HK1095770A - High-pressure sterilization to terminally sterilize pharmaceutical preparations and medical products - Google Patents

Description

Autoclaving for the terminal sterilisation of pharmaceutical preparations and pharmaceutical products

Background

Technical Field

The present invention provides a method of sterilizing a dispersion of microparticles or microdroplets of a pharmaceutical agent, such as a pharmaceutically active substance, using the technique of autoclaving (terminal sterilization), and the product resulting from the method.

Background

Increasingly, organic compounds that are poorly soluble or insoluble in aqueous solutions are being formulated as formulations for therapeutic or diagnostic effects. Such drugs present challenges for their delivery via the route of administration typically employed by medical personnel. One potential solution to this challenge is to produce microparticles thereof by preparing a dispersion of micro-or nano-sized microparticles from insoluble drug candidates. Advantages of such formulations may include higher loading, reduced toxicity, improved drug saturation solubility and/or dissolution rate, improved potency, and enhanced drug stability.

Thus, drugs that were previously not formulated in water-based systems can be manufactured to be suitable for different routes of administration. The preparation of a microparticle dispersion of a water-insoluble drug can be delivered by intravenous, oral, pulmonary, topical, intrathecal, ocular, nasal, buccal, rectal, vaginal, and transdermal routes. The optimum particle size range for these dispersions will generally depend on the particular route of administration, the characteristics of the microparticles, and other factors, e.g., in the case of intravenous administration, a particle size of less than about 7 μm is desired. The particles must be within this size range and not aggregate to safely pass through capillaries without causing emboli (Allen et al, 1987; Davis and Taube, 1978; Schroeder et al, 1978; Yokel et al, 1981).

Depending on the route of administration and other factors, these microparticle dispersions have to meet certain requirements for sterility. One useful sterilization method is conventional terminal autoclaving of the microparticle dispersion at 121 ℃. It is well known to protect pharmaceutical suspensions from particle growth and/or aggregation during storage at conventional temperatures by the presence of surfactants in the formulation. However, even in the presence of these stabilizing surfactants, the particulate suspensions are often quite heat sensitive and cannot withstand terminal autoclaving. The pharmaceutically active component, surfactant, and drug/surfactant combination need to be physically and chemically stable throughout the sterilization process at 121 ℃. The chemical susceptibility (chemical susceptibility) of the microparticle dispersion to terminal autoclaving is known as a function of sterilization time and temperature. Methods to reduce chemical instability typically involve high temperature short time sterilization methods. In this case, preservation of the heat-labile formulation and destruction of the microorganism are based on the rate difference between the respective chemical degradation and inactivation. An important problem in this process is to obtain a sufficiently rapid heat transfer so that a uniform temperature is produced throughout the product within a very short contact time.

It is also often difficult to maintain the physical stability of the drug/surfactant combination. In the presence of heat, the microparticles often aggregate, grow, and/or degrade, rendering the final dispersion unusable. In addition, the surfactant combination can be separated from the pharmaceutically active substance in an irreversible manner. For example, one mechanism for aggregation or agglomeration of solid nanoparticulate dispersions can directly involve stabilizing the precipitation of the surfactant at temperatures above the cloud point of the surfactant during the sterilization process. The term "cloud point" refers to the separation of an isotropic surfactant solution into a surfactant-rich phase and a surfactant-poor phase. At such temperatures, the surfactant often separates from the particles, causing unprotected particles to aggregate and/or grow. Thus, various patents (e.g., US5,298,262, US5,346,702, US5,470,583, US5,336,507) disclose the use of ionic and nonionic cloud point modifiers for stabilizing particle suspensions during autoclaving. These modifiers raise the cloud point of the surfactant to above 121 ℃, prevent separation of the surfactant from the drug particles, and subsequently stabilize the particles from growth during terminal sterilization.

Us patent 6,267,989 also discloses that the optimum particle size range is most important for minimizing growth and instability during autoclaving. The 6,267,989 patent reports that the highest stability is exhibited when at least 50% of the surfactant-stabilized drug particles have a weighted average particle size of 150-350 nm.

Thus, there is a continuing need to develop new and improved methods for the terminal sterilization of microparticle dispersions in the pharmaceutical field, and the present invention meets these needs.

Systems and solutions other than microparticle dispersions often require sterilization prior to use. Examples include dissolved pharmaceutical solutions, solutions for renal applications (e.g., peritoneal dialysis), and other pharmaceutical formulation forms such as lipid emulsions. Other examples include disposable medical devices such as bags containing medication (often made of plasticized PVC or other plastic), bags containing blood, dialyzers, systems for use on automated devices (e.g., blood separation devices, infusion pumps, etc.). Such systems may be sensitive to conventional sterilization techniques such as gamma sterilization, ETO sterilization, or autoclaving. For example, solutions containing glucose are susceptible to glucose breakdown after conventional sterilization techniques. Accordingly, there is also a need to provide improved sterilization techniques for providing adequate sterilization with little to no harm to the sterilized system.

Disclosure of Invention

The present invention provides methods for sterilizing a system. Such systems may be, but are not limited to, compositions such as particulate dispersions; and devices, such as containers that may contain an aqueous solution, such as a pharmaceutical formulation. The advantage of this method is that sterilization is provided without significantly impairing the efficacy of the system. The invention further provides a sterilized pharmaceutical formulation. Suitable containers include any container that is stable under the methods of the present invention, including drug delivery devices containing medical solutions.

The method involves supplying thermal energy to the system and pressurizing the system above 0.25MPa for a time sufficient to sterilize the system. Preferably, the system reaches temperatures in excess of 70 ℃. The steps of supplying thermal energy and pressurizing are performed simultaneously for a period of time at least sufficient to sterilize the system. The system may then be returned to ambient temperature and pressure for standby.

The method may be used with an empty container or a container containing any of a variety of solutions: solutions for parenteral administration; solutions for acute or chronic hemodialysis; hemofiltration solutions or hemodiafiltration solutions for acute or chronic peritoneal dialysis, ambulatory peritoneal dialysis and automated peritoneal dialysis.

The method is particularly useful for sterilization of solutions comprising glucose. The lower temperature used for sterilization minimizes glucose degradation that occurs at higher temperatures. Thus, the method may be used to sterilize solutions comprising glucose such that the glucose remains substantially undegraded. Preferably, more than about 75% of the glucose is undegraded after sterilization, more preferably more than about 80% of the glucose is undegraded, more preferably more than about 85%, or more than about 90%, or even more preferably more than about 95% of the glucose in the sterilized solution is undegraded.

These and other aspects and features of the present invention are discussed with reference to the following figures and description.

Drawings

FIG. 1 shows a micelle;

FIG. 2 shows a reversed micelle;

FIG. 3 shows a lamellar phase;

FIG. 4 shows a hexagonal phase;

FIG. 5 shows a cubic phase;

FIG. 6 shows a pressure-time-temperature profile;

FIG. 7 shows a particle size distribution curve (example 1);

FIG. 8 shows an example particle size distribution of a control sample (example 1);

FIG. 9 shows an autoclaving cycle (example 1);

FIG. 10 shows a particle size distribution curve;

FIG. 11 shows a container for a flowable substance;

FIG. 12 shows a multi-compartment peelable seal container;

FIG. 13 shows a single layer film;

FIG. 14 shows a bilayer film;

FIG. 15 shows a three-layer film;

FIG. 16 shows a three layer film;

FIG. 17 shows a four layer film;

FIG. 18 shows a four layer film;

FIG. 19 shows a five-layer film;

FIG. 20 shows a six layer film;

FIG. 21 shows a six layer film;

FIG. 22 shows a seven layer film;

FIG. 23 shows a syringe;

figure 24 shows a receiving cylinder (cartridge) for a drug delivery device; and

figure 25 shows a fluid inlet device.

Detailed description of the invention

While this invention is susceptible of embodiment in many different forms, there is shown in the drawings and will herein be described in detail specific embodiments, with the understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the invention to the specific embodiments illustrated.

The present invention provides methods of sterilizing a system without significantly impairing the usability, stability, and/or efficacy of the formulation. The present invention provides a method of sterilizing a dynamic system (i.e., a system capable of going from a steady state to an unstable state) wherein the system is subjected to an elevated pressure for a time sufficient to sterilize the system without causing the system to go from a steady state to an unstable state.

As used herein, the term "sterilize" and variants thereof refers to the killing or control of bacteria, viruses, protozoa, or other biological microorganisms in a system such that the system provides a reduced risk of infection when used in a mammal, preferably a human. Preferred methods of the invention sterilize the system to the extent that all or substantially all of the biological microorganisms are killed or unable to replicate.

Preferably, the method is used to sterilize a pharmaceutical system. Pharmaceutical formulations can be prepared by a variety of techniques known and to be developed in the art. Generally, the method provides for subjecting the system to autoclaving. The process is preferably used for autoclaving of particle dispersions. The invention further provides a sterilized pharmaceutical dispersion.

The autoclaving technique of the invention allows for the sterilization of microparticle dispersions without causing significant degradation of the pharmaceutically active substance, degradation of the surfactant, or transformation into drug/surfactant assemblies (assembly). Furthermore, heat is instantaneously transferred throughout the dispersion due to the rapid adiabatic warming of the formulation during the pressurization step. It is contemplated that the autoclaving technique is suitable for many microparticle dispersions containing different pharmaceutical compounds in a variety of container configurations.

In general, the method provides for autoclaving the pharmaceutical formulation. Pharmaceutical formulations can be prepared by a variety of techniques known and to be developed in the art. Autoclaving techniques are well suited to sterilize many different forms of formulations including dry or powder forms, liquid forms, gaseous forms, or pharmaceutically effective compounds dispersed as particles or droplets in an aqueous or organic medium. Preferably, the system to be sterilized contains some water. The presence of water has been shown to provide particular effectiveness in reducing the active microbial load. It is well known to use surfactants to stabilize pharmaceutically active substances against aggregation and particle size variation. The surfactant may be associated with the pharmaceutically active substance (the ascolite) in one of a number of ways well known in the art. The autoclaving technique of the invention allows sterilization without causing degradation of the pharmaceutically active substance or without causing significant separation of the surfactant from the pharmaceutically active substance. The process and product of the present invention do not require the use of chemical cloud point modifiers. The term "cloud point" refers to an increase in turbidity of a pharmaceutical formulation when a change in a physical property of the formulation, such as temperature or a change in pH or other physical property, causes the surfactant to separate from the pharmaceutically active substance.

Autoclaving techniques are contemplated for a variety of organic compounds.

I. Pharmaceutically active substances

In general, the method of the invention is suitable for the sterilization of pharmaceutical preparations. In a preferred method of the invention, the pharmaceutically active ingredient is such that it is associated with hydrophobic domains (e.g., hydrophobic phase assembled by surfactant, cyclodextrin cavity, oil droplets) dispersed in an aqueous solution. The pharmaceutically active substance may be selected from therapeutic agents, products for renal therapy, diagnostic agents, cosmetics, nutritional supplements, and pesticides.

The pharmaceutically active agent may be selected from a variety of known classes, such as, but not limited to: analgesics, anesthetics, stimulants, adrenergic agents, adrenergic blockers, antiadrenergic agents, adrenocorticoids, adrenocorticotropic agents, anticholinergics, anticholinesterases, anticonvulsants, alkylating agents, alkaloids, allosteric inhibitors, anabolic steroids, anorectics, antacids, antidiarrheals, antidotensics, antifolates, antipyretics, antirheumatics, psychotherapeutics, nerve blockers, anti-inflammatory agents, anthelmintics, antiarrhythmics, antibiotics, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifungals, antihistamines, antihypertensives, antimuscarinics, antimalarials, antiseptics, antineoplastics, antiprotozoals, immunosuppressants, immunostimulants, antithyroids, antivirals, anxiolytics, astringents, anti-psychotics, anti-cholinergics, anti-psychotics, anti-psychotropics, anti-psychotics, beta-adrenergic receptor blockers, contrast agents, corticosteroids, antitussives, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergic agents, hemostatics, hematologic agents, hemoglobin modifiers, hormones, hypnotics, immunological agents (immuneologicalgenes), antihyperlipidemic agents and other lipid-modulating agents, muscarinic agents (muscarinics), muscle relaxants, parasympathomimetics, parathyroid calcitonin, prostaglandins, radiopharmaceuticals, sedatives, sex hormones, antiallergics, stimulants, sympathomimetics, thyroid agents, vasodilators, vaccines, vitamins, and xanthines. Antineoplastic or anticancer agents include, but are not limited to, paclitaxel and derivative compounds, and other antineoplastic agents selected from the group consisting of alkaloids, antimetabolites, enzyme inhibitors, alkylating agents, and antibiotics. The therapeutic agent may also be a biologic, which includes, but is not limited to, proteins, polypeptides, carbohydrates, polynucleotides, and nucleic acids. The protein may be an antibody, which may be polyclonal or monoclonal.

Diagnostic agents include X-ray imaging drugs and contrast agents. Examples of X-ray imaging agents include WIN-8883 (ethyl 3, 5-diacetamido-2, 4, 6-triiodobenzoate), also known as diatrizoic acid (eda); WIN 67722, i.e., (6-ethoxy-6-oxohexyl-3, 5-bis (acetamido) -2, 4, 6-triiodobenzoate, ethyl-2- (3, 5-bis (acetamido) -2, 4, 6-triiodo-benzoyloxy) butyrate (WIN 16318), ethyl diatriz oxyacetate (WIN 12901), ethyl 2- (3, 5-bis (acetamido) -2, 4, 6-triiodobenzoyloxy) propionate (WIN 16923), N-ethyl 2- (3, 5-bis (acetamido) -2, 4, 6-triiodobenzoyloxy acetamide (WIN 65312), isopropyl 2- (3, 5-bis (acetamido) -2, 4, 6-triiodobenzoyloxy) acetamide (WIN 12855), 2- (3, diethyl 5-bis (acetamido) -2, 4, 6-triiodobenzoyloxymethylmalonate (WIN 67721); ethyl 2- (3, 5-bis (acetamido) -2, 4, 6-triiodobenzoyloxy) phenylacetate (WIN 67585); malonic acid, [ [3, 5-bis (acetylamino) -2, 4, 5-triiodobenzoyl ] oxy ] bis (1-methyl) ester (WIN 68165); and benzoic acid, 3, 5-bis (acetylamino) -2, 4, 6-triiodo-4- (ethyl-3-ethoxy-2-butenoic acid) ester (WIN 68209). Preferred contrast agents include those that are expected to disintegrate relatively rapidly under physiological conditions, thereby minimizing any particles associated with an inflammatory response. Disintegration can result from enzymatic hydrolysis, solubilization of carboxylic acids at physiological pH, or other mechanisms. Thus, iodinated carboxylic acids having poor solubility such as iodipamide acid, diatrizoic acid, and metrizoate acid; and hydrolytically unstable iodinated substances such as WIN 67721, WIN12901, WIN 68165, and WIN 68209 or others.

Other contrast agents include, but are not limited to, particulate formulations of nuclear magnetic resonance machine aids such as gadolinium chelates, or other paramagnetic contrast agents. Examples of such compounds are gadopentetate dimeglumine (Magnevist ®) and gadoteridol (Prohance ®).

Descriptions of these classes of therapeutic and diagnostic agents and lists of substances within each class can be found in Martindale, The Extra Pharmacopoeia, twenty-ninth edition, The pharmaceutical Press, London, 1989, which is incorporated herein by reference and made a part hereof. Therapeutic and diagnostic agents are commercially available and/or can be prepared by techniques known in the art.

Renal treatments include solutions for continuous ambulatory peritoneal dialysis, automated peritoneal dialysis, and hemodialysis.

A cosmetic drug is any active ingredient capable of having cosmetic activity. Examples of such active ingredients may be, inter alia, emollients, moisturizers, free radical inhibitors, anti-inflammatory agents, vitamins, depigmenting agents, anti-acne agents, anti-irritant lipophiles (antistthorheics), keratolytics, antiobesity agents, skin-coloring agents and sunscreens, and in particular linoleic acid, vitamin a acid, alkyl ascorbates, polyunsaturated fatty acids, nicotinic acid esters, vitamin E nicotinate esters, unsaponifiables of rice, soybean or shea butter (shea), ceramides, alkyds such as glycolic acid, selenium derivatives, antioxidants, beta-carotene, gamma-ferulate, and octadecyl glycerate. Cosmetic products are commercially available and/or can be prepared by techniques known in the art.

Examples of nutritional supplements contemplated for use in the practice of the present invention include, but are not limited to, proteins, carbohydrates, water-soluble vitamins (e.g., vitamin C, vitamin B complex, etc.), fat-soluble vitamins (e.g., vitamin A, D, E, K, etc.), and herbal extracts. The nutritional supplement is commercially available and/or can be prepared by techniques known in the art.

The term insecticide (pesticide) should be understood to include herbicides, insecticides (insecticides), acaricides, nematicides, ectoparasiticides and fungicides. Examples of the compounds belonging to the insecticide of the present invention may include urea, triazine, triazole, carbamate, phosphate ester, dinitroaniline, morpholine, acylalanine, pyrethroid, benzilic acid ester, diphenyl ether and polycyclic halogenated hydrocarbon. Specific examples of insecticides in each of these classes are listed in Pesticide Manual, ninth edition, British Crop Protection Council. The insecticides are commercially available and/or can be prepared by techniques known in the art.

Preferably, the pharmaceutically active substance is poorly water soluble. By "poorly water soluble" is meant that the compound has a solubility in water of less than about 10mg/mL, preferably less than 1 mg/mL. These poorly water soluble drugs are best suited for aqueous suspension formulations because of the limited alternatives to formulating these drugs in aqueous media.

In some cases, the invention may also be practiced using water-soluble pharmaceutically active substances by entrapping the compounds in a solid hydrophobic dispersed phase (e.g., a polyacetate-polyhydroxyacetate copolymer or solid lipid nanoparticles), or by encapsulating the compounds in an encapsulating surfactant assembly that is impermeable to the pharmaceutical compound. Examples of surfactant assemblies include, but are not limited to vesicles (vesicles) and micelles. Examples of water-soluble drugs include, but are not limited to, simple organic compounds, proteins, peptides, nucleotides, oligonucleotides, and carbohydrates.

Particle size of the Dispersion and route of administration

When the drug of the present invention is in particulate form (i.e., not dissolved in a solvent), the particles typically have an average effective particle size of less than about 100 μm as measured by dynamic light scattering methods such as photocorrelation spectroscopy, laser diffraction, Low Angle Laser Light Scattering (LALLS), Medium Angle Laser Light Scattering (MALLS), light opacity methods (Coulter method, for example), rheology, or microscopy (light or electron). However, the particles can be prepared in a wide range of particle sizes, such as from about 100 μm to about 10nm, from about 10 μm to about 10nm, from about 2 μm to about 10nm, from about 1 μm to about 10nm, from about 400nm to about 50nm, from about 200nm to about 50nm, or any range or combination of ranges therein. The preferred average effective particle size will depend on a variety of factors, such as the intended route of administration; formulation, solubility, toxicity and bioavailability of the compounds.

To be suitable for parenteral administration, it is preferred that the particles have an average effective particle size of less than about 7 μm, more preferably less than about 2 μm, or any range or combination of ranges therein. Parenteral administration includes intravenous, intraarterial, intrathecal, intraperitoneal, intraocular, intraarticular, intradural, intraventricular, intrapericardial, intramuscular, intradermal, or subcutaneous injection.

The particle size for oral dosage forms may exceed 2 μm. The particle size may be up to about 100 μm, provided that the particles have sufficient bioavailability and other characteristics of an oral dosage form. Oral dosage forms include tablets, capsules, caplets, soft and hard gelatin capsules, or other delivery vehicle forms for delivering a drug by oral administration.

The invention is further suitable for providing particles of a pharmaceutically active substance in a form suitable for pulmonary administration. The particle size of the transpulmonary dosage form can exceed 500nm and is typically less than about 10 μm. The particles in suspension may be aerosolized and administered by a nebulizer for transpulmonary use. Alternatively, the particles may be administered by a dry powder inhaler as a dry powder after removal of the liquid phase from the suspension, or the dry powder may be resuspended in a non-aqueous propellant for administration by a metered dose inhaler. Examples of suitable propellants are fluorinated Hydrocarbons (HFC) such as HFC-134a (1, 1,1, 2-tetrafluoroethane) and HFC-227ea (1, 1,1, 2,3, 3, 3-heptafluoropropane). Unlike chlorofluorocarbons (CFCs), HFCs exhibit little or no ozone depletion potential.

Particles and droplets of the organic compound within the above-described particle size range are collectively referred to as microparticles.

Dosage forms for other delivery routes, such as nasal, topical, ocular, nasal, buccal, rectal, vaginal, transdermal, and the like, may also be formulated from the particles produced by the present invention.

Other forms of solutions may be sterilized by the present invention. Examples of such solutions include pharmaceutical preparations for parenteral administration and solutions for renal dialysis, such as hemodialysis and peritoneal dialysis solutions.

Preparation of the microparticle Dispersion

There are various techniques for preparing pharmaceutical formulations of microparticles of pharmaceutically active substances. The sterilization techniques discussed below are suitable for sterilizing such pharmaceutical formulations. Representative but non-exhaustive examples for providing microparticles of pharmaceutically active substances are briefly discussed below.

A. Energy introduction (energe addition) technique for forming microparticle dispersions

In general, the process for preparing a dispersion of microparticles using energy introduction techniques comprises the step of adding a pharmaceutically active substance, commonly referred to as a drug, in bulk form to a suitable medium, such as water or an aqueous solution, or other fluid in which the pharmaceutical compound is insoluble, containing one or more surfactants described below, to form a pre-suspension (prespension). Energy is introduced into the pre-suspension to form a particle dispersion. The energy is introduced by mechanical milling, bead milling, ball milling, hammer milling, fluid energy milling, or wet milling. Such a technique is disclosed in U.S. Pat. No. 5,145,684, which is incorporated herein by reference and made a part hereof.

The energy introduction technique further comprises subjecting the pre-suspension to high shear conditions, including cavitation, shear or impact forces using a microfluidizer. The present invention further contemplates the use of piston gap homogenizers (piston gap homogenizers) or counter-current homogenizers to introduce energy to the pre-suspension, such as those disclosed in U.S. Pat. No. 5,091,188, which is incorporated herein by reference and made a part hereof. Suitable piston gap homogenizers are available under the product names EMULSIFLEX and French Pressure Cells from Spectronic Instruments of Avestin. Suitable microfluidizers (microfluidizer) are available from Microfluidics corp.

The step of introducing energy may also be accomplished using ultrasonic techniques. The step of sonicating may be performed using any suitable sonication device, such as a Branson Model S-450A or a Cole-Parmer 500/750 Watt Model. Such devices are well known in the art. Typically, the sonication device has a sonication sonar or probe inserted into the pre-suspension to emit ultrasonic energy sonic energy into the solution. In a preferred form of the invention, the ultrasonic treatment device is operated at a frequency of about 1kHz to about 90kHz, more preferably about 20kHz to about 40kHz, or any range or combination of ranges therein. The probe size may vary and is preferably different such as 1/2 inches or 1/4 inches.

Regardless of the energy introduction technique used, the microparticle dispersion needs to meet the appropriate sterility assurance prior to use. Sterilization may be accomplished using sterilization techniques as described below.

B. Precipitation process for preparing a dispersion of submicron sized particles

The microparticle dispersion can also be prepared by well-known precipitation techniques. The following is a precipitation technique for producing solid submicron dispersions.

Microprecipitation (microprecipitation) method

One example of a microprecipitation method is disclosed in U.S. patent 5,780,062, which is incorporated herein by reference and made a part hereof. The 5,780,062 patent discloses an organic compound precipitation process that includes: (i) dissolving an organic compound in a first water-miscible solvent; (ii) preparing a solution of the polymer and the amphiphilic molecule in an aqueous second solvent, and the organic compound is substantially insoluble in the second solvent, thereby forming a polymer/amphiphilic molecule complex; and (iii) mixing the solutions of steps (i) and (ii) so as to cause precipitation of aggregates (aggregatates) of the organic compound and the polymer/amphiphile complex.

Another example of a suitable precipitation method is disclosed in pending and commonly assigned U.S. patent application nos. 09/874,499, 09/874,799, 09/874,637, and 10/021,692, which are incorporated herein by reference and made a part hereof. The disclosed method comprises the steps of: (1) dissolving an organic compound in a first organic solvent that is miscible with water to form a first solution; (2) mixing the first solution with a second solvent or water to precipitate an organic compound to produce a pre-suspension; and (3) introducing energy in the form of high shear mixing or heating to the pre-suspension to obtain a dispersion of microparticles. One or more optional surface modifying agents, as described below, may be added to the first organic solvent or the second aqueous solution.

Emulsion precipitation (emulsification precipitation) method

One suitable emulsion precipitation technique is disclosed in pending and commonly assigned U.S. patent application No. 09/964,273, which is incorporated herein by reference and made a part hereof. In this method, the program includes the steps of: (1) providing a multiphase system having an organic phase and an aqueous phase, with a pharmaceutically active substance in the organic phase; and (2) sonicating the system to evaporate a portion of the organic phase, causing the compound to precipitate in the aqueous phase, forming a dispersion of microparticles. The step of providing a multi-phase system comprises the steps of: (1) mixing a water-insoluble solvent with a pharmaceutically active substance to form an organic solution, (2) preparing an aqueous solution with one or more surface-active compounds, and (3) mixing the organic solution with the aqueous solution to form a multi-phase system. The step of mixing the organic phase with the aqueous phase may include the use of a piston gap homogenizer, colloid mill, high speed stirring device, extrusion device, manual agitation or shaking device, microfluidizer, or other device or technique for providing high shear conditions. The coarse emulsion has oil droplets with a diameter of less than about 1 μm in water. The coarse emulsion is sonicated to form a fine emulsion and ultimately a dispersion of microparticles.

Another method of preparing a dispersion of microparticles is disclosed in pending and commonly assigned U.S. patent application No. 10/183,035, which is incorporated herein by reference and made a part hereof. The method comprises the following steps: (1) providing a multiphase system having an organic phase and an aqueous phase, the organic phase containing a drug compound; (2) providing energy to the coarse dispersion to form a fine dispersion; (3) freezing the fine dispersion; and (4) freeze-drying the fine dispersion to obtain particles of the pharmaceutical compound. The microparticles may be sterilized by the techniques described below or the microparticles may be reconstituted in an aqueous medium and sterilized.

The step of providing a multi-phase system comprises the steps of: (1) mixing a water-insoluble solvent with a pharmaceutically effective compound to form an organic solution; (2) preparing an aqueous solution with one or more surface active compounds; and (3) mixing the organic solution with the aqueous solution to form a multi-phase system. The step of mixing the organic phase with the aqueous phase may include the use of a piston gap homogenizer, colloid mill, high speed stirring device, extrusion device, manual agitation or vibration device, microfluidizer, or other device or technique for providing high shear conditions.

Precipitation by solvent anti-solvent (solvent anti-solvent)

Microparticle dispersions can also be prepared using the solvent anti-solvent precipitation techniques disclosed in U.S. Pat. Nos. 5,118,528 and 5,100,591, which are incorporated herein by reference and made a part hereof. The method comprises the following steps: (1) preparing a liquid phase of the biologically active substance in a solvent or solvent mixture to which one or more surfactants may be added; (2) preparing a second liquid phase of a non-solvent or mixture of solvents, the non-solvent being miscible with the solvent or mixture of solvents; (3) adding solutions (1) and (2) together under stirring; and (4) removing the unwanted solvent to produce a dispersion of microparticles.

Phase inversion (phase inversion) precipitation

The microparticle dispersion may be formed using phase inversion precipitation as disclosed in U.S. patent 6,235,224, U.S. patent 6,143,211, and U.S. patent application 2001/0042932, each of which is incorporated herein by reference and made a part hereof. Instead, the term is used to describe the physical phenomenon by which a polymer dissolved in a continuous phase solvent system is converted into a solid macromolecular network in which the polymer is the continuous phase. One method of inducing phase inversion is by adding a non-solvent to the continuous phase. The polymer undergoes a transition from a single phase to an unstable two-phase mixture (polymer-rich fraction and polymer-poor fraction). Micelle-type droplets of the non-solvent in the polymer-rich phase act as nucleation sites and become coated with polymer. The 6,235,224 patent discloses that phase inversion of polymer solutions under certain conditions can cause the spontaneous formation of discrete microparticles (including nanoparticles). The 6,235,224 patent discloses dissolving or dispersing a polymer in a solvent. The drug is also dissolved or dispersed in the solvent. The polymer, drug, and solvent together form a mixture having a continuous phase, wherein the solvent is the continuous phase. The mixture is then introduced into an at least ten fold excess of miscible non-solvent to cause the spontaneous formation of microencapsulated drug microparticles having an average particle size of 10nm to 10 μm. The particle size is determined by the solvent: volume ratio of non-solvent, polymer concentration, viscosity of polymer-solvent solution, molecular weight of polymer, and the nature of the solvent-non-solvent pair.

precipitation by pH Change (shift)

The microparticle dispersion can be formed by a pH-shift precipitation technique. Such techniques typically include the step of dissolving the drug in a solution having a pH at which the drug is soluble, followed by a step of changing the pH to a point where the drug is no longer soluble. The pH may be acidic or basic, depending on the particular pharmaceutical compound. The solution is then neutralized to form a dispersion of microparticles. One suitable pH-shift precipitation method is disclosed in U.S. patent 5,665,331, which is incorporated herein by reference and made a part hereof. The method comprises the steps of dissolving the drug together with a Crystal Growth Modifier (CGM) in an alkaline solution and then neutralizing the solution with an acid in the presence of one or more suitable surfactants for surface modification to form a particulate dispersion of the drug. The precipitation step is followed by a step of diafiltration and purification of the dispersion, followed by adjustment of the concentration of the dispersion to the desired level.

Other examples of pH swing precipitation methods are disclosed in U.S. patents 5,716,642, 5,662,883, 5,560,932, and 4,608,278, all of which are incorporated herein by reference and made a part hereof.

Infusion precipitation (infusion precipitation) method

Suitable injection precipitation techniques for forming the particulate dispersion are disclosed in U.S. Pat. Nos. 4,997,454 and 4,826,689, which are incorporated herein by reference and made a part hereof. The appropriate solid compound is first dissolved in an appropriate organic solvent to form a solvent mixture. Then, a precipitating non-solvent miscible with the organic solvent is injected into the solvent mixture at a temperature of about-10 ℃ to about 100 ℃ at a rate of about 0.01ml per minute to about 1000ml per minute per volume of 50ml to produce a suspension of precipitated, non-aggregated solid particles of the compound having a substantially uniform average diameter of less than 10 μm. The solution injected into the non-solvent for precipitation is preferably agitated (e.g., by stirring). The non-solvent may contain a surfactant to stabilize the particles from aggregation. The particles are then separated from the solvent. Depending on the solid compound and the desired particle size, the parameters of temperature, the ratio of non-solvent to solvent, the injection rate, the stirring rate, and the volume may vary according to the invention. Particle size and non-solvent: the ratio of solvent volumes is directly proportional to the injection temperature and inversely proportional to the injection rate and the agitation rate. The non-solvent for precipitation may be aqueous or non-aqueous, depending on the relative solubilities of the compound and the desired suspension medium.

Temperature change (temperature shift) precipitation

Temperature change precipitation techniques can also be used to form the particulate dispersion. Such a technique is disclosed in U.S. patent 5,188,837, which is incorporated herein by reference and made a part hereof. In an embodiment of the invention, the lipid globules are prepared by: (1) melting or dissolving a substance, such as a drug, to be delivered in a molten medium to form a fluid of the substance to be delivered; (2) adding the phospholipid together with the aqueous medium to the molten material or medium at a temperature above the melting temperature of the material or medium; (3) mixing the suspension at a temperature above the melting temperature of the medium until a homogenous fine formulation is obtained; and then (4) rapidly cooling the formulation to room temperature or below.

Solvent evaporation precipitation

Solvent evaporation precipitation techniques are disclosed in U.S. patent 4,973,465, which is incorporated herein by reference and made a part hereof. The 4,973,465 patent discloses a method of making microcrystals that includes the steps of: (1) providing a solution of the pharmaceutical composition and the phospholipid dissolved in a common organic solvent or solvent combination, (2) evaporating the solvent and (3) suspending the film obtained by evaporating the solvent in an aqueous solution by vigorous stirring to form a dispersion of microparticles. The solvent may be removed by introducing energy into the solution, evaporating a sufficient amount of the solvent to cause precipitation of the compound. The solvent may also be removed by other techniques known in the art, such as applying a vacuum to the solution or blowing nitrogen over the solution.

Reaction precipitation

Reactive precipitation includes the step of dissolving the drug compound in a suitable solvent to form a solution. The compound should be added in an amount equal to or below the saturation point of the compound in the solvent. The compound is modified by reaction with a chemical agent or by modification in response to the introduction of energy such as heat or ultraviolet light, such that the modified compound has a lower solubility in the solvent and precipitates from solution to form microparticles.

Compressed fluid precipitation

Suitable compressed fluid precipitation techniques are disclosed in WO 97/14407 to Johnston, which is incorporated herein by reference and made a part hereof. The method includes the step of dissolving a water-insoluble drug in a solvent to form a solution. The solution is then sprayed into a compressed fluid, which may be a gas, a fluid, or a supercritical fluid. The addition of the compressed fluid to a solution of the solute in the solvent brings the solute to or near supersaturation and precipitates out as particles. In this case, the compressed fluid functions as an anti-solvent that reduces the cohesive energy density of the solvent in which the drug is dissolved.

Alternatively, the drug may be dissolved in a compressed fluid which is then sprayed into the aqueous phase. The rapid expansion of the compressed fluid reduces the solvent power of the fluid, which in turn causes the solute to precipitate out as particles in the aqueous phase. In this case, the compressed fluid functions as a solvent.

Surface modifiers such as surfactants are included in this technique in order to stabilize the particles against aggregation.

There are many other methods for preparing a microparticle dispersion. The present invention provides a method of terminally sterilizing such dispersions without significantly affecting the efficacy of the formulation.

Type of microparticle dispersion

The microparticle dispersion can be established from the hydrophobic region and the pharmaceutically active substance in an aqueous system (e.g., surfactant assembly, cyclodextrin cavity, oil droplet) and/or from the hydrophobic region itself (if it is pharmaceutically active). In a microparticle dispersion, the hydrophobic region can be bound to the pharmaceutically active substance by a number of different mechanisms. For example, the hydrophobic region may be bound to the pharmaceutically active substance by covalent and ionic bonds, dipole-dipole interactions, induced dipole-dipole interactions, or van der waals forces. In addition, the pharmaceutically active substance may be encapsulated in the hydrophobic region.

A. Hydrophobic region

Surfactant assembly

It is known to form hydrophobic regions in aqueous solutions from a single amphoteric surfactant or a combination thereof (e.g., a phospholipid) in aqueous solution. The surfactant assembly includes micelles (fig. 1), reversed micelles (fig. 2), mixed micelles, reversed mixed micellar lamellar form (fig. 3), reversed lamellar form of hexagonal phase (fig. 4), reversed hexagonal phase of cubic phase (fig. 5), reversed cubic phase, L3 sponge phase, reversed L3 sponge phase, and mesophases. The formation of the normal or reverse phase depends on the surfactant type, surfactant concentration, pressure, and temperature. Chelates (chelates) also belong to this class.

FIG. 1 shows a micelle 10 having a plurality of amphipathic molecules 12 circumferentially spaced from one another, the nonpolar hydrophobic tails 14 of the amphipathic molecules extending axially inward to form a core 16, and the polar hydrophilic head groups 18 extending radially away from the core to form a surface 19.

Fig. 2 shows an inverted micelle 20, which inverted micelle 20 is identical to the micelle of fig. 1 in all remaining respects, except that the polar head group 18 extends inwardly toward the core and the non-polar tail extends outwardly away from the core. This is true for the general phase and its inverse counterpart. Accordingly, various reverse form drawings are omitted.

Fig. 3 shows a lamellar phase 30. The lamellar phase 30 has spatially separated amphipathic molecules 12 forming a stacked bilayer structure 32. The regions between the bilayer-like structures 32 and the hydrophobic tails are referred to as grid-like layers (palisade layers) 34 and 36.

The grid layer 34 is hydrophobic and the grid layer 36 is hydrophilic.

Fig. 4 shows a hexagonal phase 40. The hexagonal phase can be thought of as a series of normal micelles (fig. 1) stacked on top of each other to form a tubular structure 42.

Fig. 5 shows an example of the three-dimensional phase 50. Seven stereophases have been identified so far and their structures have been described experimentally. The bicontinuous volume phase 50 has a series of bi-lamellar structures 32 defining an interconnected network of intersecting tubes providing water-containing pores 52.

The L3 phase is described in U.S. patent 5,531,925, which is incorporated herein by reference and made a part hereof. The L3 phase is very similar to the cubic phase, but does not have the long range order of the cubic phase.

Complexing agents

Hydrophobic regions may also be formed in aqueous solutions by the addition of complexing agents such as cyclodextrins. Cyclodextrins are also commonly used to interact with drug compounds that are insoluble in aqueous solutions, as disclosed in U.S. Pat. No. 4,764,604, which is incorporated herein by reference and made a part hereof.

Two-phase dispersion

The hydrophobic region in an aqueous system may also be formed by a heterogeneous two-phase system, including emulsions, microemulsions, suspensions, and others.

As noted above, the invention can be practiced using any formulation in which a pharmaceutically active substance is combined with a hydrophobic region to form a microparticle dispersion, or the hydrophobic region itself if the hydrophobic region is pharmaceutically active. The pharmaceutically active substance can be incorporated into the hydrophobic region of any of these formulation types by many of the mechanisms described above. Many of these systems are described in detail in "Surfactants and Polymers in Aqueous solutions", 2003, John Wiley and sons, which is incorporated herein by reference and made a part hereof.

V. surfactant

Particularly important and safe classes of amphiphilic surfactants include phospholipids. Phospholipids are typically triglycerol derivatives having two hydroxyl groups of a glyceride attached to a fatty acid (forming a polar tail) and one terminal hydroxyl group attached to a phosphate. The phosphate is in turn linked to another compound (e.g., choline, ethanolamine, ethylamine, glycerol, or L-serine) to form a polar head group. Suitable phospholipids include, for example, lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipid, egg phospholipid or soybean phospholipid or combinations thereof. The phospholipids may be salted or desalted, hydrogenated or partially hydrogenated, or natural, semi-synthetic, or synthetic.

Suitable surfactants of the present invention include anionic surfactants, cationic surfactants, nonionic surfactants, zwitterionic surfactants, or biological surface active molecules. Suitable anionic and zwitterionic surfactants include, but are not limited to, potassium laurate, sodium lauryl sulfate, polyoxyethylene alkyl sulfate, sodium alginate, dioctyl sodium sulfosuccinate, glycerol esters, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.). Suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, dodecyldimethylbenzylammonium chloride, esteroylcarnitine hydrochloride, or alkylpyridinium halides.

Suitable nonionic surfactants include: polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (polysorbate 85), polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span), glyceryl monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, arylalkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxamers), polaxamides, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides including starch and starch derivatives such as hydroxyethyl starch (HES), polyvinyl alcohol, and polyvinylpyrrolidone. In a preferred form of the invention, the nonionic surfactant is a polyoxyethylene and polyoxypropylene copolymer, and is preferably a block copolymer of propylene glycol and ethylene glycol. Such polymers are sold under the trade name POLOXAMER, also commonly known as PLURONIC ®, and are sold by suppliers including BASF, Spectrum Chemical, and Ruger. Among polyoxyethylene fatty acid esters, those having a short alkyl chain are included. An example of such a surfactant is SOLUTOL ® HS15, polyethylene-660-hydroxystearate, manufactured by BASF Aktiengesellschaft.

Biomolecules with surface activity include molecules such as albumin, casein, heparin, hirudin or other suitable proteins.

For oral dosage forms, one or more of the following excipients may be used: gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers such as polyethylene glycol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters such as commercially available Tweens^TMPolyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium lauryl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP). Most of these Excipients are described in detail in The Handbook of Pharmaceutical Excipients, The Pharmaceutical Press, 1986, published by The American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, incorporated herein by reference. The surface modifying agents are commercially available and/or can be prepared by techniques known in the art. Two or more surface modifiers may be used in combination.

Effect of high pressure on stabilization of particle Dispersion

High pressures can stabilize microparticle systems by a number of different mechanisms, including thermodynamic (volume of reaction) or kinetic (volume of activation) mechanisms. In addition, the high pressure may chemically and/or physically stabilize the pharmaceutically active component, surfactant, and/or drug/hydrophobic region association throughout the sterilization cycle. An example of thermodynamic stability is the effect of high pressure on the cloud point of polyoxyethylene surfactants. For these systems, it is known that the cloud point rises under pressure due to hydrogen bond enhancement and hydrophobic bond rupture. Thus, a dispersion of microparticles that is unstable during autoclaving due to cloud point precipitation can be stabilized by subjecting the surfactant system to terminal sterilization at higher pressures such that the cloud point is greater than 121 ℃.

Example 1

Autoclaving of itraconazole nanosuspensions

A combined microprecipitation-homogenization process (US patent application 2002/0127278 a1) was used to produce a 1% itraconazole nanosuspension comprising 0.1% poloxamer 188, 0.1% deoxycholate, and 2.2% glycerol. The initial particle size distribution as measured by static light scattering (Horiba LA-920) is shown in FIG. 7.

As a positive control, a 5ml sample of the nanosuspension was first sterilized for 15 minutes at 121 ℃ using a conventional autoclaving cycle. This produces significant particle agglomeration as shown by the light scattering data in fig. 8. This aggregation is typical for nanosuspensions stabilized with surfactants having cloud points below 121 ℃ (poloxamer 188 has a cloud point of-110 ℃).

In contrast, when the same nanosuspension was autoclaved using the autoclave cycle shown in fig. 9, the particle size distribution of the resulting 1% itraconazole nanosuspension remained completely unchanged, as shown in fig. 10.

Autoclaving apparatus and method

An autoclave instrument typically has a sterilization chamber that controls temperature and pressure. The sterilization chamber has a lid that is secured in use. The device is capable of pressures up to 1000 Mpa. The apparatus also has a heat source capable of heating the sterilization chamber to a temperature of 120 ℃ and higher

The method of using the apparatus includes the step of providing a system in a desired form. In the case of pharmaceutical formulations, the formulation will be in powder form, a solution or as an aqueous particle dispersion. In a preferred form of the invention, the pharmaceutical formulation is contained within a container whose volume or shape varies in response to changes in pressure applied to the container. Such containers may include flexible polymeric containers or other flexible containers such as syringe barrels, cartridges for jet syringes or metered dose inhalers. These containers are discussed in more detail below. The present invention additionally contemplates the addition of pharmaceutical agents directly to the sterilization chamber.

The pharmaceutical formulation is inserted into a sterilization chamber in which the formulation is subjected to a change in pressure, a change in temperature, or both. Unlike existing autoclaves for sterilizing i.v. containers and the like, which can only reach pressures below 0.25Mpa, the method of the present invention subjects the formulation to pressures in excess of 0.25 Mpa. In a preferred form of the invention, the formulation is subjected to a pressure in excess of 0.25MPa to about 1500MPa, more preferably 0.25MPa to about 700MPa, and any range or combination of ranges therein.

The invention additionally includes the application of temperature and pressure such that the time during which the formulation is exposed to temperatures in excess of 25 ℃ is minimized. Preferably, the temperature of the system exceeds 70 ℃, more preferably 90 ℃, more preferably 100 ℃, most preferably 120 ℃ and higher. Different temperature-time-pressure profiles, such as the one shown in fig. 6, may be used to sterilize the formulation without causing the formulation to change from a stable state to an unstable state.

Specifically, fig. 6 shows a temperature-time-pressure profile in which, in a first cycle, the drug formulation is subjected to a pressure of about 700Mpa and energy is introduced to raise the temperature to about 121 ℃, followed by a second cycle of reducing the pressure to atmospheric pressure and reducing the temperature to room temperature for a period of time. Figure 6 shows that the formulation undergoes rapid temperature changes during each pressure pulse. These temperature changes are induced by instantaneous adiabatic heating and cooling from pressurization and depressurization, respectively. Typical times for achieving sterility are on the order of minutes, with 2 or more cycles being used.

A pharmaceutical formulation is considered sterile when the probability of non-sterile units is equal to or less than one part per million. This meets pharmacopoeial requirements in the united states, europe and japan.

Lethality of Sterilization Process

The 1% itraconazole nanosuspensions treated with autoclaving as described above were now tested for sterility. The effect of autoclaving on the lethality of Bacillus stearothermophilus (Bacillus stearothermophilus) has been demonstrated in saline (for bioburden, the most heat-resistant strains that have proven to be highly resistant to humidity are used, see the references ANSI/AAMI/ISO 11134-1993, Sterilization of health care products-requisitions for evaluation and hydrolysis control-Industrial 13 heat stability, the American national Standard, page 12, section A.6.6., formed by the Association of the advancement of the physical insulation and reviewed by the American national standards Institute). The test and control units inoculated with at least one million spores of Bacillus stearothermophilus were subjected to two different procedures, the first using a pressure of about 600MPa for 1 minute and the second using a pressure of about 600MPa, for six 10-second cycles. The initial and maximum temperatures in the two processes were 90 ℃ and 121 ℃ respectively. No survivors were found in both procedures (see table 1). It is expected that the same results will be obtained when a 1% itraconazole nanosuspension is inoculated and sterilized.

Table 1: lethality of Bacillus stearothermophilus in two autoclaving methods

Solutions of	Sterilization conditions	CFU/ml
			Saline solution-1-control	Is free of	1.9E106
Sterilized saline solution-1	600MPa, one 1 minute cycle, starting at 90 ℃ and high pressure at 121 DEG C	0
			Saline solution-2-control	Is free of	3.7E106
Sterilized saline solution-2	600MPa, six 10-second cycles, an initial temperature of 90 ℃, a high pressure of 121 DEG C	0

IX. Container

Various containers can be sterilized by the methods of the present invention, preferably those used as medical devices (e.g., for pharmaceutical administration, renal dialysis, and blood collection/processing). Examples of such containers include, but are not limited to, fluid administration devices (including those containing syringes), blood collection assemblies (e.g., blood bag units), disposable assemblies for automated blood processing, dialysis membrane assemblies, and peritoneal dialysis bags, tubes, and assemblies. Typically, such systems include a fluid transfer member (e.g., a tube).

Fig. 11 shows a container 150 of flowable material having dual sidewalls 152 defining a chamber 154 therebetween. Access 155 provides a sterile port for the contents of the container. FIG. 12 shows a multi-chamber container 160 having first and second chambers 162, 164 connected by a peelable seal 166. Such a multi-chamber container is particularly suitable for storing a liquid in one chamber and a powder in a second chamber or a liquid in both chambers. The peelable seal allows the components to be mixed prior to use. Suitable multi-chamber containers include, but are not limited to, those disclosed in U.S. patents 5,577,369, 6,017,598, which are incorporated herein by reference and made a part hereof. The method of claim 1, wherein the container is selected from the group consisting of a sealed fluid container, a syringe, and a sealed tube.

In a preferred form of the invention, the side wall is made of a non-PVC containing polymer. The sidewalls may be comprised of a single layer structure 170 (fig. 13) or, as shown in fig. 14, a plurality of layers 171 having first and second layers 174, 176. It is also contemplated to have more than 2 layers in the film. In another form of the invention, the sidewalls are unoriented and are not films having significant heat shrinkage.

Suitable non-PVC containing polymers for forming the sidewalls include polyolefins, copolymers of ethylene and lower alkyl acrylates, copolymers of ethylene and lower alkyl substituted alkyl acrylates, ethylene vinyl acetate copolymers, polybutadiene, polyesters, polyamides, and copolymers of styrene and hydrocarbons.

Suitable polyolefins include homopolymers and copolymers obtained by polymerizing alpha-olefins containing from 2 to 20 carbon atoms, more preferably from 2 to 10 carbons. Thus, suitable polyolefins include polymers and copolymers of propylene, ethylene, butene-1, pentene-1, 4-methyl-1-pentene, hexene-1, heptene-1, octene-1, nonene-1, and decene-1. More preferably, the polyolefin is a homopolymer or copolymer of propylene, or a homopolymer or copolymer of polyethylene.

Suitable polypropylene homopolymers may have amorphous, isotactic, syndiotactic, atactic, hemi-stereoblock or stereoblock stereochemistry. In a preferred form of the invention, a single site catalyst is used to obtain the polypropylene homopolymer.

Suitable propylene copolymers are obtained by polymerizing propylene monomers with alpha-olefins having from 2 to 20 carbons. In a more preferred form of the invention, propylene is copolymerized with ethylene in an amount of from about 1 to about 20 weight percent, more preferably from about 1 to about 10 weight percent, and most preferably from 2 to about 5 weight percent, based on the weight of the copolymer. The copolymer of propylene and ethylene may be a random or block copolymer. In a preferred form of the invention, the propylene copolymer is obtained using a single site catalyst.

It is also possible to use blends of polypropylene and alpha-olefin copolymers, wherein the propylene copolymers may differ by the number of carbons in the alpha-olefin. For example, the present invention contemplates blends of propylene and α -olefin copolymers wherein one copolymer has a 2 carbon α -olefin and the other copolymer has a4 carbon α -olefin. It is also possible to use any combination of alpha-olefins having from 2 to 20 carbons, more preferably from 2 to 8 carbons. Accordingly, the present invention contemplates blends of propylene and α -olefin copolymers wherein the first and second α -olefins have the following combination of carbon numbers: 2 and 6,2 and 8, 4 and 6, 4 and 8. It is also contemplated to use more than 2 polypropylenes and alpha-olefin copolymers in the blend. Suitable polymers may be obtained using the catalytic alloy (catalloy) method.

It may also be desirable to use high melt strength polypropylene. The high melt strength polypropylene can be a homopolymer or copolymer of polypropylene having a melt flow index in the range of 10 g/10 min to 800 g/10 min, more preferably 30 g/10 min to 200 g/10 min, or any range or combination of ranges therein. It is known that high melt strength polypropylene has free-end long chain branches of propylene units. Methods of preparing polypropylene exhibiting high melt strength characteristics are described in U.S. Pat. Nos. 4,916,198, 5,047,485, and 5,605,936, which are incorporated herein by reference and made a part hereof. One such method involves irradiation with high energy ionizing energy at 1 to 10 per minute in an environment where the active oxygen concentration is about 15% by volume⁴The megarad dose irradiates the linear propylene polymer for a period of time sufficient to produce a significant amount of chain scission of the linear propylene polymer but insufficient to gel the material. Radiation causes chain scission. Subsequent recombination of the chain fragments results in the formation of new chains and the joining of the chain fragments to the chain to form branches. This further creates the desired free endA long chain branched, high molecular weight, non-linear propylene polymer material. The irradiation is maintained until a substantial amount of long chain branches are formed. The material is then treated to deactivate substantially all of the free radicals present in the irradiated material.

High melt strength polypropylene may also be obtained as described in U.S. Pat. No. 5,416,169, which is incorporated herein by reference in its entirety and made a part hereof, wherein a specific organic peroxide (di-2-ethylhexyl peroxydicarbonate) is reacted with polypropylene under specific conditions followed by melt kneading. This polypropylene is a linear, crystalline polypropylene having a branching coefficient of substantially 1, and therefore, has no free-end long chain branches, and may have an intrinsic viscosity of about 2.5dl/g to 10 dl/g.

Suitable ethylene homopolymers include those having a density greater than 0.915g/cc and include Low Density Polyethylene (LDPE), Medium Density Polyethylene (MDPE) and High Density Polyethylene (HDPE).

Suitable ethylene copolymers are obtained by polymerizing ethylene monomers with alpha-olefins having from 3 to 20 carbons, more preferably 4 to 8 carbons. It is also desirable that the ethylene copolymer have a density of less than about 0.915g/cc, more preferably less than about 0.910g/cc, and even more preferably less than about 0.900g/cc, as measured by ASTM D-792. Such polymers are commonly referred to as VLDPE (very low density polyethylene) or ULDPE (ultra low density polyethylene). Preferably, the ethylene alpha-olefin copolymer is produced using a single site catalyst, more preferably a metallocene catalyst system. Unlike known ziegler-natta type catalysts that have multiple catalyst sites, single site catalysts are considered to have a single, sterically and electronically equivalent catalytic site. Such single site catalyzed ethylene alpha-olefins are sold under the tradename AFFINITY by Dow, under the tradename ENGAGE ® by DuPont Dow, and under the tradename EXACT by Exxon. These copolymers are generally referred to herein as m-ULDPE.

Suitable ethylene copolymers also include copolymers of ethylene and lower alkyl acrylates, copolymers of ethylene and lower alkyl substituted alkyl acrylates, and ethylene-vinyl acetate copolymers having a vinyl acetate content of from about 8% to about 40% by weight of the copolymer. The term "lower alkyl acrylate" refers to a comonomer having the structure depicted in scheme 1 below:

FIG. 1 is a schematic representation of

The R group refers to an alkyl group having 1 to 17 carbons. Thus, the term "lower alkyl acrylate" includes, but is not limited to, methyl acrylate, ethyl acrylate, butyl acrylate, and the like.

The term "alkyl-substituted alkyl acrylate" refers to a comonomer described in scheme 2 below:

FIG. 2 is a drawing

R₁And R₂Are alkyl groups having 1-17 carbons, and may have the same carbon number or different carbon numbers. Thus, the term "alkyl-substituted alkyl acrylate" includes, but is not limited to, methyl methacrylate, ethyl methacrylate, methyl ethacrylate, ethyl ethacrylate, butyl methacrylate, butyl ethacrylate, and the like.

Suitable polybutadienes include 1, 2-and 1, 4-adducts of 1, 3-butadiene (these are collectively referred to as polybutadienes). In a more preferred form of the invention, the polymer is a1, 2-adduct of 1, 3-butadiene (these are known as "1, 2-polybutadienes"). In a more preferred form of the invention, the polymer of interest is a syndiotactic 1, 2-polybutadiene, more preferably a low crystallinity syndiotactic 1, 2-polybutadiene. In a preferred form of the invention, the low crystallinity, syndiotactic 1, 2-polybutadiene will have a crystallinity of less than 50%, more preferably less than about 45%, more preferably less than about 40%, more preferably from about 13% to about 40%, and most preferably from about 15% to about 30%. In a preferred form of the invention, the low crystallinity, syndiotactic 1, 2-polybutadiene will have a melting point temperature, as measured according to ASTM D3418, of from about 70 ℃ to about 120 ℃. Suitable resins include those described by jsr (japan Synthetic rubber) under the classification name: JSR RB 810, JSR RB 820, and JSR RB 830.

Suitable polyesters include the polycondensation products of di-or polycarboxylic acids and di-or polyhydric alcohols or alkylene oxides. In a preferred form of the invention, the polyester is a polyetherester. Suitable polyetheresters are derived from the reaction of 1, 4-cyclohexanedimethanol, 1, 4-cyclohexanedicarboxylic acid and polybutylene glycol ether and are commonly referred to as PCCE. Suitable PCCEs are sold by Eastman under the trade name ECDEL. Suitable polyesters additionally include polyester elastomers which are block copolymers of a hard crystalline fraction of polybutylene terephthalate and a soft (amorphous) polyether polyol as a second fraction. Such polyester elastomers are sold under the trade name HYTREL ® by Du Pont Chemical Company.

Suitable polyamides include those derived from the ring-opening reaction of lactams having from 4 to 12 carbons. Such polyamides thus include nylon 6, nylon 10, and nylon 12. Acceptable polyamides also include aliphatic polyamides derived from the condensation reaction of diamines having a carbon number of 2-13, aliphatic polyamides derived from the condensation reaction of diacids having a carbon number of 2-13, polyamides derived from the condensation reaction of dimerized fatty acids, and amide-containing copolymers. Thus, suitable aliphatic polyamides include, for example, nylon 6, nylon 6, 10, and dimer fatty acid polyamides.

Styrene of the copolymer of styrene and hydrocarbon includes styrene and various substituted styrenes including alkyl substituted styrenes and halogen substituted styrenes. The alkyl group may contain from 1 to about 6 carbon atoms. Specific examples of substituted styrenes include alpha-methylstyrene, beta-methylstyrene, vinyltoluene, 3-methylstyrene, 4-isopropylstyrene, 2, 4-dimethylstyrene, o-chlorostyrene, m-chlorostyrene, o-bromostyrene, 2-chloro-4-methylstyrene, and the like. Styrene is most preferred.

The hydrocarbon portion of the styrene and hydrocarbon copolymer comprises a conjugated diene. Conjugated dienes that may be used are those containing from 4 to about 10 carbon atoms, more typically those containing from 4 to 6 carbon atoms. Examples thereof include 1, 3-butadiene, 2-methyl-1, 3-butadiene (isoprene), 2, 3-dimethyl-1, 3-butadiene, chloroprene, 1, 3-pentadiene, 1, 3-hexadiene and the like. Mixtures of these conjugated dienes, such as a mixture of butadiene and isoprene, may also be used. Preferred conjugated dienes are isoprene and 1, 3-butadiene.

The copolymer of styrene and hydrocarbon may be a block copolymer comprising diblock, triblock, multiblock, radial block, and mixtures thereof. Specific examples of diblock copolymers include styrene-butadiene, styrene-isoprene, and hydrogenated derivatives thereof. Examples of triblock copolymers include styrene-butadiene-styrene, styrene-isoprene-styrene, alpha-methylstyrene-butadiene-alpha-methylstyrene, and alpha-methylstyrene-isoprene-alpha-methylstyrene, and hydrogenated derivatives thereof.

The selective hydrogenation of the above-described block copolymers can be carried out by a variety of well-known processes, including hydrogenation in a catalyst such as raney nickel; noble metals such as platinum, palladium, etc.; and hydrogenation in the presence of a soluble transition metal catalyst. Suitable hydrogenation processes which may be used are those in which the diene-containing polymer or copolymer is dissolved in an inert hydrocarbon diluent such as cyclohexane and reacted with hydrogen in the presence of a soluble hydrogenation catalyst. Such methods are described in U.S. Pat. Nos. 3,113,986 and 4,226,952, the disclosures of which are incorporated herein by reference and made a part hereof.

Particularly useful hydrogenated block copolymers are hydrogenated block copolymers of styrene-isoprene-styrene, such as hydrogenated block copolymers of styrene- (ethylene/propylene) -styrene. When the polystyrene-polybutadiene-polystyrene block copolymer is hydrogenated, the resulting product has ordered copolymer blocks of ethylene and 1-butene (EB). As described above, when isoprene is used as the conjugated diene, the resulting hydrogenated product has regular ethylene and propylene copolymer blocks (EP). One example of a commercially available selectively hydrogenated product is KRATON G-1652, which is a hydrogenated SBS triblock comprising 30% styrene end blocks and the remaining mid-block being a copolymer of ethylene and 1-butene. Such hydrogenated block copolymers are commonly referred to as SEBS. Kraton G-1657 as a blend of SEBS triblock and SBS diblock is also suitable. Other suitable SEBS or SIS copolymers are sold under the trade names SEPTONX ® and HYBRART ® by Kurary.

It may also be desirable to use graft-modified styrene and hydrocarbon block copolymers by grafting an alpha, beta-unsaturated monocarboxylic or dicarboxylic acid reagent onto the selectively hydrogenated block copolymer described above.

Block copolymers of conjugated dienes and vinyl aromatic compounds are grafted with α, β -unsaturated monocarboxylic or dicarboxylic acid reagents. Carboxylic acid reagents include carboxylic acids themselves and their functionalized derivatives such as anhydrides, imides, metal salts, esters, and the like, which can be grafted onto the selectively hydrogenated block copolymer. The grafted polymer typically contains from about 0.1 to about 20 percent, more preferably from about 0.1 to about 10 percent, of grafted carboxylic acid based on the total weight of the block copolymer and carboxylic acid reagent. Specific examples of useful monocarboxylic acids include acrylic acid, methacrylic acid, cinnamic acid, crotonic acid, acrylic anhydride, sodium acrylate, calcium acrylate, and magnesium acrylate, among others. Examples of dicarboxylic acids and useful derivatives thereof include maleic acid, maleic anhydride, fumaric acid, mesaconic acid, itaconic acid, citraconic acid, itaconic anhydride, citraconic anhydride, monomethyl maleate, monosodium maleate, and the like.

Block copolymers of styrene and hydrocarbons may be modified with oils such as oil-modified SEBS sold under the product name KRATON G2705 by Shell chemical Company.

Films that can be formed from polymer blends of the above components are also contemplated. Particularly suitable polymer blends are disclosed in U.S. patent 5,849,843, which is incorporated herein by reference and made a part hereof. In a preferred form of the invention, the layers are made from a blend having 2 components, more preferably three or more components. These polymer blends may form monolayer films or may be incorporated into multilayer films as described in U.S. patent 5,998,019, which is incorporated herein by reference and made a part hereof.

Three-component composition

In a first embodiment of the three-component system, the first component imparts heat resistance and flexibility to the composition. Such components may be selected from the group consisting of amorphous polyalphaolefins and are preferably flexible polyolefins. These polyolefins can withstand elevated temperatures up to 121 ℃ without deformation, have a peak melting point greater than 130 ℃ and are highly flexible, having a modulus of no more than 40,000psi, more preferably no more than 20,000 psi. In addition, certain polypropylenes with high syndiotacticity also have the properties of high melting point and low modulus. The first component comprises 40-90% by weight of the composition.

The second component of the three component composition is a polymer susceptible to RF which imparts RF sealing capability to the composition and may be selected from either of two groups of polar polymers. The first group consists of copolymers of ethylene having an ethylene content of 50-85% and a comonomer selected from the group consisting of acrylic acid, methacrylic acid, ester derivatives of acrylic acid with alcohols having 1-10 carbons, ester derivatives of methacrylic acid with alcohols having 1-10 carbons, vinyl acetate, and vinyl alcohol. The RF susceptible polymer may also be selected from a second group consisting of polymers containing polyurethane, polyester, polyurea, polyimide, polysulfone, and polyamide segments. These functionalities may constitute 5-100% of the polymer susceptible to RF. The RF susceptible polymer comprises 5 to 50 weight percent of the composition.

Preferably, the RF component is an ethylene-methyl acrylate copolymer, with methyl acrylate comprising 15-25 wt% of the polymer. The last component of the three-component composition, which ensures compatibility between the first two components, is selected from styrenic block copolymers and is preferably maleic anhydride functionalized. The third component constitutes 5-30% by weight of the composition.

In a second embodiment of the three-component film, the first component imparts RF sealability and flexibility in the desired temperature range. The first component imparts high temperature resistance ("heat stable polymer") and is selected from the group consisting of polyamides, polyimides, polyurethanes, polypropylenes, and polymethylpentenes. Preferably, the first component constitutes 30-60% by weight of the composition, and is preferably polypropylene. The second component imparts RF sealing capability and flexibility over a desired temperature range. The RF polymer is selected from the first and second groups identified above, except ethylene vinyl alcohol. The second component comprises 30-60% by weight of the composition. The third component guarantees compatibility between the first two components and is chosen from SEBS block copolymers and, preferably, maleic anhydride functionalized. The third component constitutes 5-30% by weight of the composition.

Four-component composition

The first component of the four-component film imparts heat resistance. Such components may be selected from polyolefins, most preferably polypropylene, more specifically propylene alpha-olefin random copolymer (PPE). Preferably, the PPE has a narrow molecular weight range. PPE has desirable rigidity and resistance to autoclaving temperatures of about 121℃. However, PPE itself is too rigid to meet flexibility requirements. But when combined with some low modulus polymers, good flexibility can be achieved. Examples of acceptable PPEs include those sold under the product names Soltex 4208, and Exxon escorene pd 9272. These low modulus copolymers may include ethylene based copolymers such as ethylene-co-vinyl acetate ("EVA"), ethylene-co-alpha-olefin, or so-called ultra low density (typically less than 0.90Kg/L) polyethylene ("ULDPE"). These ULDPE include those products sold under the trademark TAFMER ® (Mitsui Petrochemical Co.), under the product name a485Exact ® (Exxon Chemical Company), under the product names 4023-. Additionally, polybutene-1 ("PB") such as those sold under the product names PB-8010, PB-8310 by Shell Chemical Company has also been found; thermoplastic elastomers based on SEBS block copolymers (Shell Chemical Company), polyisobutylene ("PIB") under the product names Vistanex L-80, L-100, L-120, L-140(Exxon Chemical Company), ethylene alkyl acrylate-methyl acrylate copolymers ("EMA") such as those under the product names EMAC 2707, and DS-1130(Chevron), and n-butyl acrylate ("ENBA") (Quantum Chemical) are acceptable copolymers. Ethylene copolymers such as acrylic and methacrylic acid copolymers and their partially neutralized salts and ionomers such as PRIMACOR ® (Dow chemical Company) and SURYLN ® (e.i. dupont de Nemours & Company) are also satisfactory.

Typically, ethylene based copolymers having melting points below about 110 ℃ are not suitable for autoclave applications. Furthermore, only a limited range of ratios of the respective components allows to simultaneously meet the requirements of flexibility and autoclave applications. Preferably, the first component is selected from the group consisting of polypropylene homopolymers and random copolymers with alpha-olefins, wherein the alpha-olefins constitute from about 30 to 60 wt%, more preferably from 35 to 45 wt%, most preferably 45 wt% of the composition. For example, a random copolymer of propylene and ethylene in which the ethylene content is 1 to 6% by weight, more preferably 2 to 4% by weight, based on the weight of the polymer, is preferred as the first component.

The second component of the four-component composition imparts flexibility and low temperature ductility and is a second polyolefin different from the first component, wherein it is free of propylene repeating units ("non-propylene based polyolefin"). Preferably, it is an ethylene copolymer comprising: ULDPE, polybutene, butene-ethylene copolymers, ethylene-vinyl acetate with a vinyl acetate content of about 18-50%, ethylene-methyl acrylate copolymers with a methyl acrylate content of about 20-40%, ethylene-n-butyl acrylate copolymers with an n-butyl acrylate content of 20-40%, ethylene-acrylate copolymers with an acrylic acid content of greater than about 15%. Examples of such products are under the product names tanner a-4085 (Mitsui); EMAC DS-1130 (Chevron); exact 4023, 4024 and 4028(Exxon), and constitutes about 25 to 50 weight percent of the composition, more preferably 35 to 45 weight percent, and most preferably 45 weight percent. In order to impart RF dielectric loss to the four-component composition, certain known high dielectric loss components ("RF susceptible polymers") are included in the composition. These polymers may be selected from the group of RF polymers in the first and second groups described above.

Other RF-active materials include PVC, 1-dichloroethylene and 1, 1-difluoroethylene, a copolymer of bisphenol a and epichlorohydrin known as phenyloxy ® (Union Carbide). However, significant levels of these chlorine-and fluorine-containing polymers can make the compositions undesirable because inorganic acids are formed upon incineration of such materials.

The polyamide of the RF susceptible polymer is preferably selected from the group consisting of aliphatic polyamides derived from the condensation reaction of diamines having a carbon number of 2-13, aliphatic polyamides derived from the condensation reaction of diacids having a carbon number of 2-13, polyamides derived from the condensation reaction of dimerized fatty acids, and amide-containing copolymers (random, block, and graft). Polyamides such as nylon are widely used in film materials because they provide abrasion resistance to the film. However, nylon is rarely used in the layer that contacts the drug solution because they typically contaminate the solution by leaching into the solution. The most preferred RF susceptible polymers are the various dimer fatty acid polyamides sold by Henkel Corporation under the product names MACROMELT and VERSAMID, which do not cause such contamination. Preferably, the RF susceptible polymer comprises from about 5 to about 30 wt%, more preferably from about 7 to about 13 wt%, and most preferably about 10 wt% of the composition.

The fourth component of the composition imparts compatibility between the polar and non-polar components of the composition (sometimes referred to as a "compatible polymeric) and is preferably a styrenic block copolymer having a hydrocarbon soft segment. More preferably, the fourth component is selected from the group consisting of SEBS block copolymers modified with maleic anhydride, epoxy, or carboxylate functionality, and preferably SEBS block copolymers containing maleic anhydride functionality ("functionalized"). This product is sold under the name KRATON RP-6509 by Shell chemical company. The compatible polymer constitutes about 5-40 wt%, more preferably 7-13 wt%, and most preferably 10 wt% of the composition. It may also be desirable to add as a fifth component an unfunctionalized SEBS block copolymer such as those sold under the product names KRATON G-1652 and G-1657 by Shell chemical company. The fifth component comprises about 5-40% by weight, more preferably 7-13% by weight, of the composition, the majority.

For each of the compositions described above, it may be desirable to add trace amounts of other additives, such as slip agents, lubricants, waxes, and antiblock agents, as needed and as is well known in the art, so long as the final composition meets the physical requirements described above.

The film may be constructed using techniques well known in the art. For example, the above components can be dry mixed in a high intensity mixer Welex mixer and fed into an extruder. The components may also be metered by weight into a high intensity mixing extruder having a twin screw design, such as the werner pfleiderer, where the product may be quenched in multiple strands in a water bath, pelletized and dried for use. In a third method the pelletization step can be avoided by feeding the product of the continuous mixer directly into the film extruder. It is also possible to incorporate a high intensity mixing section into the film extruder so that one extruder can be used to produce a molten film (alloy film).

The multilayer film 171 can utilize the above-described blend as one layer 172 and another layer such as 174. In a preferred form of the invention, layer 174 is a skin layer. The skin layer 174 imparts heat distortion resistance and abrasion resistance and is preferably polypropylene, more preferably a polypropylene copolymer blended with styrene and a hydrocarbon block copolymer. More preferably, skin layer 174 is a polypropylene copolymer blended with 0-20 wt.% of an SEBS block copolymer. The skin layer 174 has a thickness of 0.2 to 3.0 mils.

Fig. 15 shows another embodiment of the present invention having a core layer 176 interposed between the skin layer 172 and the RF layer 174. The core layer 176 imparts heat distortion resistance and flexibility to the film structure 10, and imparts compatibility between the various components in the film structure 170. Preferably, the core layer has a thickness of 0.5 to 10 mils, more preferably 1 to 4 mils. The core layer 176 includes three components. The first component is a polyolefin, and preferably polypropylene, in an amount of 20 to 60 wt%, more preferably 35 to 50 wt%, most preferably 45 wt% of the core layer 176, based on the weight of the core layer 176.

The second component of the core layer 176 is selected from the group consisting of compounds that impart flexibility to the core layer 16, including ULDPE, polybutylene copolymers. Preferably, the second component of the core layer is ULDPE or polybutene-1 in an amount of 40 wt% to 60 wt%, more preferably 40 wt% to 50 wt%, most preferably 40 wt%.

The third component of the core layer 176 is selected from compounds that impart compatibility between the components of the core layer 176 and includes a styrene-hydrocarbon block copolymer, most preferably a SEBS block copolymer. The amount of the third component is preferably 5 to 40% by weight of the core layer 176, more preferably 7 to 15%, most preferably 15%.

It is also possible to add reground scrap material recovered during the production of the vessel as a fourth component of the core layer 176. The scrap material is dispersed throughout the core layer 16. Preferably, the amount of trim scrap that may be added is from about 0 to about 50 weight percent, more preferably from about 10 to about 30 weight percent, and most preferably from about 3 to about 12 weight percent of the core layer 16.

Fig. 16 shows a film 180 having a solution contact layer 182 attached to the side of the RF layer 174 opposite the skin layer 174. The solution contact layer 182 may be one of the materials described above, more preferably comprises a polyolefin, more preferably the same material as the skin layer 174 or the same material as the core layer 176. Preferably, the solution contact layer 182 has a thickness of 0.2 to 1.0 mil, and most preferably 1.0 mil.

Fig. 17 shows another embodiment of a multilayer film structure having a skin layer 174, a core layer 176, and an RF layer 172 as described above with a discontinuous layer 190 of trim material between the skin layer 174 and the core layer 176. Fig. 18 shows a discontinuous layer of trim material 190 between the core layer 176 and the RF layer 172. Fig. 19 shows a trim material layer 190 that separates the core layer 176 into first and second core layers 176a and 176 b. Preferably, scrap layer 190 has a thickness of 0.5-5.0 mils, most preferably 1.0 mil.

Fig. 20 shows another embodiment of the present invention having six layers, including the skin layer 174, core layer 176, and RF layer 172 described above, with a barrier layer 200 interposed between the core 176 and RF layer 172, and with tie layers 202 attached to opposite sides of the barrier layer 200. Figure 21 shows a barrier layer 200 between the core layer 176 and the skin layer 174. Figure 22 shows the barrier layer 200 dividing the core layer 176 into two core layers 176a and 176 b. The barrier layer 200 increases the gas barrier properties of the film structure. The barrier layer 200 is selected from ethylene vinyl alcohol, such as that sold under the name Evalca (Evalca Co.), a highly glassy or crystalline polyamide such as scalpa ® (Dupont Chemical Co.), a high nitrile content acrylonitrile copolymer such as Barex ® sold by british petroleum. Preferably, the barrier layer 200 is ethylene vinyl alcohol and has a thickness of 0.3 to 1.5 mils, most preferably 1.0 mil.

Bonding layer 202 may be selected from modified ethylene and propylene copolymers such as those sold under the product names Prexar (Quantum Chemical Co.) and bynel (dupont) and should have a thickness of 0.2-1.0 mil, most preferably 0.5 mil.

The autoclaving technique of the invention is also suitable for sterilizing empty drain bags (empty drain bags) for renal CAPD applications, such as the containers disclosed in us patent 6,004,636, which is incorporated herein by reference and forms a part hereof. Other containers suitable for terminal sterilization using the autoclaving technique of the present invention include flexible cell culture containers such as those disclosed in U.S. patent nos. 5,935,847, 4,417,753, 4,210,686, which are incorporated herein by reference and made a part hereof. Protein compatible films and containers, such as those disclosed in U.S. patent 6,309,723, which is incorporated herein by reference and made a part hereof, may also be sterilized using the autoclaving techniques disclosed therein. In addition, the sterilization technique is also suitable for sterilizing containers for containing oxygen sensitive compounds such as deoxyhemoglobin, as disclosed in U.S. patent 6,271,351, which is incorporated herein by reference and made a part hereof. Because the sterilization technique requires only a short exposure of the container to temperatures in excess of 100℃, many containers that are not suitable for terminal sterilization using standard techniques for exposing the container to 121℃ for 1 hour can be terminal sterilized using the high pressure technique of the present invention.

Fig. 23 shows a syringe 220 having a barrel 222 and a plunger 224 as is known in the art. Syringe 220 may be made from the materials described above. The syringe barrel may be filled with one of a dispersion or dry powder of the pharmaceutical compound and then autoclaved as described above. The syringe barrel, preferably both barrel and piston, must be able to change volume in response to increased pressure and the components 222 and 224 must have sufficient heat distortion resistance to withstand the terminal sterilization process of the present invention.

Fig. 24 shows a cartridge 230 or insert having a body 232 defining a chamber 234. Chamber 234 is sealed with an end cap 236, or a pair of end caps if necessary. The cartridge may be inserted into a delivery device such as a jet injector as described in U.S. patent 6,132,395 or other delivery device capable of accessing the contents of chamber 234 and delivering the contents.

Fig. 25 shows a fluid access device 250 having a drug conduit 252 and an access device 254. The access device may be an object for piercing the access piece 154 or may be adapted to dock or connect to the syringe barrel 222 to deliver fluid from a container for sterilization for delivery to a patient or into another device for delivering a composition to a patient.

There are many containers that cannot withstand the terminal sterilization process of exposing the container to steam at 121 c for 1 hour, such as certain polymeric pharmaceutical containers.

X. products

The present invention provides sterilized products and preferably those containing pharmaceutical preparations, including, but not limited to, containers containing sterile pharmaceutical preparations, wherein the preparations have been sterilized by supplying heat to the product and pressurizing the product to a pressure greater than 0.25 Mpa. The invention also provides a sterile pharmaceutical formulation that does not contain a chemical cloud point modifier.

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. Accordingly, such changes and modifications are also intended to fall within the scope of the appended claims.

Claims (45)

1. A method of sterilizing a dynamic system having a steady state and an unstable state, comprising the steps of:

pressurizing the system beyond 0.25MPa to increase the temperature of the system for a period of time sufficient to achieve an aseptic system; and

the pressure is removed from the system before the system reaches an unstable state.

2. The method of claim 1, wherein the pressurizing step increases the temperature of the system to a temperature in excess of 70 ℃.

3. The method of claim 1, wherein the pressurizing step increases the temperature of the system to a temperature in excess of 120 ℃.

4. The method of claim 1, wherein the step of pressurizing the system is pulsed.

5. The method of claim 1, wherein the dynamic system comprises a therapeutically active compound.

6. The method of claim 1, wherein the dynamic system comprises a therapeutically active compound and a mediator.

7. The method of claim 1, wherein sterility is determined when the probability of a non-sterile system is equal to or less than one part per million.

8. The method of claim 6, wherein the medium is an aqueous solution, an organic solvent, or an oil.

9. The method of claim 8, wherein the system further comprises an excipient associated with the therapeutically active compound.

10. The method of claim 9, wherein the therapeutic compound is a solid, liquid or gas.

11. The method of claim 10, wherein the therapeutic compound is in the form of particles or droplets.

12. The method of claim 11 wherein the particles or droplets have an average effective particle size of less than 100 microns.

13. The method of claim 11 wherein the particles or droplets have an average effective particle size of less than 10 microns.

14. The method of claim 11 wherein the particles or droplets have an average effective particle size of less than 7 microns.

15. The method of claim 11 wherein the particles or droplets have an average effective particle size of less than 3 microns.

16. The method of claim 11 wherein the particles or droplets have an average effective particle size of less than 1 micron.

17. The method of claim 11 wherein the particles or droplets have an average effective particle size of less than 500 nm.

18. The method of claim 11, wherein the excipient is bound to the particles or droplets in a manner selected from the group consisting of: covalently bound to the particle or droplet, ionically bound to the particle or droplet, electronically attracted to the particle or droplet, adsorbed on the surface of the particle or droplet, and suspended in the particle or droplet.

19. The method of claim 11, wherein the excipient is a surfactant selected from one or more of anionic, cationic, nonionic and zwitterionic surfactants and biological surface active molecules.

20. The method of claim 11, wherein the particle or droplet transforms from one thermodynamic phase to another thermodynamic phase after the pressure is removed.

21. The method of claim 19, wherein the thermodynamic phase is selected from the group consisting of crystalline liquids, semi-crystalline liquids, amorphous liquids, and supercooled liquids.

22. The method of claim 21, wherein the difference in thermodynamic phase results from a transformation of a first crystal structure to a second crystal structure different from the first crystal structure.

23. The method of claim 1, comprising the additional step of supplying heat to the system by a pressurization step or additional heating.

24. The method of claim 23, wherein the temperature of the system is increased beyond 100 ℃ for a period of time exceeding 1 minute.

25. The method of claim 24, wherein the pressure is applied to the system in pulses of different pressures.

26. A method of sterilization comprising the steps of:

providing a polymeric container comprising a therapeutically active compound in a non-sterile medium;

adding heat to the vessel;

pressurizing the vessel above 0.25MPa, wherein the temperature of the vessel exceeds 70 ℃;

the step of supplying energy and the step of pressurizing are carried out for a time effective to sterilize the medium; and

heat and pressure are removed from the vessel.

27. The method of claim 26, wherein the polymeric container is manufactured from a non-PVC containing material.

28. The method of claim 26, wherein the container is fabricated from a film having a monolayer structure or a multilayer structure.

29. The method of claim 26, wherein the container is fabricated from a polymer.

30. The method of claim 26, wherein the polymeric container is adapted to be coupled to a fluid transfer member.

31. The method of claim 30, wherein the fluid transfer member is a tube.

32. The method of claim 30, wherein the fluid transfer member is a fluid delivery administration set.

33. The method of claim 1, wherein the container is selected from the group consisting of a sealed fluid container, a syringe, and a sealed tube.

34. A pharmaceutical product, comprising:

a flexible, fluid-tight polymeric container comprising a sterile therapeutic compound dispersed in an aqueous solution, the compound in the form of particles having an average particle size of less than 1 micron, and an excipient bound to the particles, wherein the solution is substantially free of a cloud point modifier.

35. The product of claim 34 wherein the container is made from a non-PVC containing material.

36. The product of claim 35, wherein the container is manufactured from a film having a single layer structure or a multi-layer structure.

37. The product of claim 35 wherein the film has more than 50% by weight polyolefin.

38. The product of claim 35 wherein the film is capable of being sealed into a container using radio frequency sealing techniques.

39. The product of claim 35, wherein the film has an elastic modulus of less than 40,000psi when measured according to ASTM D-882.

40. The product of claim 34, wherein the product has been sterilized by energizing the container and pressurizing the container to a pressure in excess of 0.25 MPa.

41. A method for sterilizing flexible medical containers, comprising the steps of:

providing a polymeric container having opposing sidewalls, said sidewalls having an elastic modulus of less than about 40,000 psi;

supplying heat to the container;

pressurizing the vessel to above 0.25 MPa; and

the heating step and the pressurizing step are terminated after an effective period of time to obtain a sterile container.

42. The method of claim 41, wherein the container is in an unfilled state.

43. The method of claim 41, wherein the container contains a fluid therein.

44. The method of claim 43, wherein the fluid is an aqueous-based solution.

45. The method of claim 41, wherein the container is of a type selected from the group consisting of an I.V. container, an efflux bag, a multi-chamber container, a protein-compatible container, a cell culture container, a blood substitute container, a cartridge for a delivery device, a syringe barrel, and a fluid administration device.