 on a weight to weight basis, respectively.   2. The composition of claim 1, comprising an oil comprising the phase and water or buffer, each in a ratio of about 2: 1: 1. (A) about 10% to about 30% (w / w) of the oil;
(B) about 0.5% to about 10% (w / w) of the solvent,
(C) about 1% to about 8% (w / w) of the surfactant,
(D) about 20% to about 80% (w / w) of the water, or (e) any combination thereof.
The composition of claim 1 comprising:   (A) at least one active agent dissolved in the solvent, (b) at least one active agent dissolved in the oil, (c) at least one active agent dissolved in the water, (d) the solvent Particles of at least one active agent present in, (e) particles of at least one active agent present in the oil, (f) particles of at least one active agent present in the water, (g) or The composition of claim 1 further comprising a combination.   8. The composition of claim 7, wherein the active agent is acyclovir, cyclosporine, naltrexone, alendronic acid, ceterizine, nicotine, testosterone, progesterone, or estradiol.   8. The composition of claim 7 comprising oil globules containing dissolved active agent.   The oil globules consist of less than about 1 μm in diameter, 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 200 nm, and less than about 100 nm 10. The composition of claim 9, having a particle size selected from the group.   8. The active agent particle, the oil droplet containing the solubilized active agent, the water droplet containing the solubilized agent, or a combination thereof, has an average particle size less than about 10 μm in diameter. Composition.   The active agent particles, oil droplets containing the solubilized active agent, water droplets containing the solubilized agent, or combinations thereof, having a diameter of less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm; 12. The composition of claim 11, having an average particle size selected from the group consisting of less than about 5 [mu] m, less than about 4 [mu] m, and about 3 [mu] m or more.   8. The active agent particle, the oil droplet containing the solubilized active agent, the water droplet containing the solubilized agent, or a combination thereof, has an average particle size of less than about 3 μm in diameter. Composition.   The active agent particles, oil droplets containing the solubilized active agent, water droplets containing the solubilized agent, or combinations thereof are less than about 2900 nm, less than about 2800 nm, less than about 2700 nm, less than about 2600 nm, about Less than 2500 nm, less than about 2400 nm, less than about 2300 nm, less than about 2200 nm, less than about 2100 nm, less than about 2 μm, 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 1 μm, 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 200 nm, less than about 100 nm, about Less than 90nm Having an average particle size selected from the group consisting of: less than about 80 nm, less than about 70 nm, less than about 60 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, and less than about 10 nm. The composition as described.   The solvent is selected from the group consisting of isopropyl myristate, triacetin, N-methylpyrrolidinone, aliphatic and aromatic alcohols, ethanol dimethyl sulfoxide, dimethylacetamide, ethoxydiglycol, polyethylene glycol, and propylene glycol. A composition according to 1.   The oil is almond oil (sweet tonsil), apricot oil, borage oil, canola oil, coconut oil, corn oil, cottonseed oil, fish oil, jojoba bean oil, lard oil, linseed oil (boiling), macadamia nut oil, medium chain triglyceride, Claims selected from the group consisting of mineral oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, squalene, sunflower seed oil, tricaprylin (1,2,3-trioctanoylglycerol), and wheat germ oil Item 2. The method according to Item 1.   The surfactant is sorbitan ester, glycerol ester, polyethylene glycol ester, block polymer, acrylic polymer (such as Pemulen), ethoxylated fatty acid ester (such as Cremophor RH-40), ethoxylated alcohol (such as Brij), ethoxylated fatty acid (such as 2. The method of claim 1 selected from the group consisting of Tween 20), monoglycerides, silicon-based surfactants, and polysorbates.   The sorbitan ester surfactant is Span and Arlacel, the glycerol ester is glyceryl monostearate, the polyethylene glycol ester is polyethylene glycol stearic acid, the block polymer is Pluronic, and the acrylic polymer is Pemulen. 18. The method of claim 17, wherein the ethoxylated fatty acid ester is Cremophor RH-40, the ethoxylated alcohol is Brij, and the ethoxylated fatty acid is Tween 20. (A) at least one solvent,
(B) at least one surfactant;
A method of disinfecting a biological or non-biological surface comprising exposing to a composition comprising (c) at least one oil, and (d) water.
A method wherein the composition meets US Pharmacopeia (USP) testing requirements for antimicrobial efficacy.

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