The assignee for this patent application is Chang;
Reporters obtained the following quote from the background information supplied by the inventors: "Due to continued advances in genetic and cell engineering technologies, proteins known to exhibit various pharmacological actions in vivo are capable of production in large amounts for pharmaceutical applications. However, one of the most challenging tasks in the development of protein pharmaceuticals is to deal with the inherent physical and chemical instabilities of such proteins, especially in aqueous dosage forms. To try to understand and maximize the stability of protein pharmaceuticals and any other usable proteins, many studies have been conducted, especially in the past two decades. These studies have covered many areas, including protein folding and unfolding/denaturation, mechanisms of chemical and physical instabilities of proteins, as well as various means of stabilizing proteins in aqueous form; see, e.g., Manning et al.,
"Because of the instability issues associated with the aqueous dosage forms, powder formulations are generally preferred to achieve sufficient stability for the desired shelf life of the product. Various techniques to prepare dry powders have been known, substantiated and practiced in the pharmaceutical and biotech industry. Such techniques include lyophilization, spray-drying, spray-freeze drying, bulk crystallization, vacuum drying, and foam drying. Lyophilization (freeze-drying) is often a preferred method used to prepare dry powders (lyophilizates) containing proteins. Various methods of lyophilization are well known to those skilled in the art; see, e.g., Pikal M J., In: Cleland J L, Langer R. eds. Formulation and Delivery of Proteins and Peptides.
"The lyophilization process consists if three stages: freezing, primary drying, and secondary drying. Because the protein product is maintained frozen throughout drying process, lyophilization provides the following advantages over alternative techniques: minimum damage and loss of activity in delicate, heat-liable materials; speed and completeness of rehydration; the possibility of accurate, clean dosing into final product containers so that particulate and bacterial contamination is reduced; permits product reconstitution at a higher concentration than it was at the time of freezing; and permits storage of the product at ambient temperatures. The latter can be particularly useful for hospital products in areas that do not have ready access to freezers, especially ultra-cold freezers.
"Unfortunately, even in solid dosage forms, some proteins can be relatively unstable and this instability may be a product of the lyophilization method used for preparing the solid dosage forms and/or the inherent instability of the actual solid dosage formulations themselves. For example, in certain instances, lyophilization processing events can force a protein to undergo significant chemical and physical changes. Such processing events include concentration of salts, precipitation, crystallization, chemical reactions, shear, pH, amount of residual moisture remaining after freeze-drying, and the like. Such chemical and physical changes include, e.g., formation of dimer or other higher order aggregates, and unfolding of tertiary structure. Unfortunately, these changes may result in loss of activity of the protein, or may result in significant portions of the active materials in the drug having been chemically transformed into a degradation product or products which may actually comprise an antagonist for the drug or which may give rise to adverse side effects. In addition to the instabilities incurred upon proteins because of the inherent steps of the lyophilization process, other disadvantages of lyophilization include: long and complex processing times; high energy costs; and expensive set up and maintenance of the lyophilization facilities. As such, use of lyophilization is usually restricted to delicate, heat-sensitive materials of high value. Additionally, lyophilized powders are typically formed as cakes, which require additional grinding and milling and optionally sieving processing steps to provide flowing powders. To try to understand and to optimize protein stability during lyophilization and after lyophilization, many studies have been conducted; see, e.g., Gomez G. et al.,
"In order to allow for parenteral administration of these powdered drugs, the drugs must first be placed in liquid form. To this end, the drugs are mixed or reconstituted with a diluent before being delivered parenterally to a patient. The reconstitution procedure must be performed under sterile conditions, and in some procedures for reconstituting, maintaining sterile conditions is difficult. One way of reconstituting a powdered drug is to inject a liquid diluent directly into a drug vial containing the powdered drug. This can be performed by use of a combination-syringe and syringe needle having diluent contained therein and drug vials which include a pierceable rubber stopper. The method of administration goes as follows: 1) the rubber stopper of the drug vial is pierced by the needle and the liquid in the syringe injected into the vial; 2) the vial is shaken to mix the powdered drug with the liquid; 3) after the liquid and drug are thoroughly mixed, a measured amount of the reconstituted drug is then drawn into the syringe; 4) the syringe is then withdrawn from the vial and the drug then be injected into the patient.
"For people requiring frequent parenteral administration of drugs, it is common practice for those people to be provided with home-use kits which may include injection cartridges, pre-filled syringes, pen injectors and/or autoinjectors to be used for the purpose of self-administration. Autoinjectors incorporating needled injection mechanisms are well known and thought to exhibit several advantages relative to simple hypodermic syringes. Such needled autoinjectors generally include a body or housing, a needled syringe or similar device, and one or more drive mechanisms for inserting a needle into the tissue of the subject and delivering a desired dose of liquid medicament through the inserted needle. To date, all known autoinjector devices have been used with liquid formulations. There still exists a need for an autoinjector that can used to deliver powdered formulations.
"Other methods of administration of powdered drugs include the use of dual-chambered injection cartridges and/or pre-filled syringe systems. Injection cartridges of the dual-chamber type are well-known and have found a wide use. They are used together with various types of injection apparatuses which serve to hold the cartridge as it is readied for injection and as injections are subsequently administered. Injection cartridges of the dual-chamber type generally comprise a cylindrical barrel, which is shaped like a bottleneck at its front end and has an open rear end. The front end is closed by a septum of rubber or other suitable material, which is secured in place by means of a capsule. This capsule has a central opening where the septum is exposed and may be pierced by a hollow needle to establish a connection with the interior of the cartridge; see e.g., U.S. Pat. No. 5,435,076 and references cited therein.
"Dual-chambered pre-filled syringe systems are well known and have found wide commercial use; see e.g., U.S. Pat. Nos. 5,080,649; 5,833,653; 6,419,656; 5,817,056; 5,489,266, and references cited therein. Pre-filled syringes of the dual-chambered type generally comprise an active ingredient which is lyophilized in one chamber, while a second chamber of the syringe contains a solvent that is mixed with the active substance immediately before application. In such devices, in order to facilitate the movement of the syringe plunger against compression of air, the chamber containing the lyophilized product typically has large head space and some additional mechanism, e.g., rotation of the plunger, screwing in the plunger, is necessary. As a result, the reconstituted drug needs to primed to remove large volumes of air prior to injection; see e.g., U.S. Pat. No. 6,817,987 which describes a hypodermic syringe which holds a solvent and a soluble component (medicament) and wherein the solvent and medicament are mixed as the user presses and then releases the plunger of the syringe. Upon complete mixing, the user attaches a needle and then rotates the plunger of the syringe to allow for the injection.
"Several syringe devices of various configurations and various processes of lyophilization have been described in, e.g., U.S. Pat. Nos. 5,752,940; 5,876,372; 6,149,628; 6,440,101, and references cited therein. Importantly, in each instance, the devices comprise multiple parts and require at least a two step, two directional reconstitution process for the delivery of the lyophilized powdered drug. Other devices used for reconstitution and delivery of powdered drugs are described in, e.g., U.S. Pat. Nos. 4,328,802; 4,410,321; 4,411,662; 4,432,755; 4,458,733; 4,898,209; 4,872,867; 3,826,260, and references cited therein.
"Unfortunately, because all of these known methods require thorough reconstitution/mixing of the lyophilized product into the diluent prior to injection, they can typically involve lengthy procedures (in excess of 10 steps) in order to reconstitute the solid drug into a liquid formulation prior to administration. Such lengthy reconstitution steps can be complex, arduous and tedious for the patient and may render injection of the lyophilized product unfeasible. Moreover, these complicated procedures present risks of foaming, risk of contamination, and risk of accidental needle pricks. There clearly still exists a need for improved delivery devices and methods.
"Co-pending U.S. patent application Ser. No. 11/172,064 ('064) provides an advancement in the technology and relates to a container closure assembly suitable for lyophilized pharmaceutical injectable products and designed to provide for direct injection of a lyophilized product without the need for a reconstitution/mixing/priming step of the powder and diluent prior to injection. The components of the disclosed container closure assembly were designed to function in a manufacturing function and an end user function and, upon completion of the lyophilization process, the assembly has minimal head space to avoid the need for priming. The disclosed container closure assembly is designed to utilize or be easily adaptable to industry standard or existing filling systems, thus providing a more economical alternative to prior art devices.
"The present invention provides an improved alternative container closure design which facilitates the easy, direct injection of the lyophilized product without the need for a reconstitution/mixing/priming step of the powder and a liquid diluent by the end user. As with the assemblies described in the '064 application, the disclosed container closure assembly is designed to utilize or be easily adaptable to industry standard or existing filling systems, thus providing a more economical alternative to prior art devices."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "The container closure assembly of the present invention consists of three operating components designed to function in a manufacturing function and an end user function: a plug component; a top cup component; and a product container component. The plug component and top cup component are specifically designed to snugly engage with each other to form a plunger assembly that can then be inserted into the product container. Alternatively, the plunger assembly may be a one piece component comprising specific features the top cup component and plug component. The plunger assembly may thus vary in size and configuration and have varying manufacturing and/or end user functionality. The product container component is specifically designed to hold a liquid to be lyophilized and capable of holding a plunger assembly. The product container may vary in size and configuration but is typically cylindrical in shape, and has at one end an opening and at the opposing end an ejection port. An important, unique design feature of the product container is a spiral mixing channel that is integrated into the product container at the lower base and which serves to improve product yield.
"Importantly, the container closure assembly of the present invention is designed to utilize or be easily adaptable to industry standard or existing lyophilization systems, thus providing an economical alternative. Upon completion of the lyophilization process, the plunger assembly is compressed such that it compresses the powdered pharmaceutical product, i.e., there is minimum head space between the product container and the plunger assembly, and the plunger assembly serves as a path to allow for the flow of liquid into the container closure assembly, i.e., allow for liquid to encounter the powder and rapidly reconstitute without the need for priming. Because of the unique assembly design, the container closure assembly facilitates the easy, direct injection of the lyophilized product without the need for a reconstitution/mixing/priming step of the powder and a liquid diluent by the end user.
"Another object of the present invention is an improved process for the preparation of a container closure assembly containing a lyophilized powder product. This improved process comprises the following steps: 1) utilizing an industry standard vial manufacturing filling line, the product container is loaded into the equipment in a similar manner as regular vials; 2) the product container is filled with liquid active ingredient; 3) a plunger assembly is dropped into an 'open' position on top of the product container, engaged with the product container in the same manner as lyophilization stoppers are mounted to regular vials; 4) the complete container closure assembly is then placed into the lyophilizer; 5) upon lyophilization, vapor is allowed to escape via the openings between the plunger assembly and product container; 6) upon completion of lyophilization, vertical compression of the lyophilizer shelves will seal the plunger assembly into the product container with minimal head space; and 7) the sealed container closure assembly is bonded to provide a tamper resistant assembly which retains the sterility of the active ingredient.
"Another object of the present invention is an improved method for the administration of a lyophilized pharmaceutical powder product using the container closure system of the present invention. In one embodiment, this improved method of administration comprises the following steps: 1) a tangential force is applied to the tab seal at the top end of the sealed container closure assembly containing the lyophilized powder product to allow attachment via friction fit to either a luer-lock or luer-slip syringe containing the diluent; 2) the detachable base at the ejection port end of the container closure assembly is detached, thus exposing a tip for the attachment of a standard type needle; 3) a standard type needle is attached to said exposed tip of the container closure assembly; 4) the injection is then initiated as normal by inserting the needle into the injection site; and 5) force is applied to the syringe plunger whereupon the diluent in the syringe will be forced through the container closure assembly, encounter the lyophilized powder and rapidly reconstitute the powder to allow the liquefied product mixture to flow into the injection site, completing the injection. Importantly, there is no requirement for a reconstitution/mixing/priming step of the powder and diluent by the end user.
BRIEF DESCRIPTION OF THE FIGURES
"FIG. 1 shows an elevation perspective view from the upper base of a product container contemplated for use in the container closure assembly of the present invention.
"FIG. 2 shows a perspective view of a product container contemplated for use in the container closure assembly of the present invention, shown along a vertical plane.
"FIG. 3 shows an elevation perspective view from the bottom of a top cup component contemplated for use in the container closure assembly of the present invention.
"FIG. 4 shows a perspective view of a top cup component contemplated for use in the container closure assembly of the present invention.
"FIG. 5 shows a perspective view of a plug portion contemplated for use in the container closure assembly of the present invention.
"FIG. 6 is a perspective view showing the arrangement of elements and parts for one embodiment of the container closure assembly of the present invention.
"FIG. 7 shows a perspective view of an embodiment of the container closure assembly whereupon a plunger assembly consisting of a top cup component and a plug component are installed upon the product container after the filling the product container with liquid active ingredient and prior to placement of the container closure assembly within a freeze drying apparatus, i.e., the plunger assembly is installed in an 'open' position in the product container.
"FIG. 8 shows a perspective view of an embodiment of the container closure assembly upon completion of the freeze drying cycle whereupon the liquid active ingredient has formed into a dry powder and the plunger assembly has been compressed by the freeze dryer shelves to create a sealed container closure assembly.
"FIG. 9 shows a perspective view of an alternative product container design contemplated for use in the container closure assembly of the present invention, wherein the ejection port of the product container comprises a nozzle spray tip for nasal delivery.
"FIG. 10 is a graph depicting the 'gradient delivery' injection profile associated with the administration of a powdered drug using the powder formulations, lyophilization processes, and container closure assembly of the present invention. Protein concentration is plotted versus cumulative injection volume.
"FIG. 11 is a graph depicting an injection profile representative of those associated with the administration of a powdered drug using prior art devices which require a reconstitution and/or mixing step of the powdered drug with a diluent prior to injection. Protein concentration is plotted versus cumulative injection volume."
For more information, see this patent application: Chang,
Keywords for this news article include: Patents, Peptides, Proteins, Amino Acids.
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