Spray-coated pharmaceutical powder compositions for transdermal administration using a needleless syringe comprise seed particles coated with a pharmaceutical composition, the said coated seed particles having an average size of about 10 to 100 xcexcm and having an envelope density ranging from about 0.1 to about 25 g/cm3.

The invention relates to a method for producing powdered pharmaceutical compositions. More specifically, the invention relates to a method for forming dense, substantially solid particles from pharmaceutical compositions, where the particulate compositions are particularly suitable for transdermal particle delivery from a needleless syringe system.
The ability to deliver pharmaceuticals through skin surfaces (transdermal delivery) provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and noninvasive alternative to traditional drug administration systems, conveniently avoiding the major problems associated with oral delivery (e.g., variable rates of absorption and metabolism, gastrointestinal irritation and/or bitter or unpleasant drug tastes) or parenteral delivery (e.g., needle pain, the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the disposal of used needles).
However, despite its clear advantages, transdermal delivery presents a number of its own inherent logistical problems. The passive delivery of drugs through intact skin necessarily entails the transport of molecules through a number of structurally different tissues, including the stratum corneum, the viable epidermis, the papillary dermis, and the capillary walls in order for the drug to gain entry into the blood or lymph system. Transdermal delivery systems must therefore be able to overcome the various resistances presented by each type of tissue. In light of the above, a number of alternatives to passive transdermal delivery have been developed. These alternatives include the use of skin penetration enhancing agents, or xe2x80x9cpermeation enhancers,xe2x80x9d to increase skin permeability, as well as non-chemical modes such as the use of iontophoresis, electroporation or ultrasound. However, these alternative techniques often give rise to their own unique side effects, such as skin irritation or sensitization. Thus, the spectrum of pharmaceuticals that can be safely and effectively administered using traditional transdermal delivery methods has remained limited.
More recently, a novel transdermal drug delivery system that entails the, use of a needleless syringe to fire powders (i.e., solid drug-containing particles) in controlled doses into and through intact skin has been described. In particular, commonly owned U.S. Pat. No. 5,630,796 to Bellhouse et al. describes a needleless syringe that delivers pharmaceutical particles entrained in a supersonic gas flow. The needleless syringe is used for transdermal delivery of powdered drug compounds and compositions, for delivery of genetic material into living cells (e.g., gene therapy) and for the delivery of biopharmaceuticals to skin, muscle, blood or lymph. The needleless syringe can also be used in conjunction with surgery to deliver drugs and biologics to organ surfaces, solid tumors and/or to surgical cavities (e.g., tumor beds or cavities after tumor resection). In theory, practically any pharmaceutical agent that can be prepared in a substantially solid, particulate form can be safely and easily delivered using such devices.
One particular needleless syringe generally comprises an elongate tubular nozzle having a rupturable membrane initially closing the passage through the nozzle and arranged substantially adjacent to the upstream end of the nozzle. Particles of a therapeutic agent to be delivered are disposed adjacent to the rupturable membrane and are delivered using an energizing means which applies a gaseous pressure to the upstream side of the membrane sufficient to burst the membrane and produce a supersonic gas flow (containing the pharmaceutical particles) through the nozzle for delivery from the downstream end thereof The particles.can thus be delivered from the needleless syringe at delivery velocities of between Mach 1 and Mach 8 which are readily obtainable upon the bursting of the rupturable membrane.
Another needleless syringe configuration generally includes the same elements as described above, except that instead of having the pharmaceutical particles entrained within a supersonic gas flow, the downstream end of the nozzle is provided with a bistable diaphragm which is moveable between a resting xe2x80x9cinvertedxe2x80x9d position (in which the diaphragm presents a concavity on the downstream face to contain the pharmaceutical particles) and an active xe2x80x9cevertedxe2x80x9d position (in which the diaphragm is outwardly convex on the downstream face as a result of a supersonic shockwave having been applied to the upstream face of the diaphragm). In this manner, the pharmaceutical particles contained within the concavity of the diaphragm are expelled at a supersonic initial velocity from the device for transdermal delivery thereof to a targeted skin or mucosal surface.
Transdermal delivery using either of the above-described needleless syringe configurations is carried out with particles having an approximate size that generally ranges between 0.1 and 250 xcexcm. For drug delivery, an optimal particle size is usually at least about 10 to 15 xcexcm (the size of a typical cell). For gene delivery, an optimal particle size is generally substantially smaller than 10 xcexcm. Particles larger than about 250 xcexcm can also be delivered from the device, with the upper limitation being the point at which the size of the particles would cause untoward damage to the skin cells. The actual distance which the delivered particles will penetrate depends upon particle size (e.g., the nominal particle diameter assuming a roughly spherical particle geometry), particle density, the initial velocity at which the particle impacts the skin surface, and the density and kinematic viscosity of the skin In this regard, optimal particle densities for use in needleless injection generally range between about 0.1 and 25 g/cm3, preferably between about 0.8 and 1.5 g/cm3, and injection velocities generally range between about 100 and 3,000 m/sec.
It is a primary object of the invention to provide a spray-coated powder composition for administration from a needleless syringe. It is also a primary object of the invention to provide suitable spray-coating methods for producing such powder compositions.
In one aspect of the invention, a spray-coated powder composition for administration from a needleless syringe is provided. The powder composition is formed from seed particles that are coated with an aqueous pharmaceutical composition. More especially, the spray-coated powder composition comprises seed particles coated with a pharmaceutical composition, the said coated seed particles having an average size of about 10 to 100 xcexcm and having an envelope density ranging from about 0.1 to about 25 g/cm3.
The coated seed particles can have an average size of about 20 to 70 xcexcm. Preferably, they have an envelope density ranging from about 0.8 to about 1.5 g/cm3. The coated seed particles typically have a substantially spherical aerodynamic shape and/or a substantially uniform, nonporous surface. The powders may also be characterized in that the coated seed particles have a pharmaceutical composition loading of about 1 to 50 wt %. The spray-coated powder compositions can contain, as the active pharmaceutical agent, any small molecule drug substance, organic or inorganic chemical, vaccine, or peptide (polypeptide and/or protein) of interest.
In another aspect of the invention, a method for preparing the spray-coated powder composition is provided. The method comprises spray-coating an aqueous pharmaceutical composition onto seed particles under conditions sufficient to provide coated particles having an average size of about 10 to 100 xcexcm and an envelope density ranging from about 0.1 to about 25 g/cm3. In one particular embodiment, the method entails the steps of: (a) suspending the seed particles in a reaction chamber using a hot air flow; (b) atomizing an aqueous pharmaceutical composition into a fine spray and introducing the spray into the reaction chamber; (c) allowing the spray to spread over the surface of the suspended seed particles to coat them with a thin film; and then (d) drying the coated seed particles. If desired, the aqueous pharmaceutical composition can be sprayed into the reaction chamber in a direction that is transverse to the direction of the hot air flow.
It is an advantage of the invention that free-flowing powder compositions can be produced having well defined particle size, density and mechanical properties which collectively are suitable for transdermal delivery from a needleless syringe. Further advantages of the methods of the invention include flexible pharmaceutical loading (up to about 50 wt %), overall process efficiency (no need for post-formulation fractionation, classification or sieving operations), and the methods are readily scalable. The invention further provides:
a dosage receptacle for a needleless syringe, said receptacle containing a therapeutically effective amount of a spray-coated powder composition of the invention; and
a needleless syringe which is loaded with such a powder composition.
These and other objects, aspects, embodiments and advantages of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.
Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified compositions or process parameters as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting.
All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.
It must be noted that, as used in this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to xe2x80x9ca particlexe2x80x9d includes a mixture of two or more such particles, reference to xe2x80x9can excipientxe2x80x9d includes mixtures of two or more such excipients, and the like.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although a number of methods.and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.
In describing the present invention, the following terms will be employed, and are intended to be defined as indicated below.
By xe2x80x9ctransdermal delivery,xe2x80x9d applicant intends to include both transdermal (xe2x80x9cpercutaneousxe2x80x9d) and transmucosal routes of administration, i.e., delivery by passage of a drug or pharmaceutical agent through the skin or mucosal tissue. See, e.g., Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Hadgraft and Guy (eds.), Marcel Dekker, Inc., (1989); Controlled Drug Delivery. Fundamentals and Applications, Robinson and Lee (eds.), Marcel Dekker Inc., (1987); and Transdermal Delivery of Drugs, Vols. 1-3, Kydonieus and Berner (eds.), CRC Press, (1987).
As used herein, the term xe2x80x9cpharmaceuticalxe2x80x9d or xe2x80x9cpharmaceutical agentxe2x80x9d intends any compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacologic and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, as well as biopharmaceuticals including molecules such as peptides, hormones, nucleic acids, gene constructs and the like. More particularly, the term xe2x80x9cpharmaceuticalxe2x80x9d or xe2x80x9cpharmaceutical agentxe2x80x9d includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; local and general anesthetics; anorexics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antihistamines; anti-inflammatory agents; antinauseants; antineoplastics; antipruritics; antipsychotics; antipyretics; antispasmodics; cardiovascular preparations (including calcium channel blockers, beta-blockers, betaagonists and antiarrythmics); antihypertensives; diuretics; vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; therapeutic proteins (e.g., antigens, antibodies, growth factors, cytokines, interleukins, lymphokines, interferons, enzymes, etc.), peptides and-fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like).
The above pharmaceuticals or pharmaceutical agents, alone or in combination with other agents, are typically prepared as pharmaceutical compositions which can contain one or more added materials such as carriers, vehicles, and/or excipients. xe2x80x9cCarriers,xe2x80x9d xe2x80x9cvehiclesxe2x80x9d and xe2x80x9cexcipientsxe2x80x9d generally refer to substantially inert materials which are nontoxic and do not interact with other components of the composition in a deleterious manner. These materials can be used to increase the amount of solids in particulate pharmaceutical compositions. Examples of suitable carriers include water, silicone, gelatin, waxes, and like materials. Examples of normally employed xe2x80x9cexcipients,xe2x80x9d include pharmaceutical grades of carbohydrates including monosaccharides, disaccharides, cyclodextrans, and polysaccharides (e.g., dextrose, sucrose, lactose, trehalose, raffinose, mannitol, sorbitol, inositol, dextrans, and maltodextrans); starch; cellulose; salts (e.g. sodium or calcium phosphates, calcium sulfate, magnesium sulfate); citric acid; tartaric acid; glycine; high molecular weight polyethylene glycols (PEG); Pluronics; surfactants; and combinations thereof. Generally, when carriers and/or excipients are used, they are used in amounts ranging from about 0.1 to 99 wt % of the pharmaceutical composition.
The terms xe2x80x9cindividualxe2x80x9d and xe2x80x9csubjectxe2x80x9d are used interchangeably herein to refer to any member of the subphylum cordata, including, without limitation, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like. The terms do not denote a particular age. Thus, both adult and newborn individuals are intended to be covered. The methods described herein are intended for use in any of the above vertebrate species, since the immune systems of all of these vertebrates operate similarly.
The term xe2x80x9cpowder,xe2x80x9d as used herein, refers to a composition that consists of substantially solid particles that can be delivered transdermally using a needleless syringe device. The particles that make up the powder can be characterized on the basis of a number of parameters including, but not limited to, the average particle size, the average particle density, particle morphology (e.g., particle aerodynamic shape and particle surface characteristics), and particle penetration energy (P.E.).
The average particle size of the powders produced according to the present invention can vary widely and is generally between about 10 and 100 xcexcm, more typically between about 20 and 70 xcexcm. The average particle size of the powder can be measured as a mass mean aerodynamic diameter (MMAD) using conventional techniques such as microscopic techniques (where particles are sized directly and individually rather than grouped statistically), absorption of gasses, permeability or time of flight. If desired, automatic particle-size counters can be used (e.g., Aerosizer Counter, Coulter Counter, HIAC Counter, or Gelman Automatic Particle Counter) to ascertain the average particle size.
Actual particle density, or xe2x80x9cabsolute density,xe2x80x9d can be readily ascertained using known quantification techniques such as helium pycnometry and the like. Alternatively, envelope (xe2x80x9ctapxe2x80x9d) density.measurements can be used to assess the density of a particulate pharmaceutical composition produced according to the methods of the invention. Envelope density information is particularly useful in characterizing the density of objects of irregular size and shape. Envelope density is the mass of an object divided by its volume, where the volume includes that of its pores and small cavities but excludes interstitial space. A number of methods of determining envelope density are known in the art, including wax immersion, mercury displacement, water absorption and apparent specific gravity techniques. A number of suitable devices are also available for determining envelope density, for example, the GeoPyc(trademark) Model 1360, available from the Micromeritics Instrument Corp. The difference between the absolute density and envelope density of a sample pharmaceutical composition provides information about the sample""s percentage total porosity and specific pore volume.
Particle morphology, particularly the aerodynamic shape of a particle, can be readily assessed using standard light microscopy. It is preferred that the particles which make up the instant powders have a substantially spherical or at least substantially elliptical aerodynamic shape. It is also preferred that the particles have an axis ratio of 3 or less to avoid the presence of rod- or needle-shaped particles. These same microscopic techniques can-also be used to assess the particle surface characteristics, e.g., the amount and extent of surface voids or degree of porosity.
Particle penetration.energies can be ascertained using a number of conventional techniques, for example a metallized film P.E. test.
In one embodiment, a powdered pharmaceutical composition is provided, wherein the powder composition (which is comprised of particles) is produced using a spray-coating technique. The powders are suitable for transdermal administration from a needleless syringe delivery system, and as such, the particles which make up the powdered composition must have sufficient physical strength to withstand sudden acceleration to several times the speed of sound and the impact with, and passage through, the skin and tissue. The particles are formed by spray-coating an aqueous pharmaceutical composition onto suitable seed particles. The particles can be delivered from a needleless syringe system such as those described in commonly owned International Publication Nos. WO 94/24263, WO 96/04947, WO 96/12513, and WO 96/20022, all of which are incorporated herein by reference.
The aqueous pharmaceutical compositions can contain, as the active pharmaceutical agent, any small molecule drug substance, organic or inorganic chemical, vaccine, or peptide (polypeptide and/or protein) of interest. In particular embodiments, the pharmaceutical agent is a biopharmaceutical preparation of a peptide, polypeptide, protein or any other such biological molecule. Exemplary peptide and protein formulations include, without limitation, insulin; calcitonin; octreotide; endorphin; liprecin; pituitary hormones (e.g., human growth hormone and recombinant human growth hormone (hGH and rhGH), HMG, desmopressin acetate, etc); follicle luteoids; growth factors (such as growth factor releasing factor (GFRF), somatostatin, somatotropin and platelet-derived growth factor); asparaginase; chorionic gonadotropin; corticotropin (ACTH); erythropoietin (EPO); epoprostenol (platelet aggregation inhibitor); glucagon; interferons; interleukins; menotropins (urofollitropin, which contains follicle-stimulating hormone (FSH); and luteinizing hormone (LH)); oxytocin; streptokinase; tissue plasminogen activator (TPA); urokinase; vasopressin; desmopressin; ACTH analogues; angiotensin II antagonists; antidiuretic hormone agonists; bradykinin antagonists; CD4 molecules; antibody molecules and antibody fragments (e.g., Fab, Fab2, Fv and sFv molecules); IGF-1; neurotrophic factors; colony stimulating factors; parathyroid hormone and agonists; parathyroid hormone antagonists; prostaglandin antagonists; protein C; protein S; renin inhibitors; thrombolytics; tumor necrosis factor (TNF); vaccines (particularly peptide vaccines including subunit and synthetic peptide preparations); vasopressin antagonists analogues; and xcex1-1 antitrypsin. Additionally, nucleic acid preparation, such as vectors or gene constructs for use in subsequent gene delivery, can be used.
The pharmaceutical agent is typically prepared as an aqueous pharmaceutical composition using a suitable aqueous carrier, along with suitable excipients, protectants, solvents, salts, surfactants, buffering agents and the like. Suitable excipients can include free-flowing particulate solids that do not thicken or polymerize upon contact with water, which are innocuous when administered to an individual, and do not significantly interact with the pharmaceutical agent in a manner that alters its pharmaceutical activity. In general, excipients which are sticky, or have high hygroscopicity are avoided particularly for powder formulations where the pharmaceutical is loaded onto the seed particle at a high concentration (e.g.,  greater than 10 wt %). Examples of normally employed excipients include, but are not limited to, pharmaceutical grades of dextrose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium or calcium phosphates, calcium carbonate, calcium sulfate, sodium citrate, citric acid, tartaric acid, glycine, high molecular weight polyethylene glycols (PEG), and combinations thereof. Suitable solvents include, but are not limited to, methylene chloride, acetone, methanol, ethanol, isopropanol and water. Generally pharmaceutically acceptable salts having Molarities ranging from about 1 mM to 2M can be used. Pharmaceutically acceptable salts include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients, vehicles and auxiliary substances is available in REMINGTON""S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. 1991), incorporated herein by reference.
The seed particles can be comprised of any parenterally acceptable powder (e.g., crystalline or amorphous), are selected to have good flowability (i.e., are fluidizable), and are sufficiently dense for efficient use with needleless transdermal delivery systems. Crystalline particles are generally preferred due to their inherently high particle density and overall penetration energy. Seed particles having an overall spherical or at least elliptical shape are preferred. Particles generally are selected to have an axis ratio of 3 or less, for example 2 or less or 1.5 or less, in order to avoid rod- or needle-shaped particles which are difficult to reprocess and are generally less flowable.
Suitable seed particles can be comprised of any pharmaceutically acceptable carbohydrate (e.g., sugars such as lactose, mannitol, trehalose, etc.), polysaccharide, starch, biodegradable polymer (e.g. PLGA, a copolymer of L-lactic acid and glycolic acid), or the like. The seed particles can have an average size of about 5 to 100 xcexcm, for example about 10 to 95 xcexcm or about 20 to 70 xcexcm. Seed particle preparations having a substantially homogenous average particle size, can be readily obtaining using standard sieving or other particle classification methodologies.
The spray-coated powders can be formed using any standard spray-coating processing apparatus. In this regard, batch-type fluid-bed processors have long been used to perform drying, granulation, and coating operations in the pharmaceutical industry for preparing solid dosage forms. Olsen, K. W. (1989) xe2x80x9cBatch fluid-bed processing equipment: A design overview,xe2x80x9d Part I., Pharm. Technol. 13:34-46, Olsen, K. W. (1989) xe2x80x9cBatch fluid-bed processing equipment: A design overview,xe2x80x9d Part II., Pharm. Technol. 13:39-50. With the advent of the Wxc3xcirster spray coater, seed particles as small as 50 xcexcm in size can, at least in theory, be coated. Iyer et al. (1993), Drug Devel. Ind. Pharm. 19:981-989. However, to date, the spray coating of seed particles having an average size of 100 xcexcm or less has been limited, particularly for protein or peptide pharmaceuticals. Maa et al. (1996) Intl. J. Pharmaceutics 144:47-59.
Spray coating processors that can fluidize seed particles of 10 xcexcm or larger, for example 20 xcexcm and larger, and which can atomize a fine spray (droplet size of 30 xcexcm or less, preferably 10 xcexcm or less) are preferred. Suitable processors include any commercially available Wxc3xcirster spray coater, or Wxc3xcirster HS spray coater (available from Glatt Air Techniques, Inc.). For fluid-bed processing, the spray coating processor can utilize any suitable spraying method which is selected in consideration of the desired characteristics for the finished product. These spraying methods (e.g., top, bottom or tangential (rotary coater)) are generally known to those skilled in the art.
The liquid delivery system for the spray coat processor typically utilizes a binary nozzle, where the aqueous pharmaceutical composition is supplied at a relatively low pressure through an orifice and is atomized by air. Pneumatic nozzles can be used to produce smaller droplets. The atomization conditions, including atomization gas flow rate, atomization gas pressure, liquid flow rate, etc., can be controlled to produce droplets from the pharmaceutical composition having an average diameter of about 30 xcexcm or less, with droplets having an average size of 10 xcexcm or less being preferred. Typically, the atomizing air pressure, liquid flow rate and the fluidizing air temperature and volume are the most significant process variables and have the greatest effect over the particle characteristics of the resultant coated particles. Drying temperature conditions of about 50-150xc2x0 C. inlet temperature and about 30-100xc2x0 C. outlet temperature are preferred. The thickness of the pharmaceutical coat can be controlled by the drying time, and the present methods can provide spray-coated powders formed from seed particles loaded with from about 1 to 50 wt % (e.g., about 0.5 to 15 wt % of active pharmaceutical agent in compositions containing both active pharmaceutical agent and carrier), preferably  greater than 10 wt % of the aqueous pharmaceutical composition.
If desired, a secondary coating process can be used to provide further structural integrity in the coated particles, for example, where the spray-coated powder particles are coated with a standard sugar excipient using the same sort of spray-coating procedure as described herein above. In some cases, it may be desirable to coat the spray-coated powder particles with the same sugar used as the seed (e.g., mannitol, lactose, trehalose, or the like). Other secondary coating materials include, but are not limited to, pharmaceutical grades of carbohydrates including monosaccharides, disaccharides, cyclodextrans, and polysaccharides (e.g., dextrose, sucrose, raffinose, mannose, sorbitol, inositol, dextrans, and maltodextrans); starch; cellulose; salts (e.g. sodium orcalcium phosphates, calcium sulfate, magnesium sulfate); citric acid; tartaric acid; glycine; high molecular weight polyethylene glycols (PEG); Pluronics; surfactants; and combinations thereof. The secondary coating material can also be used to optimize the particles for delivery to mucosal target surfaces (e.g., by coating the spray-coated powder particles with a lipid), or to alter or retard solubility characteristics of the particles after delivery into an aqueous environment (e.g., by applying a secondary coating containing a salt, starch, dextran, or the like).
The spray-coating methods of the present invention can be used to produce powders that are suitable for transdermal delivery from a needleless syringe delivery device. Typical powders are characterized in that the individual particles have an average size in the range of about 20 to 70 xcexcm, an envelope density ranging from about 0.1 to about 25 g/cm3, preferably ranging from about 0.8 to about 1.5 g/cm3, and have a substantially spherical aerodynamic shape with a substantially uniform, nonporous surface.
The particles which make up the spray-coated powders of the present invention will also have a particle penetration energy suitable for transdermal delivery from a needleless syringe device. Such penetration energies can conveniently be assessed using a metallized film P.E. measuring procedure as follows: A metallized film material (e.g., a 125 xcexcm polyester film having a 350 xc3x85 layer of aluminum deposited on a single side) is used as a substrate into which the powder is fired from a needleless syringe (e.g., the needleless syringe described in U.S. Pat. No. 5,630,796 to Bellhouse et al.) at an initial velocity of about 100 to 3000 m/sec. The metallized film is placed, with the metal coated side facing upwards, on a suitable surface. A needleless syringe loaded with a spray-coated powder produced according to the methods of the invention is placed with its spacer contacting the film, and then fired. Residual powder is removed from the metallized film surface using a suitable solvent. Penetration energy is then assessed using a BioRad Model GS-700 imaging densitometer to scan the metallized film, and a personal computer with a SCSI interface and loaded with MultiAnalyst software (BioPad) and Matlab software (Release 5.1, The MathWorks, Inc.) is used to assess the densitometer reading. A program is used to process the densitometer scans made using either the transmittance or reflectance method of the densitometer. The penetration energy of the spray-coated powders should be equivalent to, or better than that of reprocessed mannitol particles of the same size (mannitol particles that are freeze-dried, compressed, ground and sieved according to the methods of commonly owned International Publication No. WO 97/48485, incorporated herein by reference).
Once produced, the spray-coated powders of the present invention can be packaged in individual unit dosages. As used herein, a xe2x80x9cunit dosagexe2x80x9d intends a dosage receptacle containing a therapeutically effective amount of a spray-coated pharmaceutical produced according to the methods of the present invention. The dosage receptacle is generally one which fits within a needleless syringe device to allow for transdermal delivery from the device. Such receptacles can be capsules, foil pouches, sachets, cassettes, or the like.


A wristwatch including a casing having top and bottom parts and a movement therein, an upper housing formed as an integral unit, including: top and bottom transparent panels, drive shafts extending through the bottom transparent panel, the drive shafts having top and bottom ends, time indicating hands fixed to the top ends of the drive shafts, and side walls fixed to and maintaining the top and bottom transparent panels spaced apart to define a chamber therein for enclosing the time indicating hands, a replaceable watch face, and coupling elements for releasably securing the upper housing to the top of the casing, with the replaceable watch face situated below the bottom transparent panel of the upper housing and above the top part of the casing, and with the bottom end of the drive shafts releasably coupled to the movement.

1. Field of the Invention
This invention is in the field of wristwatches and more particularly wristwatches with removable watch faces.
2. Prior Art
It is known that wristwatches are one of the most commonly used devices in the world, and it is further known that for many persons a wristwatch is not only a timepiece but also is an accessory of dress and even a fashion statement. In the latter regard, it is desirable not only that a wristwatch be highly attractive, but also be one that coordinates or harmonizes with the other articles of dress, such as a person""s suit, shirt or jewelry.
While some persons wear the same watch for all occasions and with all different attire, either because they cannot afford additional watches or because the dress coordination issue is not important to them, for others, one particular watch cannot possibly be acceptable for numerous different styles and levels of dress, from casual dress to business dress to formal dress, and furthermore, one watch is not likely to match particularly well with many different outfits within one of these dress categories.
The obvious solution, if one has the means, is to purchase numerous different watches for the different situations. Notwithstanding the differences in watches based on quality and design of the watch movement and of the casing and bracelet, the appearance of the watch face itself often has the most immediate visual impact.
This has led some innovators to make a watch changeable in appearance by having interchangeable watch faces. Numerous prior art patents, namely U.S. Pat. No. 4,660,992 to Paul et al., U.S. Pat. No. 4,796,240 to Stevens, U.S. Pat. No. 5,008,869 to Dweck, U.S. Pat. No. 5,018,118 to Ross, U.S. Pat. No. 5,168,479 to Lima, U.S. Pat. No. 5,787,055 to Alpert, U.S. Pat. No. 5,793,710 to Jacobi, and U.S. Pat. No. 6,118,735 to Li disclose watches with removable watch faces. One common feature and drawback with these prior art watches, is that when the watch housing is opened to allow access to the watch face, the hour, minute and second hands become exposed, and since they are very fragile there is a great likelihood that they will be damaged by anyone who is not a professional watchmaker working in a controlled environment. Thus, this kind of interchangeable watch face is not suitable for consumers to change a watch face by themselves.
In the above-listed prior art is an alternate approach for interchangeable watch faces, namely, to provide an opening in the form of a slit in the side wall of the watch casing, so that a watch face can be slid out of the casing through the slit, and a replacement watch face slid into the casing via the slit. Here, the watch face would be positioned parallel to and below the plane of the hands. In this kind of arrangement, there is typically a drive shaft extending from the watch movement perpendicularly upward to and fixedly connected to the hands. This drive shaft is usually a series of three concentric tubes which are very tiny in nature. In order to use a replaceable watch face that slides in from the side, such watch face needs to have a notch extending from a peripheral edge radially inward to the center, so that the watch face can be positioned to have the notch straddle the drive shaft as it is slid into place, as seen in prior art patents, U.S. Pat. No. 4,660,992, U.S. Pat. No. 5,793,710, and U.S. Pat. No. 6,118,735.
A still further variation in structure is seen in U.S. Pat. No. 5,751,667 to Nunes, where there is an outer crystal and an inner transparent panel below the hands; however, these transparent elements are separable to gain access to the chamber below to change the golf tees or other graphic display articles, so that the hands become exposed to damage.
The present invention seeks to provide an alternative solution to the problem of establishing different appearances for a single wristwatch in a simple, convenient, inexpensive manner which is also safe from risk and damage to the hands of the watch.
It is a first object of this invention to provide a wristwatch wherein the owner of a watch can alter the basic appearance of the watch by altering the watch face in a manner which does not risk damage to the hands.
It is a further object to provide a wristwatch where a watch face is removable, and new watch faces are replaceable in a position below the hands but visible through the transparent crystal while the hands remain protected.
It is a still further object to provide a wristwatch with a removable watch face where the hands are protected by encasing the hands between a sandwich of outer transparent crystal and inner crystal above and below the hands, respectively, where said outer and inner transparent panes are secured together by an outer perimeter casing, thus forming an integral unit or cartridge. In a preferred embodiment, this casing has screw threads on the bottom outer periphery or elsewhere for engagement with mating screw threads in a casing of such wristwatch, which casing includes therein the watch movement or drive mechanism, which is typically an electric motor with an output drive mechanism.
It is an additional object of this invention of providing a wristwatch with a removable watch face where the hands are within a removable cartridge or upper housing that includes an outer transparent crystal and an inner transparent pane, with the hands secured and protected between these two transparent elements.
It is a further object to provide a wristwatch with a removable watch face where the casing, which contains the movement, includes at its top a recess to receive the watch face and to receive and hold the cartridge containing the hands and crystal, and to allow coupling of the drive shafts fixed to the hands with the movement in the casing.
Since the casing which contains the watch movement includes a laterally extending adjustment stem, the cartridge containing the hands and the outer crystal and inner glass can be attached to the housing by merely rotating it in the recess until the mating threads engage and become secured to each other. The rotation causes no interference of any parts because the drive stems simply engage with the drive shaft from the movement and are free to rotate in the lower transparent pane of the cartridge. Thereafter, the time is set by the adjustment knob.
Other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention.
The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.


A spinal implant system is provided for correcting spinal abnormalities. The system involves connectors configured to fit over spinal implant rods, a transverse rod, and a locking member for fixing each connector to the spinal implant rod and transverse rod. The connector is configured such that when the locking member is in a first position, the transverse rod is temporarily fixed to the connector, and when the locking member is in a second position, both the transverse rod and spinal implant rod are fixed to the connector.

Many spinal fixation systems have been developed for use in correcting and stabilizing spinal defects and facilitating spinal fusion. Typically, one or more rods are placed adjacent the spinal column in a longitudinal direction and are fixed to the vertebrae. Such systems are described in U.S. Pat. Nos. 5,688,275 and 6,080,156.
In certain situations it is desired to provide transverse stability and rigidity to the implanted spinal rods. Such systems are described in U.S. Pat. Nos. 5,527,314, 5,716,355, and 6,551,318. Existing transverse connecting devices are generally of two types: adjustable connectors and fixed connectors. Adjustable devices have the advantage of being able to accommodate different distances between the spinal implant rods. They also allow the compression or distraction between the two spinal implant rods. However, they usually have the disadvantage of being complicated and involving several components that must be assembled during surgery. Fixed transverse connectors are generally simple and easy to use. They may be composed only of one piece with two setscrews. They may have a relatively low profile, can be loaded on top of the spinal implant rods, and can also be bent to conform to the anatomy. However, they lack the ability to adjust to different distances between the spinal implant rods. Fixed transverse connectors come in incremental lengths, which makes the inventory large. Use of both types of systems often requires attachment of the transverse connector components to the spinal implant rods prior to implanting the longitudinal spinal implant rods. This requires significant pre-operative planning and does not allow modification of the system, such as adding connectors, during the procedure.

Transverse connector for rod-based spinal implants


It has been discovered that the polymerization of unsaturated compounds, such as butadiene, may be inhibited by the addition of a diene and/or alkanolamine inhibitor. The inhibitor is believed to catalytically destroy peroxides present, such as hydrogen peroxide, which may be present in trace amounts. Particularly useful inhibitors include, but are not limited to, ethylenediamine (EDA) and monoethanolamine (MEA).

The present invention relates to methods and compositions for inhibiting the polymerization of diene monomers, and more particularly relates, in one embodiment, to methods and compositions for inhibiting the polymerization of butadiene monomers by decomposing hydrogen peroxide.
In the production of olefins, such as a diene, the so-called popcorn polymer having a porous, three-dimensional structure occurs frequently and undesirably in process apparatus due to the unintentional polymerization of the olefin. Popcorn polymerization occurs in refining and distillation of the monomer, or during recovery of the monomer after termination of intentional polymerization such as during the production of poly-butadiene and synthetic rubber, in particular styrene-butadiene rubber. Popcorn polymerization occurs both in the gaseous phase and the liquid phase. It is more likely to occur when the concentration of the olefin monomer is high and the temperature is high. Trace amounts of peroxides used to intentionally generate free radicals to initiate and perpetuate polymerization may remain in these systems to produce free radicals that cause polymerization at undesirable locations.
Numerous olefin monomers such as styrene, xcex1-methyl styrene, acrylic acid and esters thereof, vinyl acetate, acrylonitrile, acrylamide, methacrylamide, etc. and such dienes (diolefins) as 1,3-butadiene, isoprene, and chloroprene, upon reaching refining devices during production and recovery, are exposed to certain conditions such as high temperature, high monomer concentration, coexistence of vapor and liquid phase, humidity, trace oxygen and iron rust which are highly conducive to the occurrence of popcorn polymerization. Fouling of equipment can even occur when unsaturated compounds in petroleum or its derivatives undesirably polymerize.
In the manufacturing of synthetic rubber and plastics for use by the military and others, the primary choice of feedstock is butadiene. Butadiene (BD) is a colorless gas at room temperature. Most of the supply of butadiene comes from olefin plants because butadiene is co-produced when other olefins are manufactured. Butadiene can be produced by catalytically dehydrogenating butane or butylene.
The dehydrogenating of butane or butylene to butadiene may be accomplished by passing the feed gas over a catalyst bed at 1200xc2x0 F. (649xc2x0 C.) and at reduced pressure. The effluent gas then passes through an extractive distillation process.
Although butadiene can be manufactured by catalytic dehydrogenation, most of the butadiene produced domestically is obtained by extractive distillation. Butadiene can be recovered and purified from C4 streams by using a solvent that reduces the boiling point of the butadiene. The most popular solvents used to facilitate this extraction are N-methylpyrrolidone (NMP) and dimethylformamide (DMF).
The crude butadiene is further purified by distillation through a series of towers that separate residual solvent, C4 compounds, and other contaminants. A further component of the BD manufacturing process is the Recovery Solvent Section. From the stripper column, a slip stream of lean solvent is regenerated to remove heavies and contaminants. This reduces the presence of polymer loading and decomposition products.
During the purification steps of BD production, there are some undesirable BD polymerization reactions. Of these, the most unwanted is the formation of popcorn polymer. The effect of popcorn polymer on BD processing equipment is so severe that this material has actually been found to bend heat exchanger tubes.
Poly-butadiene can be produced commercially by way of an aqueous homopolymerization reaction. In order to actuate this polymerization process, hydrogen peroxide is used in excess of 7400 ppm to initiate butadiene to react to form poly-butadiene (Poly-BD). However, the presence of peroxides and trace levels of Poly-BD in the water from the decanter drum used in the process results in undesirable polymerization at the acetone column. Presently, Poly-BD manufacturers use sodium sulfite to control peroxide levels in the feed to the acetone drum, which feeds the acetone column, but this program is not very efficient in reducing peroxide levels. Also, other chemical suppliers have attempted to treat the polymerization problems with commercial antioxidants, but have experienced very little success. This failure can be linked directly to the economic limitations on inhibitor usage to control such relatively large concentrations of peroxides. This results in relatively small, but still significant amounts of hydrogen peroxide and other peroxides that are not destroyed, but which in turn results in undesired polymerization in the acetone column. Currently commercial Poly-BD producers can spend large sums annually on the use of sodium sulfite that is capable of removing only about 50% of the residual peroxides.
It would be desirable if a composition and method could be devised to inhibit the undesirable and unintentional polymerization of unsaturated (vinyl) monomers, particularly butadiene, but without having to require relatively large, and therefore costly, amounts of inhibitors.
Accordingly, it is an object of the present invention to provide a method and composition to effectively inhibit the polymerization of vinyl compounds, such as butadiene.
It is another object of the present invention to provide a method and composition to effectively inhibit the polymerization of olefins that is less expensive than using conventional antioxidant inhibitors because relatively less amount of the inhibitor is required to achieve acceptable polymerization inhibition.
Still another object of the invention is to permit use of a composition to effectively inhibit the polymerization of butadiene that uses readily available compounds.
In carrying out these and other objects of the invention, there is provided, in one form, a method for inhibiting the polymerization of unsaturated monomers that are polymerized by free radicals generated by peroxides, the method comprising adding to the unsaturated monomers an effective polymerization-inhibiting amount of an inhibitor selected from the group consisting of diamines, alkanolamines, and mixtures thereof.
It has been discovered that the use of diamines and alkanolamines can effectively destroy hydrogen peroxide more efficiently than some commercially used inhibitors, such as sodium sulfite. It is believed that these classes of chemicals destroy hydrogen peroxide through one or more catalytic decomposition interactions, although it is not desired to limit the invention to any one particular theory or mechanism. Such compounds would include, but not be limited to, ethylenediamine (EDA) and monoethanolamine (MEA). These materials have been found to completely destroy hydrogen peroxide in a poly-butadiene sample obtained from a commercial Poly-BD producer in less than 30 minutes. A standard hydrogen peroxide test kit that can be purchased commercially was used to test for the effectiveness of these amines on peroxide destruction. The heat induced gum test, a standard test used to evaluate inhibitors in the petrochemical industry, was used herein to evaluate the effectiveness of these materials to inhibit polymerization of the Poly-BD sample.
It is expected that the polymerization inhibitors of this invention can be used in conjunction with any system that uses peroxides to generate free radicals for the intentional polymerization of a vinyl monomer, yet has trouble with trace amounts of the peroxide remaining in the system and causing polymerization at undesirable places and times. It is anticipated that the vinyl monomers with which the inhibitors of this invention may be used include, but are not necessarily limited to, styrene, xcex1-methyl styrene, acrylic acid and esters thereof, vinyl acetate, acrylonitrile, acrylamide, methacrylamide, 1,3-butadiene, isoprene, chloroprene, and mixtures thereof. The monomer that is preferred to be inhibited against undesirable polymerization is 1,3-butadiene, or simply butadiene (BD).
The peroxides that may be treated and decomposed to prevent polymerization include, but are not necessarily limited to, hydrogen peroxide, alkyl peroxides, alkyloxy peroxides, aryl peroxides, aralkyl peroxides, and mixtures thereof.
The diamines useful as polymerization inhibitors in the compositions and methods of the invention have the structure:
X1X2NCH2CH2NY1Y2xe2x80x83xe2x80x83(I)
where X1, X2, Y1, and Y2 are independently selected from the group consisting of hydrogen, straight or branched alkyl groups of 1 to 20 carbon atoms and alkylaryl groups of 1 to 20 carbon atoms. Preferably, the straight or branched alkyl groups have at least 2 carbon atoms and/or have up to 5 carbon atoms and the alkylaryl groups preferably have at least 2 carbon atoms and/or have up to 5 carbon atoms. Examples of suitable diamines include, but are not necessarily limited to, ethylenediamine, methylenediamine, propylenediamine, butylenediamine, dibutylethylenediamine, and mixtures thereof. A preferred diamine is ethylenediamine (EDA).
The alkanolamines useful in the methods and compositions of this invention have the structure:
X1X2NCH2CH2NOHxe2x80x83xe2x80x83(II)
where X1 and X2 are as defined above. Examples of suitable alkanolamines include, but are not necessarily limited to, monoethanolamine, ethyidiethanolamine, 2-amino-2-propanol, 3-amino-1,2-propanediol, 1-amino-2-propanol, and mixtures thereof. A preferred alkanolamine is monoethanolamine (MEA).
In one non-limiting embodiment of the invention, the process and compositions involve an absence of manganese (Mn) compounds.
Progrtions
A number of factors affect the effective amounts of the diamines and/or alkanolamines of this invention that would be useful to inhibit the polymerization of an unsaturated compound, including, but not necessarily limited to, the nature of the unsaturated compound, the concentration of the unsaturated compound, the nature and concentration of the peroxide, the temperature and pressure environment of the unsaturated compound, the nature of the particular diamine and/or alkanolamine used, and the like. These complex, interrelated factors make it difficult to specify in advance and/or with precision what effective proportions of the inhibitors should be in any given situation. Nevertheless, some general guidelines as to the effective proportion of the inhibitors in the unsaturated compound may be given.
The composition of this invention may have from about 1 to about 10,000 ppm of the inhibitor based on the total amount of unsaturated compound being treated. Preferably, the proportions are at least about 50, and may be less than about 500 ppm of the inhibitor, based on the total amount of unsaturated compound being treated.
The inhibitors may be simply mixed together into the unsaturated monomers to be inhibited. The inhibitors are not expected to work more advantageously at a particular temperature or pressure.

Use of diamines and alkanolamines to inhibit unsaturated monomer polymerization


New and novel copolymers of vinylidene fluoride and hexafluoropropylene having lower or no crystallinity together with processes for their manufacture and use are disclosed.

This invention relates to compositions of matter classified in the art of chemistry as fluoropolymers, more specifically to copolymers of vinylidene fluoride (VDF) and hexafluoropropylene (HFP) and still more specifically to such copolymers having very low or no crystallinity and to processes for their preparation and use. The copolymers at all levels of HFP content remain highly flexible, thermoplastic copolymers which show low surface tack even at high HFP levels.
Fluoropolymers and copolymers of VDF, collectively VDF-based polymers wherein the VDF portion is greater than the total molecular percent of comonomers, are well known and widely used. Among the variety of fluoropolymers based upon tetrafluoroethylene, chlorotrifluoroethylene, and other speciality fluorine-containing monomers, the VDF polymers are unique offering the widest possible range of processing options to obtain articles having the beneficial attributes associated with improved chemical resistance and surface properties associated with the high concentration of carbon fluorine bonds. Thus, among the wide spectrum of fluoropolymers, the VDF polymers may be melted in typical processing equipment for thermoplastic resin for extrusion or molding or combinations such as extrusion-blown film and molding into tanks.
This versatility in processing options is related to the linear polymer chain structure and the presence of the highly polar-CF2-groups alternating along the VDF polymer chain. The microstructure of the polymer chain and morphology of these polymers reflects these two factors in many interesting ways as described in Polymeric Materials Encyclopedia, 1996, Vol II, CRC Press; Vinylidene Fluoride-Based Thermoplastics (Overview and Commercial Aspects), J. S. Humphrey, pp. 8585 to 8588; Vinylidene Fluoride-Based Thermoplastics (applications), J. S. Humphrey and E. J. Bartoszek, pp. 8588-8591; Vinylidene Fluoride-Based Thermoplastics (Blends with Other Polymers), J. S. Humphrey and X. Drujon, pp. 8591-8593; Vinylidene Fluoride-Based Thermoplastics (Homopolymerization and Copolymerization), J. S. Humphrey and X. Drujon, pp. 8593-8596.
The balance between amorphous and crystalline regions, the nature and extent of the crystalline regions, and the interphase between these regions affects the mechanical properties significantly, and hence, the ultimate applications for a given resin composition.
At one end of the spectrum there are totally amorphous thermoplastic polymers and at the other S extreme the highly crystalline polymers. The microstructure of the polymer chain determines the flexibility (or alternately the stiffness) at a given temperature. This mechanical behavior is controlled by the type and amount of the crystalline phase (if any) and the dynamics of the molecular motion along the chain such that at some temperature the polymer undergoes a second order change in response to applied stresses, the so-called glass transition temperature (Tg). Above the Tg the polymer chain has molecular motions which are free to rotate, stretch, etc. and thereby absorb the energy input. Below the Tg the molecular motions are frozen and the stresses may lead to brittle fracture or glass-like behavior.
The immediate invention is concerned more with the morphology and crystalline/amorphous.ratio of the VDF polymers and the ultimate end uses. It is therefore important to understand the background of the present invention in the context of the teaching how crystalline and amorphous content fit into the range of polymers which are classed as thermoplastic, elastomer-modified thermoplastic, or elastomeric resins. In this particular invention, the key attribute is related to highly flexible resins related to the latter two categories. This invention produces a variety of VDF-HFP resins, which are differentiated quite clearly from prior art with respect to the low level of crystallinity compared to resins of the otherwise same nominal monomer ratio composition produced by standard teachings. Thus, the present invention relates to a novel fluoro-thermoplastic having a unique combination of properties including excellent flexibility, low temperature processability, high clarity,solution stability and room temperature film forming capability from aqueous dispersions.
U.S. Pat. No. 3,051,677 describes batch emulsion and continuous emulsion processes for copolymerization of vinylidene fluoride and hexafluoropropylene (HFP) in the range of 30 to 70 weight percent of hexafluoropropylene monomer and 70 to 30 weight percent vinylidene fluoride monomer. The copolymers described in this reference have relatively high crystallinity as is confirmed by the properties described in the document for the products exemplified. Analogous materials from a batch process are described by Moggi, et. al. in Polymer Bulletin, Vol. 7 pp. 115-122 (1982).
U.S. Pat. No. 3,178,399 describes both batch and semi-continuous emulsion processes for preparing HFP-VDF copolymers having between 85 and 99 mole percent VDF and 1 and 15 mole percent HFP (approximately 2 to 30 weight percent HFP and 70 to 98 weight percent VDF). Once again, the copolymers produced have relatively high internal crystallinity and this fact is evidenced by the physical data provided for those copolymers actually exemplified. This patent discloses that Tensile X Reversible Elongation was increased as the overall HFP proportion decreased in the copolymer. This implies that crystallinity increases as HFP content decreases.
U.S. Pat. No. 5,093,427 describes HFP-VDF copolymers, with the other extreme crystalline melting behavior, containing from about 1 to 20 weight percent HFP wherein, based on the synthetic method described, a polymer containing significant portions of homopolymer and other copolymer portions having a high proportion of HFP in the copolymer results. Thus, compositions of the copolymers described in this reference are significantly different from the copolymers contemplated by the present invention.
Indonesian Patent Application W-980105, published Nov. 26, 1998 as number 020.295A equivalent to WO 98/38242 and to U.S. patent application Ser. No. 09/031,014, the contents of which have been included in CIP Application 09/641,015 discloses an emulsion process for producing HFP-VDF copolymers having highly homogenous distribution of the comonomers in individual claims and from chain to chain thereby having reduced extractable content and improved solution clarity over HFP-VDF copolymers prepared according to the techniques of the preceding references. These materials differ from the copolymers of the present invention because the products of this patent application are limited to lower percentages of HFP content, the solubility and solution stability properties as well as the reduced melting points are attributed to the homogeneous distribution of the comonomers and no discussion of the crystallinity or lack thereof of the polymers described and whether or not it might be related to any of the properties observed for those polymers is provided.
In Polymer, Vol. 27, p. 905 (1986) and Vol. 28, p. 224 (1987), Moggi, et al. Report synthesis of HFP-VDF copolymers and studies of various physical properties and how these properties may be correlated to certain internal structural features such as crystallinity, monomer sequencing in individual molecules and the like. The limited synthesis information indicates that the polymers formed were analogous to those prepared according to the previous references except for U.S. patent application Ser. No. 09/031,014 and the limited physical data provided is consistent with this interpretation and that the polymers described had a high degree of crystallinity.
Although it is well established in the prior art to reduce crystallinity by means of adding higher amounts of HFP to the copolymer, there is no prior art suggesting how to produce as low crystallinity as is provided by the present invention at any given nominal proportion of HFP. Thus, the copolymers disclosed herein have measurably lower crystallinity at any given HFP level than copolymers with the same nominal HFP content produced in accordance with processes enabled by any of the above listed references.
The invention provides in its first composition aspect a vinylidene fluoride, hexafluoropropylene copolymer having from about 1 to about 66 weight percent hexafluoropropylene content and having low crystallinity.
By a vinylidene fluoride hexafluoropropylene copolymer having from about 1 to about 66 weight percent hexafluoropropylene content having low crystallinity is meant that such copolymers have measurably lower crystallinity than copolymers produced according to the prior art references, which provide sufficient details for a reproductive synthesis of the materials described therein. Thus, the copolymers having 36% by weight or greater HFP content have the heats of fusion calculated from any endotherms detected in a differential scanning calorimeter (DSC) scan (described below), of about 0 J/g and for copolymers having less than 36 weight % HFP content any endotherm detected in a DSC scan as described below is at least about 1.5 J/g less than the endotherm detected for copolymers of substantially (xc2x11.00 wt %) similar HFP content for copolymers produced according to the prior art listed above. Thus, the copolymers having from greater than 0 to 28.5 wt % HFP content have an endotherm on melting which is defined by the relationship:
xcex94H=56.49xe2x88x921.854(HFP wt %)
and the copolymers having from greater than 28.5 up to less than 36 weight % HFP content have an endotherm on melting which is defined by the relationship:
xcex94H=54.81xe2x88x921.53(HFP wt %).
In addition, the copolymers of from greater than 0 to 30 wt % HFP also have lower DSC melting points at a given HFP content than any of the copolymers of the same HFP content described in any of the references cited above and the melting point for a copolymer having a particular HFP content in the greater than 0 to 30 wt % HFP range is defined by the relationship:
Melt Temp. (xc2x0 C.)=162.16xe2x88x923.192(HFP wt %).
Copolymers having greater than 30 wt % HFP produced according to such prior art, as will be illustrated in the examples below, all exhibit exotherms in their DSC scans run as described below significantly greater than 0/J/g. Those having lower than 30% HFP content all have higher crystallinity as defined by higher xcex94H of melting determined by DSC than those of this invention.
The DSC scan measuring the crystalline content is performed according to ASTM D 451-97 using a Perkin Elmer 7 DSC apparatus with an Intercooler II attachment. The instrument is equipped with a dry box with an N2 purge through the dry box. Specimens of 9 to 10 mg are used and crimped in aluminum pans.
For samples with a low degree of crystallinity, the DSC run is begun at xe2x88x9250xc2x0 C. followed by a 10xc2x0 C./min ramp to 180xc2x0 C.
For samples with an HFP content lower than 30 wt. % and, thus, a higher degree of crystallinity, the DSC run is performed in a three step cycle. The cycle is begun at xe2x88x9250xc2x0 C. followed by a 10xc2x0 C./min ramp to 180xc2x0 C. with a 10 minute hold. The sample is then cooled at a rate of 10xc2x0 C./min to xe2x88x9250xc2x0 C. and then unheated at the 10xc2x0 C./min rate to 180xc2x0 C.
In comparison with other previously known copolymers of VF2/HFP produced by the above cited references, the reduced crystalline content of VF2/HFP at a given HFP level provides a unique combination of properties among which are those offering the following advantages:
(i) Reduced tack: allows ease of handling and better field performance;
(ii) Improved miscibility with other polymers, particularly with different esters of polyacrylates and polymethacrylates;
(iii) Lower melting temperature: allows easier manufacturing for typical molding processes;
(iv) Higher elongation at yield point: allows better performance;
(v) Lower stress at yield point: allows ease of process and manufacturing due to lower modulus;
(vi) Enhanced blendability: lower crystallinity: allows more intimate blending with other polymers because of reduction in size and in volume fraction of hard domains;
(vii) Clearer solution/haze free solution: reduction in size and in volume fraction of hard domains caused by reduced crystallinity, results in enhanced salvation of polymer chain which consequently retards the gelation of the polymer solution;
(viii) Improved optical clarity of polymer film.and plaque sheets;
(ix) Improved elastomeric properties;
(x) Longer shelf stability of solution: better solubility due to reduction of crystalline domains, results in enhanced salvation of polymer chain which consequently retards the gelation of polymer solution.
Surprisingly, as the crystallinity of the HFP copolymers decreases, it has been found that the Tg increases and still more surprisingly, It has been found that when blended with acrylic polymers, for the copolymers of the present invention, the Tg for the mixture actually increases. This is highly unexpected because normally a mixture of polymers shows lower Tg than pure polymer.
For example, two copolymers of the present invention were mixed in equal parts by weight with three different polyacrylate esters and the Tg values for each mixture determined and compared with the Tg values for identically proportioned mixture of a standard commercially available VDF/HFP copolymer which had a xcex94H of melting of 37.2 (KYNAR(copyright) Flex 2750, available from ATOFINA Chemicals, Inc., Philadelphia, Pa. which contains about 15.5 wt % HFP). All three copolymers had a Tg of about xe2x88x9225xc2x12xc2x0 C. Copolymer sample 1 (sample 1) of the present invention had about 16.5 wt % HFP content and a xcex94H of melting of 30.4 while copolymer sample 2 (sample2) of the present invention had about 14.1 wt % HFP content and a xcex94H of melting of 26.7. A blend of 50 wt % polymethylmethacrylate with the KYNAR Flex had, as expected, a Tg of 24.2xc2x0 C., while the analogous mixture with sample 1 had Tg of 34.3xc2x0 C. and the analogous mixture with sample 2 had Tg of 40.8xc2x0 C. A blend of 50 wt % polyethylmethacrylate with the KYNAR Flex had, as expected, a Tg of 17.8xc2x0 C., while the analogous mixture with sample 1 had Tg of 26.3xc2x0 C. and the analogous mixture with sample 2 had Tg of 30xc2x0 C. A blend of 50 wt % polybutylmethacrylate with the KYNAR Flex had, as expected, a Tg of 11.7xc2x0 C., while the analogous blend with sample 1 had Tg of 18.6xc2x0 C. and the analogous blend with sample 2 had Tg of 23.1xc2x0 C.
HFP content was alternatively determined by 19F NMR using the following methods.
In preparation for the NMR analysis, VDF/HFP copolymer samples were dissolved in a 5 mm diameter NMR tube. Samples of less than 10 wt % HFP were dissolved in DMSO-d6 at 86xc2x0 C., while samples of more than 10 wt % HFP were dissolved in acetone-d6 at 50xc2x0 C. An amount of copolymer, 2 to 4 mg, was placed in a tube and enough solvent was added to fill the tube to 5.5 cm (about 0.75 ml of solvent). A heating block was used to bring the samples to temperature. The samples were heated for at least one hour, until the solid was dissolved and there was no gel present, but in the case of DMSO-d6, for a time no longer than 8 hours in order to avoid degradation. Tubes were inverted to check for gel.
Spectra were acquired on either a Bruker DMX or a Varian Mercury 300 spectrometer operated at 80xc2x0 C. in the case of DMSO-d6 solvent or at 50xc2x0 C. in the case of acetone-d6 solvent. Specific parameters for the instruments were as follows:
Spectra were analyzed according to the signal assignments described in Pianca et al., Polymer, vol. 28, 224-230 (February 1987). As a check on the accuracy of the NMR acquisitions, the integrals of the CF3""s and the CF""s were compared to see if they were in a ratio of 3 to 1.
The synthetic technique described herein also provides a method for preparing a high solids small particle size latex of the copolymers of the invention. This high solids small particle latex which because of its low crystallinity offers the following applied use properties in addition to those mentioned above:
(i) lower minimum film forming temperature (MFFT) which means that the resin is able to form continuous film at lower temperatures, e.g. at room temperature where the substrate may be heat sensitive.
(ii) Longer latex stability giving a longer shelf life;
(iii) Higher concentration of polymer in latex which provides lower cost per unit weight of polymer for transportation and storage as well as better film formation characteristics;
(iv) Improved optical properties: superior to prior art in terms of clarity. It is important in many coating applications to have clear film forming resin.
Copolymers produced according to the prior art are those produced by the methods enabled by those references listed above.
The tangible embodiments of the first composition aspect of the invention are white or light colored solids having physical and chemical characteristics tending to confirm the molecular structure assigned herein.
The aforementioned chemical and physical characteristics taken together with the method of synthesis and standard analytical technique measurements, such as dynamic mechanical analytical, infrared and nuclear magnetic resonance spectroscopic and differential scanning calorimetric measurements further positively confirm the aforesaid structure for the first composition aspect of the invention.
The tangible embodiments of the first composition aspect of the invention possess the inherent applied use characteristics of being useful in formulating high performance coatings, films and foams, as encapsulants, in fiber optic applications, and as thermoplastic polymers having UV and chemical. resistance when fabricated into shaped objects including wire and cable insulation, pipes and other extruded or molded objects.
Special mention is made of embodiments of the first composition aspect of the invention wherein the hexafluoropropylene residue content is greater than 5 weight %, preferably greater than 10 weight %, still more preferably greater than 15 weight % and still more preferably greater than 30 weight %.
The invention provides in a second composition aspect, an object having at least one surface and having a coating comprising at least one embodiment of the first composition aspect of the invention on said surface.
The invention provides in a third composition aspect of the invention, a formed object comprising at least one embodiment of the first composition aspect of the invention.
The invention provides in a fourth composition aspect, an embodiment of the first composition aspect of the invention prepared by a process as described hereinafter.
The manner of making and using the embodiments of the invention will now be illustrated with reference to specific embodiments thereof.
The vinylidene fluoride, hexafluoropropylene copolymers of the first composition aspect of the invention are conveniently made by an emulsion polymerization process, but suspension and solution processes may also be used. In an emulsion polymerization process, a reactor is charged with deionized water, water soluble surfactant capable of emulsifying the reactor mass during polymerization and the reactor and its contents are deoxygenated while stirring. The reactor and contents are heated to the desired temperature and vinylidene fluoride, hexafluoropropylene and, optionally, chain transfer agent to control copolymer molecular weight are added. When the desired reaction pressure is reached, initiator to start and maintain the reaction is added. To obtain the VDF/HFP copolymers of the present invention, the initial charge of VDF and HFP monomers is such that the weight ratio of HFP to VDF is an exact first ratio which is from three to five times the weight ratio of HFP to VDF to be fed during the reaction. HFP and VDF are fed during the reaction in a proportion such that the total amount of HFP added over the entire course of the reaction is approximately equal to the proportionate amount of HFP desired in the final copolymer. The VDF/HFP ratios are, thus, different in the initial charge and in the continuous feed. The process uses total amounts of VDF and HFP, monomers such that the amount of HFP incorporated in the final copolymer is up to about 66 wt % of the combined total weight of the monomers.
To determine the exact first ratio for a particular reaction to provide the optimum low crystallinity at any desired HFP ratio at a desired reaction temperature and pressure, one of skill in the art will understand how to perform a few pilot scale run varying the initial HFP concentration in the desired range to select the proper exact ratio keeping other reaction conditions constant.
The reactor is a pressurized polymerization reactor preferrably a horizontal polymerization reaction equipped with a stirrer and heat control means. The temperature of the polymerization can vary depending on the characteristics of the initiator used, but it is typically between 30xc2x0 and 130xc2x0 C., and most conveniently it is between 50xc2x0 and 120xc2x0 C. The temperature is not limited to this range, however, and might be higher or lower if a high-temperature or low-temperature initiator is used. The pressure of the polymerization is typically between 20 and 80 bar, but it can be higher if the equipment permits operation at higher pressure. The pressure is most conveniently between 40 and 60 bar.
Surfactants used in the polymerization are water-soluble, halogenated surfactants, especially fluorinated surfactants such as the ammonium, substituted ammonium, quarternary ammonium, or alkali metal salts of perfluorinated or partially fluorinated alkyl carboxylates, the perfluorinated or partially fluorinated monoalkyl phosphate esters, the perfluorinated or partially fluorinated alkyl ether or polyether carboxylates, the perfluorinated or partially fluorinated alkyl sulfonates, and the perfluorinated or partially fluorinated alkyl sulfates. Some specific, but not limiting examples are the salts of the acids described in U.S. Pat. No. 2,559,752 of the formula X(CF2)nCOOM, wherein X is hydrogen or fluorine, M is an alkali metal, ammonium, substituted ammonium (e.g., alkylamine of 1 to 4 carbon atoms), or quaternary ammonium ion, and n is an integer from 6 to 20; sulfuric acid esters of polyfluoroalkanols of the formula X(CF2)nCH2OSO3M, where X and M are as above; and salts of the acids of the formula CF3(CF2)n(CX2)mSO3M, where X and M are as above; n is an integer from 3 to 7, and m is an integer from 0 to 2, such as in potassium perfluorooctyl sulfonate. The surfactant charge is from 0.05% to 2% by weight on the total monomer weight used, and most preferably the surfactant charge is from 0.1% to 1.0% by weight.
A paraffin antifoulant may be employed, if desired, although it is not preferred, and any long-chain, saturated, hydrocarbon wax or oil may be used. Reactor loadings of the paraffin may be from 0.01% to 0.3% by weight on the total monomer weight used.
After the reactor has been charged with deionized water, surfactant, and any optional paraffin antifoulant, the reactor is either purged with nitrogen or evacuated to remove oxygen. The reactor is brought to temperature, and chain-transfer agent may optionally be added. The reactor is then pressurized with a mixture of vinylidene fluoride and hexafluoropropylene.
Chain-transfer agents which may be used are well-known in the polymerization of fluorinated monomers. Alcohols, carbonate esters, ketones, carboxylate esters, and ethers are oxygenated compounds which serve as chain-transfer agents. Specific, but not limiting examples, are isopropyl alcohol, such as described in U.S. Pat. No. 4,360,652, acetone, such as described in U.S. Pat. No. 3,857,827, and ethyl acetate, as described in the published Unexamined Application (Kokai) JP 58065711. Other classes of compounds which serve as chain-transfer agents in the polymerization of fluorinated monomers are halocarbons and hydrohalocarbons such as chlorocarbons, hydrochlorocarbons, chlorofluorocarbons, and hydrochlorofluorocarbons all having 1 to 6 carbon atoms; specific, but not limiting examples are trichlorofluoromethane, such as described in U.S. Pat. No. 4,569,978, and 1,1-dichloro-2,2,2-trifluoroethane. Chain-transfer agents may be added all at once at the beginning of the reaction, in portions throughout the reaction, or continuously as the reaction progresses. The amount of chain-transfer agent and mode of addition which is used depends on the activity of the agent and the desired molecular weight characteristics of the product. The amount of chain-transfer agent used is from 0.05% to 5% by weight on the total monomer weight used, and preferably it is from 0.1 to 2% by weight.
The reactor is pressurized by adding vinylidene fluoride and hexafluoropropylene in a definite ratio (first exact ratio) such that the hexafluoropropylene ratio in the VDF/HFP mixture initially charged ranges from about 3 to about 5 times the ratio of hexafluoropropylene fed into the reactor during the reaction. The exact ratio can be selected by a series of controlled laboratory runs as described above.
The reaction can be started and maintained by the addition of any suitable initiator known for the polymerization of fluorinated monomers including inorganic peroxides, xe2x80x9credoxxe2x80x9d combinations of oxidizing and reducing agents, and organic peroxides. Examples of typical inorganic peroxides are the ammonium or alkali metal salts of persulfates, which have useful activity in the 65xc2x0 C. to 105xc2x0 C. temperature range. xe2x80x9cRedoxxe2x80x9d systems can operate at even lower temperatures and examples include combinations of oxidants such as hydrogen peroxide, t-butyl hydroperoxide, cumene hydroperoxide, or persulfate, and reductants such as. reduced metal salts, iron (II) salts being a particular example, optionally combined with activators such as sodium formaldehyde sulfoxylate or ascorbic acid. Among the organic peroxides which can be used for the polymerization are the classes of dialkyl peroxides, peroxyesters, and peroxydicarbonates. Exemplary of dialkyl peroxides is di-t-butyl peroxide, of peroxyesters are t-butyl peroxypivalate and t-amyl peroxypivalate, and of peroxydicarbonates are di (n-propyl) peroxydicarbonate, diisopropyl peroxydicarbonate, di (sec-butyl) peroxydicarbonate, and di (2-ethylhexyl) peroxydicarbonate, and di (2-ethylhexyl) peroxydicarbonate. The use of diisopropyl peroxydicarbonate for vinylidene fluoride polymerization and copolymerization with other fluorinated monomers is taught in U.S. Pat. No. 3,475,396, and its use in making vinylidene fluoride/hexafluoropropylene copolymers is further illustrated in U.S. Pat. No. 4,360,652. The use of di (n-propyl) peroxydicarbonate in vinylidene fluoride polymerizations is described in the Published Unexamined Application (Kokai) JP 58065711. The quantity of an initiator required for a polymerization is related to its activity and the temperature used for the polymerization. The total amount of initiator used is generally between 0.05% to 2.5% by weight on the total monomer weight used. Typically, sufficient initiator is added at the beginning to start the reaction and then additional initiator may be optionally added to maintain the polymerization at a convenient rate. The initiator may be added in pure form, in solution, in suspension, or in emulsion, depending upon the initiator chosen. As a particular example, peroxydicarbnates are conveniently added in the form of an aqueous dispersion.
As the reaction progresses, a mixture of vinylidene fluoride and hexafluoropropylene monomers is fed in a definite ratio (second effective ratio) so as to maintain reaction pressure. The proportion of hexafluoropropylene in the second effective ratio used corresponds to the monomer unit ratio desired in the final composition of the copolymer, and it can range up to 66% of the combined weight of the monomers being fed continuously throughout the reaction. The feed of vinylidene fluoride, hexafluoropropylene, and optionally initiator and chain-transfer agent is continued until the desired solid content is obtained.
Upon reaching the desired solids level in the reactor, the feed of monomers is discontinued, but the feed of initiator is continued to consume residual monomers, To minimize compositional drift at this stage, after the reactor pressure drops by 10 to 20 bar from the continuous reaction pressure, a portion of VDF is added to bring reactor pressure back up to the initial set point and initiator feed continues until the reactor pressure falls about 15 to 25 bar. After a delay time of about 10 to 20 minutes then the reactor is cooled as quickly as possible. After reaching ambient temperatures (200 to 35xc2x0 C.), the unreacted monomers are vented and the latex produced by the reaction is drained into a suitable receiving vessel. To obtain dry resin, the latex is coagulated by conventional methods, the coagulum is separated and the separated coagulum may be washed. To provide powder, the coagulum is dried.
For the coagulation step, several well-known methods can be used including freezing, the addition of acids or salts, or mechanical shear with optional heating. The powder, if desired, can be further processed into pellets or other convenient resin forms.
One of skill in the art will recognize that small quantities of a third monomer known to be copolymerizable with VDF(up to about 10% by weight of the HFP level) may also be included in the above described synthesis to provide VDF based terpolymers also having low crystallinity. Such known copolymerizable monomers may, for example, be selected from among C(2-8) alkenes containing at least one fluorine atom besides HFP, an alkyl vinyl ether containing at least one fluorine atom, an aliphatic or cyclic C(3-6) ketone containing fluorinated xcex1-xcex1, positions and non-fluorinated C(2-4) unsaturated hydrocarbons, C(3-6) alkyl vinyl ethers or C(4-6) vinyl esters.
Among the applied uses for the resin is in paint bases for coatings. It will be understood by one of skill in the art that such paint bases will conventionally include a portion of an acrylic resin and that formation of paints varnishes and related coating materials and coatings therefrom may be accomplished by standard methods well known to those of skill in the art

Low crystallinity vinylidene fluoride hexafluoropropylene copolymers


A process for the production of a device having a surface microstructure of wells or channels. In the process one or more steps of screen-printing the microstructure as a curable material onto a plastic substrate, and curing the material. Such a device is also obtained by applying onto a substrate a material that is polymerizable or depolymerizable by irradiation, applying a negative or positive resist photoresist respectively, irradiating the structure and removing the unpolymerized or depolymerized material.

This invention relates to the fabrication of microstructures for use in assays.
There is considerable interest in the production of microstructures for the testing and quantitation of species, for the monitoring of binding reactions between molecules, for the manufacture of micro-fluidic systems for drug discovery, for genetic analysis and for clinical diagnostic assays. In particular, there is increasing interest in the development of smaller micro-plates for chemical synthesis, for combinatorial chemistry, for high throughput screening assays, and for binding reactions. The traditional 96-well microtitre plate is being superseded by systems in which there are a greater number, e.g. up to 2304, wells on a plate; see Lemmo et al, Anal. Chem. (1997) 69:543-551.
Plates with greater numbers of small wells have considerable advantages, including the use of lower amounts of expensive reagents and the greater number of reactions that can be screened on one plate, thus reducing costs and maximising throughput. It is also desirable to produce microstructures for valving and pumping liquids on the same device.
According to one aspect of the present invention, a method for the manufacture of a microstructure comprises the use of screen-printed layers over a sheet material. According to a second aspect of the invention, a microstructure is obtained by photoresist technology.
The methods of the invention allow the production of microstructures, on a plastics substrate, in large volume at low cost. Depending on the technique that is used, they allow the construction of microstructures having resolution down to 3-5 xcexcm. In one particular embodiment, the microstructure is in the form of a microtitre plate array, into which chemicals, reagents or other materials are dispensed for the carrying out of reactions of interest to the pharmaceutical and diagnostic industry. A device made by this method may be used for analysis of liquid samples, for the detection of binding events between binding partners, for drug discovery applications and for combinatorial chemistry and other reactions.

Production of microstructures for use in assays