Patent Grant
8777011
The present application claims the benefit of U.S. Provisional Application No. 60/343,309, filed on Dec. 21, 2001, which is incorporated herein by reference in its entirety.
The need for effective therapeutic treatment of patients has resulted in the development of a variety of pharmaceutical formulation delivery techniques. One traditional technique involves the oral delivery of a pharmaceutical formulation in the form of a pill, capsule, elixir, or the like. However, oral delivery can in some cases be undesirable. For example, many pharmaceutical formulations may be degraded in the digestive tract before they can be effectively absorbed by the body. Inhaleable drug delivery, where an aerosolized pharmaceutical formulation is orally or nasally inhaled by a patient to deliver the formulation to the patient's respiratory tract, has proven to be a particularly effective and/or desirable alternative. For example, in one inhalation technique, a pharmaceutical formulation is delivered deep within a patient's lungs where it may be absorbed into the blood stream. Many types of inhalation devices exist including devices that aerosolize a dry powder, devices comprising a pharmaceutical formulation stored in or with a propellant, devices which use a compressed gas to aerosolize a liquid pharmaceutical formulation, and similar devices.
In one dry powder aerosolization technique, a capsule containing an inhaleable dry powder is loaded into a chamber in an aerosolization device. Within the chamber, the dry powder is at least partially emptied and dispersed to aerosolize the dry powder so that it may be inhaled by a patient. However, in conventional devices, there may be inconsistent aerosolization of the dry powder for some pharmaceutical formulations. As a result, the therapeutic effects of the pharmaceutical formulation may less than ideal.
Therefore, it is desirable to be able to provide a powdered pharmaceutical formulation stored in a capsule that is consistently aerosolizable. It is further desirable to prevent degradation of a pharmaceutical formulation stored in a capsule.
The present invention satisfies these needs. In one aspect of the invention, a package is provided for storing a capsule which contains an aerosolizable pharmaceutical formulation. The package includes a moisture barrier around the capsule to improve the aerosolization of the pharmaceutical formulation.
In another aspect of the invention, a package for storing an aerosolizable pharmaceutical formulation comprises a capsule adapted to contain the aerosolizable pharmaceutical formulation; and a moisture barrier around the capsule, the moisture barrier comprising a material that is resistant to moisture passage, whereby the moisture barrier reduces the amount of moisture in contact with the aerosolizable pharmaceutical formulation so that the aerosolizable pharmaceutical formulation may be aerosolized when the capsule is opened.
In another aspect of the invention, a package for storing an aerosolizable pharmaceutical formulation comprises a capsule adapted to contain the aerosolizable pharmaceutical formulation, and a bottle adapted to contain a plurality of capsules, the bottle comprising an evacuating mechanism, whereby the bottle reduces the amount of moisture in contact with the aerosolizable pharmaceutical formulation so that the aerosolizable pharmaceutical formulation may be aerosolized when the capsule is opened.
In another aspect of the invention, a package for storing a pharmaceutical formulation comprises a capsule adapted to contain the pharmaceutical formulation, wherein a wall of the capsule comprises a metal, whereby the wall reduces the amount of moisture in contact with the pharmaceutical formulation.
In another aspect of the invention, a package for storing a aerosolizable pharmaceutical formulation comprises a capsule adapted to contain the aerosolizable pharmaceutical formulation, and a multi-layered package around the capsule, the multi-layered package comprising an upper layer and a lower layer, wherein the upper layer and the lower layer each comprise a metal, whereby the multi-layered package reduces the amount of moisture in contact with the aerosolizable pharmaceutical formulation so that the aerosolizable pharmaceutical formulation may be aerosolized when the capsule is opened.
In another aspect of the invention, a method of storing a aerosolizable pharmaceutical formulation comprises containing the aerosolizable pharmaceutical formulation within a capsule, and surrounding the capsule with a moisture barrier to reduce the amount of moisture in contact with the aerosolizable pharmaceutical formulation so that the aerosolizable pharmaceutical formulation may be aerosolized when the capsule is opened.
These features, aspects, and advantages of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings which illustrate exemplary features of the invention. However, it is to be understood that each of the features can be used in the invention in general, not merely in the context of the particular drawings, and the invention includes any combination of these features, where:
The present invention relates to storing a pharmaceutical formulation. Although the process is illustrated in the context of storing a dry powder pharmaceutical formulation in a capsule, the present invention can be used in other processes and should not be limited to the examples provided herein.
A package 100 according to the present invention is shown schematically in
Some pharmaceutical formulations are particularly sensitive to moisture. For example, some dry powder pharmaceutical formulations that are to be aerosolized and inhaled by a user may become agglomerated when in the presence of excessive moisture. The agglomerations may affect the aerosol characteristics of the pharmaceutical formulation and reduce the therapeutic effects of the pharmaceutical formulation delivery. Accordingly, the package 100 of the present invention may be adapted to provide sufficient moisture protection over a predetermined amount of time for a particular pharmaceutical formulation. For example, the moisture barrier 115 or the combination of the moisture barrier 115 with the capsule 105 may provide moisture protection for at least about 2 days, more preferably for at least about 1 week, and most preferably for at least about 3 weeks.
The capsule 105 may be of a suitable shape, size, and material to contain the pharmaceutical formulation 110 and to provide the pharmaceutical formulation 110 in a usable condition. For example, the capsule 105 may comprise a wall 120 which comprises a material that does not adversely react with the pharmaceutical formulation. In addition, the wall 120 may comprise a material that allows the capsule 105 to be opened to allow the pharmaceutical formulation 110 to be aerosolized. In one version, the wall 120 comprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC), polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar, or the like. Alternatively or additionally, the capsule wall 120 may comprise a polymeric material, such as polyvinyl chloride (PVC). In one version, the capsule 105 may comprise telescopically a joined sections, as described for example in U.S. Pat. No. 4,247,066 which is incorporated herein by reference in its entirety. The interior of the capsule 105 may be filled with a suitable amount of the pharmaceutical formulation 110, and the size of the capsule 105 may be selected to adequately contain a desired amount of the pharmaceutical formulation 110.
The moisture barrier 115 may be sufficiently thick to decrease the amount of moisture that is able to pass through the barrier 115. In one version, the moisture barrier 115 comprises a material that is resistant to moisture passage in order to reduce the thickness of the barrier 115. For example, the moisture barrier 115 may comprise one or more metals, such as aluminum or the like, and/or other moisture barrier materials, such as polyamides, polyvinyl chlorides and the like.
In one version, the moisture barrier 115 may comprise a bottle 125 that holds a single dose of an aerosolizable pharmaceutical formulation. For example, in the version shown in
In another version, the moisture barrier 115 may comprise a bottle 150 that contains multiple doses of an aerosolizable pharmaceutical formulation. Unlike the versions of
In another version, the moisture barrier 115 may comprise a container 200 that stores capsules 105 containing an aerosolizable pharmaceutical formulation in a reduced moisture environment and ejects a predetermined number of the capsules 105 while maintaining the reduced moisture environment. For example, as shown in
In another version, the moisture barrier 115 comprises a housing 280 having a plurality of compartments 285 that each contain a single dose or a portion of a single dose of an aerosolizable pharmaceutical formulation in a capsule 105, as shown in
In one version, the moisture barrier comprises a multi-layered package 400. In one particular version, the multi-layered package 400, such as a blister, surrounds a capsule 105 containing a pharmaceutical formulation that is susceptible to degradation and/or reduced aerosol performance when exposed to excessive amounts of moisture, such as a dry powder aerosolizable pharmaceutical formulation. The multi-layered package 400 may comprise one or more materials that provide improved moisture barrier properties. For example, the multi-layered package 400 may comprise one or more metals, such as aluminum or the like, and/or other moisture barrier materials. The moisture barrier may be provided below and above the pharmaceutical formulation to provide additional moisture protection. For example, as shown in the version of
The sealing process is further illustrated in
The sealing material 417 is positioned between the upper layer 415 and the lower layer 405 and comprises a material that can seal the upper layer 415 to the lower layer 405 when heat and/or compression is applied to the sandwiched layers. For example, in one version, the sealing material comprises a layer of heat activated sealer, such as lacquer, or polymethyl methacrylate (PMMA), or the like. The heat activated sealer may be provided on the lower surface of the upper layer 415. When heated to a sufficient temperature, such as at least about 160° C., and often at least about 180° C., the heat activated sealer changes state so that when cooled, the upper layer 415 is sealed to the lower layer 405. Alternatively, the heat activated sealer may be provided on an upper surface of the lower layer 405 or may be a separate sheet positioned between the upper layer 415 and the lower layer 405. In another version, the heat activated sealer may be the material of the upper layer 415 and/or the lower layer 405. In this version, sufficient heat may be applied to melt the material between the layers so that the layers may be fused to one another upon cooling. Alternatively, the sealing material may comprise an adhesive or bonding material that does not require heat to activate.
In another version, the moisture barrier 115 may be provided by the material of the capsule 105. For example, as shown in
In another version, as shown in
In one version, the package 100 is adapted to contain a dry powder pharmaceutical formulation 110, as discussed above. The capsule 105 may contain the pharmaceutical formulation in a form where it may be aerosolized for inhalation by the user. For example, when in a powdered form, the powder may be initially stored in the capsule 105, as described in U.S. Pat. No. 4,995,385, U.S. Pat. No. 3,991,761, U.S. Pat. No. 6,230,707, and PCT Publication WO 97/27892, the capsule being openable before, during, or after insertion of the capsule into an aerosolization device. The powder may be aerosolized by an active element, such as compressed air, as described in U.S. Pat. No. 5,458,135, U.S. Pat. No. 5,785,049, and U.S. Pat. No. 6,257,233, or propellant, as described in U.S. patent application Ser. No. 09/556,262, filed on Apr. 24, 2000, and entitled “Aerosolization Apparatus and Methods”, and in PCT Publication WO 00/72904. Alternatively the powder may be aerosolized in response to a user's inhalation, as described for example in the aforementioned U.S. patent application Ser. No. 09/583,312 and U.S. Pat. No. 4,995,385. All of the above references being incorporated herein by reference in their entireties.
The package 100 of the present invention has been found to be particularly effective when used to store a capsule that is to be used in an aerosolization device that includes a puncturing element, such as the device described in U.S. Pat. No. 4,995,385 and similar devices. The improved moisture protection provided by the package 100 allows for better deagglomeration during the aerosolization process, which results in more finely divided particles for inhalation by the user. In addition, the improved moisture protection prevents the capsule material from becoming brittle. This brittle prevention allows the puncturing element to more efficiently and consistently create one or more openings into the capsule during use. Without the moisture protection, the capsule may become brittle and may shatter, create capsule particles, and/or have less reproducible openings when punctured. Accordingly, the moisture barrier afforded by the present package 100 provides numerous aerosolization benefits.
In a preferred version, the invention provides a capsule 105 that may be used with a system and method for aerosolizing a pharmaceutical formulation and delivering the pharmaceutical formulation to the lungs of the user. The pharmaceutical formulation may comprise powdered medicaments, liquid solutions or suspensions, and the like, and may include an active agent.
The active agent described herein includes an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. An active agent for incorporation in the pharmaceutical formulation described herein may be an inorganic or an organic compound, including, without limitation, drugs which act on: the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous system. Suitable active agents may be selected from, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagnonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, anti-infectives (antibiotics, antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, anepileptics, bronchodilators, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent, when administered by inhalation, may act locally or systemically.
The active agent may fall into one of a number of structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.
Examples of active agents suitable for use in this invention include but are not limited to one or more of calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including penicllinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant agents like methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefmetazole, ceftazidime, loracarbef, and moxalactam, monobactams like aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate and where applicable, analogues, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms of the above. In reference to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, unglycosylated, pegylated forms, and biologically active fragments and analogs thereof.
Active agents for use in the invention further include nucleic acids, as bare nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid constructions of a type suitable for transfection or transformation of cells, i.e., suitable for gene therapy including antisense. Further, an active agent may comprise live attenuated or killed viruses suitable for use as vaccines. Other useful drugs include those listed within the Physician's Desk Reference (most recent edition).
The amount of active agent in the pharmaceutical formulation will be that amount necessary to deliver a therapeutically effective amount of the active agent per unit dose to achieve the desired result. In practice, this will vary widely depending upon the particular agent, its activity, the severity of the condition to be treated, the patient population, dosing requirements, and the desired therapeutic effect. The composition will generally contain anywhere from about 1% by weight to about 99% by weight active agent, typically from about 2% to about 95% by weight active agent, and more typically from about 5% to 85% by weight active agent, and will also depend upon the relative amounts of additives contained in the composition. The compositions of the invention are particularly useful for active agents that are delivered in doses of from 0.001 mg/day to 100 mg/day, preferably in doses from 0.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/day to 50 mg/day. It is to be understood that more than one active agent may be incorporated into the formulations described herein and that the use of the term “agent” in no way excludes the use of two or more such agents.
The pharmaceutical formulation may comprise a pharmaceutically acceptable excipient or carrier which may be taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject. In addition to the active agent, a pharmaceutical formulation may optionally include one or more pharmaceutical excipients which are suitable for pulmonary administration. These excipients, if present, are generally present in the composition in amounts ranging from about 0.01% to about 95% percent by weight, preferably from about 0.5 to about 80%, and more preferably from about 1 to about 60% by weight. Preferably, such excipients will, in part, serve to further improve the features of the active agent composition, for example by providing more efficient and reproducible delivery of the active agent, improving the handling characteristics of powders, such as flowability and consistency, and/or facilitating manufacturing and filling of unit dosage forms. In particular, excipient materials can often function to further improve the physical and chemical stability of the active agent, minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, particle surface properties, such as rugosity, ease of inhalation, and the targeting of particles to the lung. One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of active agent in the formulation.
Pharmaceutical excipients and additives useful in the present pharmaceutical formulation include but are not limited to amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates, such as sugars, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present singly or in combination. Suitable excipients are those provided in WO 96/32096, which is incorporated herein by reference in its entirety. The excipient may have a glass transition temperature (Tg) above about 35° C., preferably above about 40° C., more preferably above 45° C., most preferably above about 55° C.
Exemplary protein excipients include albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids (outside of the dileucyl-peptides of the invention), which may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. Preferred are amino acids and polypeptides that function as dispersing agents. Amino acids falling into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. Dispersibility—enhancing peptide excipients include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic amino acid components such as those described above.
Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.
The pharmaceutical formulation may also include a buffer or a pH adjusting agent, typically a salt prepared from an organic acid or base. Representative buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers.
The pharmaceutical formulation may also include polymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin), polyethylene glycols, and pectin.
The pharmaceutical formulation may further include flavoring agents, taste-masking agents, inorganic salts (for example sodium chloride), antimicrobial agents (for example benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (for example polysorbates such as “TWEEN 20” and “TWEEN 80”), sorbitan esters, lipids (for example phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for example EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and/or additives suitable for use in the compositions according to the invention are listed in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), both of which are incorporated herein by reference in their entireties.
“Mass median diameter” or “MMD” is a measure of mean particle size, since the powders of the invention are generally polydisperse (i.e., consist of a range of particle sizes). MMD values as reported herein are determined by centrifugal sedimentation, although any number of commonly employed techniques can be used for measuring mean particle size. “Mass median aerodynamic diameter” or “MMAD” is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction.
In one version, the powdered formulation for use in the present invention includes a dry powder having a particle size selected to permit penetration into the alveoli of the lungs, that is, preferably 10 μm mass median diameter (MMD), preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range of 0.1 μm to 5 μm in diameter. The delivered dose efficiency (DDE) of these powders may be greater than 30%, more preferably greater than 40%, more preferably greater than 50% and most preferably greater than 60% and the aerosol particle size distribution is about 1.0-5.0 μm mass median aerodynamic diameter (MMAD), usually 1.5-4.5 μm MMAD and preferably 1.5-4.0 μm MMAD. These dry powders have a moisture content below about 10% by weight, usually below about 5% by weight, and preferably below about 3% by weight. Such powders are described in WO 95/24183, WO 96/32149, WO 99/16419, and WO 99/16422, all of which are all incorporated herein by reference in their entireties.
Although the present invention has been described in considerable detail with regard to certain preferred versions thereof, other versions are possible, and alterations, permutations and equivalents of the version shown will become apparent to those skilled in the art upon a reading of the specification and study of the drawings. For example, the relative positions of the elements in the expedients for carrying out the relative movements may be changed. Also, the various features of the versions herein can be combined in various ways to provide additional versions of the present invention. Furthermore, certain terminology has been used for the purposes of descriptive clarity, and not to limit the present invention. For example, the use of the terms “upper” and “lower” may be reversed in the specification. Therefore, the appended claims should not be limited to the description of the preferred versions contained herein and should include all such alterations, permutations, and equivalents as fall within the true spirit and scope of the present invention.
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| Number | Date | Country | |
|---|---|---|---|
| 20030106827 A1 | Jun 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60343309 | Dec 2001 | US |
