System supplying solid bodies for controllable release of particles built in into them and method of obtaining such solid bodies
32 claims: 7 independent, 25 dependent
- 1Zastrzeżenia patentowe 1. Kompozycja farmaceutyczna o wysokiej stabilności podczas suszenia i przechowywania, w· postaci cząstek wybranych z proszków odpowiednich do inhalacji, mikroigiełek i mikrowłókien. zawierająca substancję aktywną, znamienna tym, ze stanowi roztwór stały, utworzony z substancji aktywnej i ze związku zdolnego do tworzenia postaci szklistej. stanowiącego węglowodany wyższe niż monosacharydy.
- 2Kompozycja według zastrz. 1. znamienna tym, ze jako węglowodan zawiera trehalozę, maltozę, laktozę. maltulozę, izomaltulozę, laktulozę, nieredukujące glikozydy związków polihydroksylowych wybrane spośród alkoholi cukrowych, innych polialkoholi o łańcuchu prostym, rafinozy, stachiozy, melezytozy, dekstranu, sacharozy i ich alkoholi cukrowych lub maltitolu, laktitolu, palatynitu, 2-D-glukopiranozylo-1 — 6-mannitolu i ich poszczególnych alkoholi cukrowych.
- 3Kompozycja według zastrz. 2, znamienna tym, ze jako węglowodan zawiera trehalozę.
- 4Kompozycja według zastrz. 1, znamienna tym, ze ma postać proszku swobodnie sypiącego się.
- 5Kompozycja według zastrz. 1, znamienna tym, ze dodatkowo zawiera akceptowalne fizjologicznie szkło karboksylanowe, azotanowe, siarczanowe lub dwusiarczanowe.
- 6Kompozycja według zastrz. 1, znamienna tym, że ma postać igieł o średnicach 1 do 50 pm i długości 5 do 150 pm.
- 7Kompozycja według zastrz. 1, znamienna tym, ze ma postać igieł o średnicach 0,1 do 4 mm i długości 1 do 30 mm.
- 8Kompozycja według zastrz. 1, znamienna tym, ze cząstki są mikrokuleczkami mającymi wielkość ziaren 0,1 do 10 pm.
- 9Kompozycja według zastrz. 8, znamienna tym, ze cząstki mają wielkość 1 do 4 pm.
- 10Kompozycja według zastrz. 1, znamienna tym, że jako substancję aktywną zawiera substancję wybraną z grupy obejmującej proteinę lub peptyd, nukleotyd, oligonukleotyd lub kwas nukleinowy, w tym DNA i RNA.
- 11Kompozycja według zastrz. 10, znamienna tym, ze jako substancję aktywną. zawiera substancję wybraną z grupy obejmującej enzym, hormon wzrostu, czynnik wzrostu, przeciwciało monoklonalne, interferon, interleukin lub cytokinę.
- 12Kompozycja według zastrz. 1, znamienna tym, ze jako substancję aktywną zawiera substancję wybraną z grupy obejmującej cyklosporynę A, insulinę, estrogen, progesteron, testosteron, estradiol lub tamoksifen.
- 13Kompozycja według zastrz. 1, znamienna tym, ze dodatkowo zawiera dopuszczalną fizjologicznie sól, regulującą straty wody w kompozycji tak, ze przy wilgotności otoczenia prężność pary wodnej wody krystalizacyjnej wynosi co najmniej 2 000 Pa w 20°C i nie jest zakłócana przy tworzeniu szkła podłoża.
- 14Kompozycja według zastrz. 1, znamienna tym, ze dodatkowo zawiera inhibitor reakcji Maillarda.
- 15Kompozycja farmaceutyczna o wysokiej stabilności podczas suszenia i przechowywania, w postaci cząstek, wybranych z proszków odpowiednich do inhalacji, mikroigiełek i mikrowłókien, zawierająca substancję aktywną, znamienna tym, ze stanowi roztwór stały, utworzony z substancji aktywnej i z hydrofobowej pochodnej węglowodanowej (HDC), mającej szkielet węglowodanowy o długości do pięciu jednostek cukrowych i w której więcej niż jedna grupa hydroksylowa węglowodanu jest zestryfikowana bądź zeteryfikowana.
- 16Kompozycja według zastrz. 15, znamienna tym, ze jako hydrofobową pochodną węglowodanową zawiera heksaoctan sorbitolu, pentaoctan α-glukozy, pentaoctan β-glukozy, 184 068 tetraoctan ł-O-oktylo-P-D-glukozy, oktaoctan trehalozy, oktapropanonian trehalozy, oktaoctan sacharozy, oktapropanonian sacharozy, oktaoctan celobiozy, oktapropanonian celobiozy, undekaoctan ralinozy i undekapropanonian rafinozy.
- 17Kompozycja według zastrz. 15, znamienna tym, ze dodatkowo zawiera akceptowalne fizjologicznie szkło karboksylanowe, azotanowe, siarczanowe lub dwusiarczanowe.
- 18Kompozycja według zastrz. 15, znamienna tym, że ma postać igieł o średnicach 1 do 50 pm i długości 5 do 150 pm.
- 19Kompozycja według zastrz. 15, znamienna tym, że ma postać igieł o średnicach 0,1 do 4 mm i długości 1 do 30 mm.
- 20Kompozycja według zastrz. 15, znamienna tym, że cząstki są mikrokuleczkami mającymi wielkość ziaren 0,1 do 10 pm.
- 21Kompozycja według zastrz. 20, znamienna tym, ze cząstki mają wielkość 1 do 4 pm.
- 22Kompozycja według zastrz. 15, znamienna tym, ze jako substancję aktywną zawiera substancję wybraną z grupy obejmującej proteinę lub peptyd, nukleotyd, oligonukleotyd lub kwas nukleinowy, w tym DNA i RNA.
- 23Kompozycja według zastrz. 22, znamienna tym, że jako substancję aktywną zawiera substancję wybraną z grupy obejmującej enzym, hormon wzrostu, czynnik wzrostu, przeciwciało monoklonalne, interferon, interleukin lub cytokinę.
- 24Kompozycja według zastrz. 15, znamienna tym, że jako substancję aktywną zawiera substancję wybraną z grupy obejmującej cyklosporynę A, insulinę, estrogen, progesteron, testosteron, estradiol lub tamoksifen.
- 25Kompozycja według zastrz. 15, znamienna tym, ze dodatkowo zawiera dopuszczalną fizjologicznie sól, regulującą straty wody w kompozycji tak, ze przy wilgotności otoczenia prężność pary wodnej wody krystalizacyjnej wynosi co najmniej 2 000 Pa w 20°C i nie jest zakłócana przy tworzeniu szkła podłoża.
- 26Kompozycja według zastrz. 15, znamienna tym, ze dodatkowo zawiera inhibitor reakcji Maillarda.
- 27Sposób wytwarzania kompozycji farmaceutycznej o wysokiej stabilności podczas suszenia i przechowywania, w postaci cząstek, wybranych z proszków odpowiednich do inhalacji, mikroigiełek i mikrowłókien, znamienny tym, ze stapia się związek zdolny do tworzenia postaci szklistej, stanowiący węglowodany wyższe niż monosacharydy, po czym wprowadza się substancję aktywną, a następnie stop oziębia się, przy czym proces stapiania prowadzi się w temperaturze wystarczającej do upłynnienia węglowodanów, lecz niepowodującej znaczącego osłabienia działania substancji aktywnej.
- 28Sposób wytwarzania kompozycji farmaceutycznej o wysokiej stabilności podczas suszenia i przechowywania, w postaci cząstek, wybranych z proszków odpowiednich do inhalacji, mikroigiełek i mikrowłókien, znamienny tym, ze stapia się związek zdolny do tworzenia postaci szklistej, stanowiący hydrofobową pochodną węglowodanową (HDC) mającą szkielet węglowodanowy o długości do pięciu jednostek cukrowych i w której więcej niż jedna grupa hydroksylowa węglowodanu jest zestryfi kowana bądź zeteryfikowana, po czym wprowadza się substancję aktywną, a następnie stop oziębia się, przy czym proces stapiania prowadzi się w temperaturze wystarczającej do upłynnienia HDC, lecz niepowodującej znaczącego osłabienia działania substancji aktywnej.
- 29Sposób wytwarzania kompozycji farmaceutycznej o wysokiej stabilności podczas suszenia i przechowywania, w postaci cząstek, wybranych z proszków odpowiednich do inhalacji, mikroigiełek i mikrowłókien, znamienny tym, ze rozpuszcza się lub zawiesza się w rozpuszczalniku substancję aktywną i związek zdolny do tworzenia postaci szklistej, stanowiący węglowodany wyższe niż monosacharydy, po czym roztwór bądź zawiesinę suszy się.
- 30Sposób według zastrz. 29, znamienny tym, z e stosuje się suszenie rozpyłowe.
- 31Sposób wytwarzania kompozycji farmaceutycznej o wysokiej stabilności podczas suszenia i przechowywania, w postaci cząstek, wybranych z proszków odpowiednich do inhalacji, mikroigiełek i mikrowłókien, znamienny tym, ze rozpuszcza się lub zawiesza się w rozpuszczalniku substancję aktywną i związek zdolny do tworzenia postaci szklistej, 184 068 stanowiący hydrofobową pochodną węglowodanową (HDC) mającą szkielet węglowodanowy o długości do pięciu jednostek cukrowych i w której więcej niż jedna grupa hydroksylowa węglowodanu jest zestryfikowana bądź zeteryfikowana, po czym roztwór bądź zawiesinę suszy się.
- 32Sppsóówedhłg zz.atrz.31. znamienny tym, żżstosujesięsuszznierooppłowe.
Independent claims32
467 paragraphs in 12 sections, as filed
The subject of the invention is a pharmaceutical composition with high stability during drying and storage and a method of producing a pharmaceutical composition with high stability during drying and storage. This composition is a solids dose delivery system.
Solid delivery systems are useful in a wide range of applications, such as the controlled release of labile molecules, in particular biologically active substances, such as pharmaceuticals, enzymes, vaccines, and biological control agents, such as artificial fertilizers, anti-pest agents and pheromones.
Delivery in the form of a solid of doses of biologically active substances to biological tissues, such as mucous, skin, ocular, subcutaneous, intradermal and pulmonary tissue, gives a number of advantages in comparison with existing methods, such as topical administration of liquid, transdermal administration, so-called plaster, and subcutaneous injection. The delivery of solid doses can be by direct transdermal delivery of such fixed doses, which reduces the risk of infection by eliminating the use of conventional needles and syringes, and provides a more accurate dosage than vial vials, and also significantly reduces or eliminates the unpleasant sensations that often accompany subcutaneous injection. Several solid dose delivery solutions have been developed, including systems using transdermal and ballistic delivery devices.
Topical administration is used for various biologically active substances such as wound healing antibiotics. These topical ointments, gels, creams etc. must often be re-administered to maintain efficacy. This is especially difficult for burn wounds and ulcers.
The systems used for direct drug delivery are usually multi-layered laminates with a drug reservoir layer, these laminates sticking to the skin, i.e., they are transdermal patches such as those described in document UP 4 906 463. However, many drugs are not suitable for transdermal delivery. because they do not exhibit such percutaneous drug release rates that would be able to provide such delivery.
Therapeutic compositions have also been developed for transdermally implanted systems for the slow release of certain pharmaceuticals over an extended period of time, on the order of months or years. A well-known example is Norplant® for the supply of steroid hormones.
In the case of controlled drug delivery through membrane penetration, the drug is encapsulated within a closed chamber by a polymer membrane that limits the permeation rate. Such a drug reservoir may contain either drug particles or a suspension (or solution) of solid drug in a liquid or matrix type dispersing medium. Polymeric membranes can be made of a homogeneous or heterogeneous non-porous polymeric material, or of a micro-porous or semi-transparent membrane. The drug reservoir can be encapsulated within the polymeric membrane by compression, encapsulation, microencapsulation or other methods. Implants release drugs by dissolving these drugs in the inner core and slowly diffusing through the outer matrix. The release of the drug from such an implanted therapeutic system should be relatively constant and strongly depends on the dissolution rate of the drug in the polymeric membrane or on the diffusion rate through the microporous or semipermeable membrane. Over time, the inner core may dissolve significantly, but in systems currently used, the outer matrix does not dissolve.
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Implants are placed under the skin by making cuts on the skin and squeezing the implants between the skin and muscle. At the end of their use, these implants are surgically removed if they have not dissolved. Document US 4 244 949 describes implants whose outer matrix is made of inert plastic, such as polytetrafluoroethylene resin. Examples of implantable therapeutic systems of this type are Progestasert IUD and Ocusert
Other implantable therapeutic systems rely on controlled drug delivery from a diffusion type matrix. The drug reservoir is formed by uniformly / dispersing the drug particles in a lipophilic or hydrophilic polymer matrix. The drug particles can be dispersed in the pollmer matrix by mixing this drug with a viscous liquid polymer or semi-solid polymer at room temperature, followed by crosslinking this polymer, or by mixing the drug particles with the molten polymer at elevated temperature. Dispersions can also be prepared by dissolving drug and / or polymer particles in an organic solvent, followed by mixing and evaporation of the solvent in a mold at elevated temperature or under vacuum. The rate of drug release from this type of delivery is not constant. Examples of implantable therapeutic systems of this type are vaginal contraceptive rings and Compuduse implants. Document PCT / GB 90/00497 describes glassy slow release systems for the production of implantable devices. The implants described are blologlc / not absorbed and do not require surgical removal. However, they are introduced by surgical methods. Furthermore, these devices are severely limited as to the type of biologically active substance that can be introduced as they must be resistant to heating and / or dissolution to allow it to be incorporated into this supplying device.
In the case of micro-batch drug delivery controlled by dissolution, a drug reservoir constituting a suspension of drug particles in an aqueous solution of a water-miscible polymer forms a homogeneous dispersion of numerous separate, non-leachable, microscopic drug reservoirs in the polymer matrix. Such micro-dispersion can be prepared using a high energy dispersion method. The release of the drug from this type of drug delivery device occurs either in the process of interfacing or in a process controlled by diffusion from the matrix. An example of this type of drug delivery device is the Syncro-Mate-C Implant.
For cast polymeric implants, biologically active substances that cannot tolerate organic solvents are unsuitable. In the case of extruded polymeric systems, biologically active substances that cannot withstand the elevated temperatures necessary for the production of strains are unsuitable. In all cases, biologically active substances that are unstable at body temperature are unusable, especially for longer periods of time.
Various compositions have been developed for aerosol administration to the mucosal surface, especially by inhalation (nasopharyngeal or pulmonary). Compositions for administering medications by inhalation are typically liquid pharmaceutical compositions and devices for delivering this liquid in the form of an aerosol. Document US 5 011 678 describes suitable compositions containing an active pharmacological substance - a biologically friendly amphiphilic steroid and a biologically friendly propellant (fluorocarbon). Document US 5 006 343 describes suitable compositions containing liposomes - pharmaceutically active substances and a certain amount of vesicular, surface-active protein that effectively improves the transfer of liposomes across the lung surface.
The disadvantage of using aerosol compositions is that the maintenance of pharmaceuticals in aqueous suspensions or solutions can lead to clustering and reduced activity and bioavailability. Reduction in action can be partially avoided by cooling, but this limits the usefulness of these compositions. This is especially true for peptides and hormones. For example, synthetic gonadotropin, releasing hormone analogs (GnRH), such as a nafarelin agonist or ganirelex antagonist designed to enhance potency, increases hydrophobicity and diaphragm binding. These compounds are sufficiently hydrophobic in nature to be concentrated in an aqueous solution
184 068 and create an ordered structure that increases viscosity over time. As a result, the bioavailability of nasal or pulmonary compositions may be unacceptably low. The use of powder compositions avoids many such disadvantages. The required particle sizes of such powders are 0.5-5 microns in order to obtain deep alveolar deposits when delivered to the lungs. Unfortunately, powders with these particle sizes tend to absorb water and stick together, thereby reducing the deposition of these powders in deep bubble regions. Powders with larger particle sizes are suitable for delivery to the nose and throat, but the tendency of such powders to stick together reduces the surface area of the particles available for contact with the diaphragms and absorption through the diaphragms. There are currently devices in use that scatter clusters formed by electrostatic interaction (e.g. Turbohaler ™); however, they do not disperse clusters formed due to moisture. It would be beneficial to have powders that do not absorb moisture and do not stick together, thereby increasing the effective concentration of the drug in the lungs.
Also disclosed are media providing doses of solids for ballistic transdermal administration. For example, US 3,948,263 describes a ballistic animal implant for veterinary use, consisting of an external polymeric coating encapsulating a biologically active substance. Similarly, US 4 326 524 discloses a solid dose ballistic missile comprising a biologically active substance and an internal binder without an outer casing. Delivery takes place with the help of compressed gas or an explosion. US 979 993 also describes gelatin-coated tranquilizers that are carried by ballistic shells for implantation. However, these ballistic devices are only suitable for veterinary applications for large animals, due to the relatively large size of the dose delivered, usually on the order of several millimeters.
Ballistic delivery at the cellular level is also effective. The general principle of ballistic feeding is to use a supersonic wave front, which is produced by releasing compressed gas to impulse particles contained in an adjacent chamber. For example, nucleic acids adsorbed on tungsten microprojectile particles are effectively delivered to live epidermal plant cells. See Klein (1987) Nature 327: 70-73. The particle delivery gun (PIG) is a better controlled device. Vain et al. (1993) Plant Cell, Tissue and Organ Culture 33: 237-246.
Devices have been described that shoot out ampoules containing medications using gas pressure (documents: US 4 790 824 and PCT / GB 94/00753). Several devices that inject fluids have also been described (US documents: 5,312,335 and 4,680,027). However, there are few compositions suitable for ballistic delivery. Pharmaceutical powder compositions in their current form are not suitable for ballistic administration. The particles of the available powder forms are usually irregular, of varying sizes, shapes and density. This lack of homogeneity leads to the deposition of powders and losses on the surface of the skin during their administration and creates problems with the regulation and density of substances as to the depth of delivery to subcutaneous and intradermal tissues.
For ballistic delivery, it would therefore be beneficial to establish solid-state drug delivery systems of specific sizes, shapes, densities and dissolution rates to ensure more uniform distribution. Additional benefits would arise if the shape of the substrate could be adjusted to facilitate or regulate penetration through the epidermis and hard layers of the skin. The small size of the delivery systems, preferably combined with a high delivery momentum, would also increase convenience of administration and reduce tissue damage. The production of such solid dose delivery systems should be such that neither the delivery substrate nor the delivered substances deposited therein are damaged, or that their effectiveness does not decrease. In addition, deposited substances should be stable when loaded into or onto the substrate so that effective administration can be achieved and to facilitate storage of loaded delivery systems. The production of solid dose delivery media and their loading with localized substances to obtain solid dose delivery systems and administration of such systems should be relatively simple and economical.
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The present invention uses solid, glassy delivery substrates suitable for loading with a wide variety of substances called deposited substances (tenants) to obtain solid delivery systems. The choice of glassy delivery substrates depends on the nature of the substances deposited and on the desired delivery speed of these deposited substances, a wide range of speeds and delivery methods being provided. These delivery systems can be selected in size and shape for various methods of administration.
The composition according to the invention is systems for delivering doses of rapidly soluble solids, containing carbohydrates and a deposited substance. These delivery systems can be formulated as powders with homogeneous particle sizes and as larger, implantable systems.
The composition of the invention may also contain new glassy substrates made of hydrophobic carbohydrate derivatives (HDC). These HDCs are non-toxic and the release of deposited substances from these systems can be strongly controlled in terms of release of deposited substances over long periods of time. This release from HDC delivery systems can occur by devitrification, dissolution and / or hydrolysis. HDC delivery systems are particularly suited for the delivery of hydrophobic localized substances such as antipark agents, pheromones, steroid hormones, peptides, peptide mimetics, antibiotics and other organic pharmaceutical agents such as synthetic corticosteroids, bronchodilators and immunomodulators and immunosuppressants. cyclosporin A (CSA).
In addition, the composition of the invention may also be complex compositions of various glassy substrates to establish combined delivery systems. These combined delivery systems include HDC combined with carbohydrates and / or other slowly water-soluble glassy substances such as carboxylate, nitrate and phosphate glasses to produce solid dose systems with a wide range of new properties
Systems for supplying solid dose for multiphase delivery are possible, comprising an HDC outer part slowly dissolving in an aqueous solution and containing a hollow chamber therein, and an inner part contained in that chamber, the inner part containing at least one carbohydrate and a therapeutically effective amount of at least one deposited substance.
Biologically active substances are delivered to the body by administering the above-described systems that deliver doses of solids to biological tissues. Administration can be mucosal, oral, topical, subcutaneous, intradermal, intramuscular, intravenous and inhalation.
The methods for producing solid dose systems in accordance with the invention are that the carbohydrate and / or HDC, deposited substances and all other ingredients are mixed and processed in a wide variety of ways, including dissolution in the molten substance followed by rapid cooling, drying spray, freeze drying, air drying, vacuum drying, fluid bed drying, co-precipitation and supercritical liquid evaporation. The resulting glasses can be heated to soften and then extruded, pulled or spun into solid or hollow fibers. Dry ingredients can also be mixed in aqueous or organic solutions and dried, e.g. by spray drying, freeze drying, air drying, vacuum drying, fluidized bed drying, co-precipitation and supercritical liquid evaporation.
It is possible to produce delivery systems suitable for slow or pulsed release of deposited substances. The production methods consist of combining the deposited substances in solid stabilizing solutions, glass-forming carbohydrates and / or HDC and / or other glass-forming substances with lower dissolution or decomposition rates than in the case of carbohydrates, and processing these components as described above. The proportions of the substance can be adjusted to provide a wide range of precisely defined release rates. These methods produce complex compositions of carbohydrates and / or HDC and other water-soluble and / or metabolizable glasses, plastics, and glass modifiers.
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Systems and methods for delivering solid doses also include solid dosage forms that are fibers, spheres, tablets, discs, particles, and needles with a relatively uniform size distribution. The substrates can be microscopic or macroscopic.
A variety of substances can be used as localized substances, including (but not limited to) diagnostic, therapeutic, preventative, and other biologically active agents. These delivery systems and methods of use provide a variety of dosage regimens for delivering the substances contained therein and are suitable for a wide range of applications, including agricultural, veterinary and medical applications.
Dosing systems for solids contain substrates that deliver solids doses and substances contained therein. The delivery systems are composed to ensure the exact delivery speed of the deposited substances embedded in these systems. Delivery systems are particularly suitable for delivering biologically active particles to animals, including humans.
Methods for delivering pharmaceutical agents (but not limited to) include mucosal, oral, topical, subcutaneous and intradermal, intramuscular, intravenous and inhalation administration.
The production of such delivery systems is carried out by the methods of the invention.
The term solid dose as used herein means that the deposited substance incorporated into the substrate is in solid rather than liquid form, and this solid form is the form used for delivery.
Placed substances means molecules, macromolecules and assemblies of macromolecules, synthetic and natural, and cell fractions, live and dead cells, bacteria and viruses, and other active substances introduced into the medium; A wide range of substances embedded in the medium is suitable for use, which is described below. An effective amount of a deposited substance means the amount necessary to achieve the desired effect. For example, in the case of a biologically active substance, an effective amount means an amount that produces the desired physiological response. The substrate is solid and is amorphous or glassy. Other additives may be added to these delivery systems: buffers, dyes, etc. The term substrate as used herein includes any glass forming or glass forming substance as defined in the claims of the invention. The term delivery system (s) includes solid dosage forms containing substrates and the substances they contain. Delivery systems formed from specific substrates have different names and, unless otherwise noted, the term delivery systems includes each.
The pharmaceutical composition with high stability during drying and storage, in the form of particles selected from powders suitable for inhalation, microneedles and microfibers, containing the active substance, according to the invention is characterized in that it is a solid solution formed from the active substance and from a compound capable of forming glassy form, being higher in carbohydrates than monosaccharides.
Preferably, the composition as a carbohydrate contains trehalose, maltose, lactose, maltulose, isomaltulose, lactulose, non-reducing glycosides of polyhydroxyl compounds selected from sugar alcohols, other straight chain polyalcohols, raffinose, stachyose, mesitylose, dextran, and lactose , palatinite, 2-D-glucopyranosyl-1-> 6-mannitol and their individual sugar alcohols.
More preferably, the composition contains trehalose as a carbohydrate.
Preferably, the composition is in the form of a free flowing powder.
Preferably, the composition additionally comprises physiologically acceptable carboxylate, nitrate, sulfate or disulfate glass.
Preferably, the composition is in the form of needles with a diameter of 1 to 50 pm and a length of 5 to 150 pm.
Preferably, the composition is in the form of needles with a diameter of 0.1 to 4 mm and a length of 1 to 30 mm.
Preferably, the composition is in the form of microspheres with a grain size of 0.1 to 10 µm.
More preferably, the composition is in the form of microspheres with a grain size of 1 to 4 pm.
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Preferably, the composition as the active substance comprises a substance selected from the group consisting of a protein or peptide, nucleotide, oligonucleotide or nucleic acid, including DNA and RNA. '
More preferably, the composition as the active substance comprises a substance selected from the group consisting of enzyme, growth hormone, growth factor, monoclonal antibody, interferon, interleukin or cytokine.
Preferably, the composition as active substance comprises a substance selected from the group consisting of cyclooporyns A, insulin, estrogen, progesterone, testosterone, estradiol or tamoxifen.
Preferably, the composition additionally contains a physiologically acceptable salt that regulates water loss in the composition such that at ambient humidity the water vapor pressure of the crystallization water is at least 2,000 Pa at 20 ° C and is not disturbed when forming the substrate glass.
Preferably, the composition additionally comprises an ardi mailing inhibitor.
The compositions of the invention are solid dose systems with a high release rate of deposited substances. Surprisingly, it has been found that carbohydrates can be processed to obtain powders with a homogeneous particle size distribution in the form of microspheres or needles. Carbohydrates can also be processed to form macroscopic delivery forms suitable for formulating implantable devices. A wide range of dosage forms and methods for making these dosage forms are presented herein. It has been found that these carbohydrates are particularly useful where in other cases denaturing conditions would prevent the formulation of solid dosage forms of biologically active substances. In particular, such conditions mean elevated temperatures (above which biologically active substances in other cases denature) and the presence of organic solvents.
Dose systems of solids with adjustable release rates of deposited substances contain carboxylate glass as the organic substrate. It has been found that organic carboxylates form stable, amorphous substrates by evaporation of dissolution.Sy ^ and ^; ^^ source ^; and These organic glasses release it contained substances in them at precisely defined speeds, depending on the carboxylate anion and the metal cation used in the composition . Like carbonate-containing substrates, these glasses can also be processed, either individually or in mixtures with other organic carboxylates and / or carbohydrates and / or HDC, to obtain powders with uniform particle size distribution in the form of microspheres, needles and / or implantable devices to form a wide range of macroscopic delivery forms.
The pharmaceutical composition with high stability during drying and storage, in the form of particles, selected from powders suitable for inhalation, microneedles and microfibers, containing the active substance, according to the invention is also characterized in that it is a solid solution formed from the active substance and a hydrophobic carbohydrate derivative (HDC), having a carbohydrate skeleton up to five sugar units in length and in which more than one carbohydrate hydroxyl group is esterified or etherified.
Preferably, the composition as a hydrophobic carbohydrate derivative contains sorbitol hexaacetate, α-glucose pentaacetate, β-glucose pentaacetate, 1-O-octyl-P-D-glucose tetraacetate, trehalose octaacetate, trehalose octapropanoate, saccharose octaacetate, octoocaposanoate , raffinose undecaacetate and raffinose undecapropanoate.
Preferably, the composition additionally comprises physiologically acceptable carboxylate, nitrate, sulfate or disulfate glass.
Preferably, the composition is in the form of needles with a diameter of 1 to 50 pm and a length of 5 to 150 pm.
Preferably, the composition is in the form of needles with a diameter of 0.1 to 4 mm and a length of 1 to 30 mm.
Preferably, the composition is in the form of microspecules with a grain size of 0.1 to 10 µm.
More preferably, the composition is in the form of microspheres with a grain size of 1 to 4 pm.
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Preferably, the composition as active substance comprises a substance selected from the group consisting of a protein or peptide, nucleotide, oligonucleotide or nucleic acid, including
DNA and RNA.
More preferably, the composition as the active substance comprises a substance selected from the group consisting of enzyme, growth hormone, growth factor, monoclonal antibody, interferon, interleukin or cytokine.
Preferably, the composition as active substance comprises a substance selected from the group consisting of cyclosporin A, insulin, estrogen, progesterone, testosterone, estradiol or tamoxifen.
Preferably, the composition additionally comprises a physiologically acceptable salt that regulates water loss in the composition such that at ambient humidity the water vapor pressure of the crystallization water is at least 2,000 Pa at 20 ° C and is not disturbed when forming the glass of the substrate.
Preferably, the composition additionally comprises a Maillard inhibitor.
The compositions according to a variant of the invention are dose systems of solids with newly defined and adjustable rates of release of deposited substances. In this solution, the substrate is hydrophobic carbohydrate derivatives (HDC). Surprisingly, it has been found that HDC forms stable glassy substrates that release deposited substances when in contact with water at precisely defined speeds, depending on the type of carbohydrate, the hydrophobic fragment (s) used to form the derivative of this carbohydrate, and the degree of derivative formation. Like carbohydrate-containing substrates, HDC-containing substrates can also be processed to obtain powders with a homogeneous particle size distribution in the form of microspheres or needles. HDC can also be processed to produce a wide range of macroscopic delivery forms.
Dosage forms and methods for making these dosage forms are discussed in the description. It has been found that these delivery systems are particularly useful where the nature of the substances deposited prevents the preparation of solid dosage forms. These systems are delivery systems for hydrophobic deposited substances that are either difficult to prepare in dosage form or difficult to obtain physiologically effective concentrations due to lack of solubility in aqueous plants.
Delivery systems occur as solid solutions, emulsions, suspensions or coacervates of substances deposited in a solid support. When located, these substances are resistant to higher temperatures inside the substrate than when they occur alone. The specific temperature resistance depends on the substrate used. The components of these delivery systems can thus be kept in molten form for short periods of time without damaging the deposited substances during this processing. These delivery systems can be further processed in the same manner and are resistant to damage during sintering with nitrates and / or carboxylates and / or HDC and / or with other glass-forming substances.
Complex compositions of various substrates and delivery systems provide a wide range of combined delivery media.
Although single forms of the composition may be used in the present invention, more than one medium, more than one deposited substance, and more than one additive may be present in the composition. Determination of effective amounts of these compounds is within the reach of specialists.
Carbohydrate-containing delivery systems are discussed below.
It has been found that carbohydrate-containing delivery systems can be processed into a wide range of solid dosage forms, particularly suitable for the therapeutic administration of deposited substances.
The term carbohydrates as used herein includes disaccharides, trisaccharides, oligosaccharides and their corresponding sugar alcohols, polysaccharides and chemically modified carbohydrates such as hydroxyethyl starch and sugar copolymers (Ficoll). Both natural and synthetic carbohydrates are suitable for use here. Synthetic carbohydrates include (but are not limited to) those in which the glycosidic linkage is replaced by a linkage
184 068 thiol or carbon. Both carbohydrate forms, both D and L, can be used. These carbohydrates may be non-reducing or reducing. Suitable substrates are those in which the deposited substances can be dried and stored without loss of their significant capacity due to denaturation, clumping or other mechanisms. Loss prevention can be improved by the addition of various additives, such as Maillard inhibitors, as described later. The addition of such inhibitors is particularly advantageous in combination with reducing carbohydrates.
Reducing carbohydrates suitable for use in the composition of the invention are known to those skilled in the art and include (but are not limited to) maltose, lactose, maltulose, isomaltulose and lactulose.
Non-reducing carbohydrates include (but are not limited to) trehalose, raffinose, stachyose, sucrose and dextran.
Other useful carbohydrates include non-reducing glycosides and polyhydroxy compounds selected from sugar alcohols and other straight chain polyalcohols. Sugar alcohol glycosides are preferably monoglycosides, and especially compounds obtained by reduction of disaccharides such as lactose, maltose, lactulose and maltulose. The preferred glycosidic group is glucoside or galactoside, and the preferred sugar alcohol is sorbitol (glucitol). Particularly preferred carbohydrates are: maltitol (4-O-3-D-glucopyranosyl D-glycitol), lactitol (4-O-β-D-galactopyranosyl-D-glu-eitol), palatinite (GPS mixture, aD-glucopyranosyl-1- > 6-sorbitol and GPM), aD-glucopyranosyl-1-> 6-mannitol and its individual sugar alcohols, GPS and GPM components.
Preferably, the carbohydrate is in the form of hydrate, including trehalose, lactitol and palatinite, and most preferably is trehalose. Surprisingly, it has been found that solid dose delivery systems containing certain sugar hydrates, such as trehalose, do not exhibit the stickiness or stickiness of solid dosage forms that exhibit other carbohydrates. Trehalose is therefore the preferred carbohydrate for preparation, packaging and administration.
Trehalose (α-D-glucopyranosyl-αD-glucopyranoside) is a naturally occurring, non-reducing disaccharide. Initially, it was found to be associated with the prevention of damage when drying certain plants and animals, which can dry without damage and recover after rehydration. Tetralose has been shown to be useful in preventing denaturation of proteins, viruses and foodstuffs during drying [see documents: US 4,891,319; 5,149,653; 5,026 566; Blakeley et al. (1990) Lancet 336: 854-855; Roser (July 1991) Trends in Food Sci. and Tech. 166-169; Colaco et al. (1992) Biotechnol. Internat., 345-350; Roser (1991) BioPharm. 4: 47-53; Colaco et al. (1992) Bio / Tech. 10: 1007-1011; and Roser et al. (May 1993) New Scientist, pp. 25-28].
Other carbohydrates that can be used are disclosed, e.g., in WO 91/18091, 87/00196 and US 4,891,191 and 5,098,893, which describe the use of polyols as glasses for stabilizing particles during drying and storage to restore original form before use. It has now been found that the solid dosage forms of the present invention are suitable for direct use as delivery systems for the controlled release of substances contained therein. In addition, these polyols can be used in conjunction with other amorphous matrices to obtain delivery systems that - as it has now been discovered - exhibit a wide range of release rates and characteristics that can be easily and accurately controlled to produce excellent solid dose systems.
The method of producing a pharmaceutical composition with high stability during drying and storage, in the form of particles, selected from powders suitable for inhalation, microneedles and microfibers, according to the invention is characterized by melting a compound capable of forming a glassy form, carbohydrates higher than monosaccharides. after which the active substance is introduced and then the alloy is cooled, wherein the melting process is carried out at a temperature sufficient to liquefy the carbohydrates, but without causing a significant weakening of the active substance.
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The method of producing a highly stable pharmaceutical composition during drying and storage, in the form of particles, selected from powders suitable for ,ρΗοΙοction, microneedles and microfibers, according to the invention is also characterized in that the active substance and the compound are dissolved or suspended in a solvent to form a glassy form, higher carbohydrates than moposocharides melt, and the solution or suspension is dried.
Preferably, spray drying is used.
It has been found that deposited substances, preferably soluble in organic solubilizers, can be dried in trehalose from a mixture of organic / aqueous solubilizers, resulting in complex compositions that are easily restored to their original state in aqueous solvents. The deposited substances are dissolved in an orgopi / zpym / aqueous solvent in combination with an effective amount of trehalose, and then dried. In this way, solid solutions, emulsions, suspensions or coacervates of the deposited substance in trehalose glass are obtained, which then easily dissolve in an aqueous solution, giving a thoroughly dispersed suspension of the pleroaauyzed / placed substance. It has been shown that the CSA immunosuppressant (which is poorly soluble in water and is usually administered in the form of an oil emulsion) can be dried in a trehalose solution in a 1: 1 ethanol 'water mixture to obtain clear glass from trehalose containing CSA. This glass can be ground to obtain a free-flowing powder, which can also be tableted and which, when water is added, immediately dissolves, giving a thoroughly dispersed suspension of CSA in water.
HDC delivery systems are discussed below.
Dosing systems for solids in which the medium contains at least one HDC are called HDC delivery systems. HDCs form a separate group of non-toxic carbohydrate derivatives that enter into rye in the production of solid dose substrates. Although numerous HDCs have been used, their advantages of easy glass formation have not yet been presented. The solution according to the invention therefore uses glassy forms of HDC, which are also referred to as amorphous matrix forming compositions. HDC delivery systems are particularly suitable for use in the controlled, pulsed or delayed release of substances contained therein. Any of these stored substances can be incorporated into HDC access systems.
HDCs easily form glass either from a suddenly cooled alloy or after evaporation of an organic solvent. HDC can also be processed by methods presented for carbohydrates.
In zpa / zepie used in the description HDC refers to a wide range of hydrophobic carbohydrate derivatives in which at least one hydroxyl group is substituted with a hydrophobic fragment, which includes esters and ethers. Numerous examples of suitable HDCs and their synthesis are described in Developmepts of Food Coubohyduate - 2nd ed. By CK Lee, Applied Science Publishers, London (1980). Other syntheses have been described, for example, by Akoh et al. (1987) J. Food Sci. 52 '1570; Khan et al. (1993) Tetra. Letts 34 '7767; Khan (1984) Pure & Appl. Chem, 56 '833-844, and Khan et al. (199θ) Carb. Res. 198 '275-283. Special examples of HDC include (but are not limited to) sorbitan hexagon (SHAC), five / ton α-glucose (α-GPAC), beta-glucose (β-GPAC), four-tap / 1-O-octyl -eD-glucose (oGTA), trehalose eight-octapap (TOAC), trehalose eight-octoprotein (TOPR), sucrose eight-octacetate (SOAC), cellobiose octacetate (COAC), raffinose monoacetate (RUDA), sucrose oozoose, and octoplioniose zteuo-O-methyl-treholoa and di-O-methylosae-O-acetyl-sochoroa. An example of a suitable HDC in which the carbohydrate is treholose is the compound of formula 1.
In formula 1, the hydroxyl group, or its less hydrolyze! Iowa derivative such as an ester or ether, or any functional modification of this compound in which at least one R is not a hydroxyl but a hydrophobic derivative. Suitable functional modifications include (but are not limited to) those in which the atom is present
184 068 oxygen is replaced with a heteroatom such as N or S. The extent of substitution may also be different and may be a mixture of various derivatives. Full substitution of hydroxyl groups is not needed, which provides the opportunity to choose changes in physical properties (such as solubility) of the substrate. R can be any chain length from C<sub>2 </sub>up and this chain can be straight, branched, cyclic or modified. While Formula 1 depicts trehalose disaccharide, the carbohydrate among those discussed herein has a carbohydrate backbone with a sugar chain length ending in a pentose sugars, and the location of the glycosidic linkage may change.
There are no restrictions on the various aspects of HDC. For example, the sugar components of each HDC may change, the position and nature of the glycosidic linkage between sugars may also change, and the type of substitution may vary within a given HDC. A representative example of HDC, substituted with both ester and ether groups, is 2,3,4,5-tetraacetate 10-octyl-eD-glucopyranoside of formula 2, wherein R is O<sub>2</sub>C'CH<sub>?</sub>.
The possibility of modifying HDC properties by slight changes in their composition makes them extremely suitable for solids doses, especially when compared to polymeric systems, which often depend on areas of crystallinity when changing their properties, especially biological erosion. HDC delivery systems can be designed to display precise properties, such as release rate of deposited substances This can be achieved by changes in the modification of a given carbohydrate or by combining a set of different HDCs.
It has been found that clean single HDC glasses are stable at ambient temperatures and at least 60% humidity. On the other hand, mixtures of HDC glasses with specific substances placed therein are unexpectedly stable at ambient temperatures and humidity conditions of at least up to 95%. It should be noted that the incorporation of up to 10% (weight / volume) of extremely hygroscopic deposited substances, such as the synthetic corticosteroid 6α, 9α-difluoro-11p, 21-dihydroxy-16a, 17α-propyl methylene dioxy-4-pregnene-3,20-dione (XPDO), gives HDC glasses that are stable when exposed to a relative humidity of up to 95% at room temperature for more than a month, and also immediately release their substances within 5-10 minutes after adding to liquid water. The same effect of HDC glass stability was found for TOAC glasses containing 10% (by volume) CSA embedded as a deposited substance.
It was also found that the addition of other HDCs at the same levels also gives mixed HDC glass, which is also resistant to devitrification at 95% relative humidity. Thus, TOAC glasses, containing 10% (w / v) GPAC or TOPR, show complete resistance to devitrification at a relative humidity of 95%. It is interesting that these composite HDC glasses behave differently in liquid water; GPAC / TOAC glass is devitrified from the air / chni much faster than TOPR / TOAC glass (see Figures 13 and 14). This ability to set the dissolution rate of HDC composite glasses makes them particularly useful as controlled release delivery substrates.
HDC glasses can be made either by evaporating the solvent or by rapidly cooling the molten HDC. Due to the low softening temperatures of some HDC glasses, the thermally resistant substances such as drugs and biological molecules located therein can be introduced into molten HDC without decomposition during the production of delivery systems. It has surprisingly been found that these deposited substances exhibit zero order release kinetics when the amorphous matrix forming compositions erode in aqueous solutions. Release occurs after the surface devitrification process. HDC delivery systems can be easily modeled into any shape or form as described herein. Such modeling can be effected by extrusion, casting, etc. by any means known in the art. HDC-providing media are non-toxic and inert to any substances dissolved in them that can be incorporated into them.
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HDC delivery systems when forming compositions such as matrices and / or coatings, undergo heterogeneous surface erosion when placed in an aqueous environment. Without being bound by any particular theory, it can be assumed that the possible mechanism of their degradation begins with the initial surface devitrification due to supersaturation at the interface, followed by low erosion and / or dissolution of surface layers at low speed. Arrays can be modified by careful selection of components to obtain the desired rates of devitrification and, consequently, the required release rates of the deposited substances, since the devitrified matrix does not create any obstacle to the release of the substance contained in it.
Molten HDC are excellent solvents for many organic molecules. This makes them particularly suitable for delivering biologically active substances that are difficult to incorporate into the composition by other means. Over 20% by weight of organic molecules can be introduced into the HDC delivery systems. It is worth noting that HDCs are neutral and do not show any reactivity to substances dissolved in them, i.e. substances embedded in them. It is described in more detail below that HDCs are capable of dispersing very fine suspensions of carbohydrate delivery systems to obtain complex composite delivery systems.
The method of producing a pharmaceutical composition with high stability during drying and storage, in the form of particles selected from powders suitable for inhalation, microneedles and microfibers, according to the invention is also characterized in that a compound capable of forming a glassy form is melted. constituting a hydrophobic carbohydrate derivative (HDC) having a carbohydrate skeleton up to five sugar units in length and in which more than one carbohydrate hydroxyl group is esterified or etherified, after which the active substance is introduced, and then the melt is cooled, with the melting process carried out at sufficient to liquefy HDC, but without significantly reducing the effect of the active substance.
High purity HDC components are produced using established principles of chemical or enzymatic synthesis. HDC and the substances located in them can be thoroughly mixed together in appropriate molar ratios and melted to obtain clarity. Suitable melting conditions mean (but are not limited to) melting in an open glass flask at a temperature between 100 and 150 ° C for 1-2 minutes. This gives a liquid alloy that can be allowed to cool slightly, and then, if necessary, dissolving the deposited substance in the molten mass, cool it quickly to vitrification, e.g. by placing on a bronze plate or in a metal form to shape the delivery substrates. It is also possible to carefully regulate the temperature of the molten mass and introduce localized substances into the previously molten HDC composition, or mix with the cooling molten HDC mass before it cools down quickly.
HDC molten masses are heat resistant and allow the introduction of organic particles without denaturation, or suspensions of core particles without changing their physical nature. Molten glass can also be used to coat particles of micron size, which is particularly important when formulating compositions of low-hygroscopic powders containing hygroscopic active substances for the administration of medicaments by inhalation.
The method of producing a pharmaceutical composition with high stability during drying and storage, in the form of particles, selected from powders suitable for inhalation, microneedles and microfibers, according to the invention is also characterized in that the active substance and a compound capable of forming are dissolved or suspended in the solvent. vitreous form, constituting a hydrophobic carbohydrate derivative (HDC) having a carbohydrate backbone up to five sugar units in length and in which more than one carbohydrate hydroxyl group is esterified or etherified, and the solution or suspension is dried.
Preferably, spray drying is used.
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Glassy HDC supply substrates can therefore also be made by evaporating HDC and deposited substances introduced as a solution in a solvent or in a mixture of solvents. HDC ingredients easily dissolve in many organic solvents. Suitable solvents include (but are not limited to) dichloromethane, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and higher alcohols. The nature of the solvent is irrelevant as it is removed completely during the manufacture of the delivery systems. It is preferred that both components, HDC and deposited substance, are soluble in the given solvent. However, the solvent can only dissolve HDC, leaving the deposited substance in suspension. When concentrating the solvent, no more crystallization occurs with more preferred HDCs. Instead, an amorphous solid forms, which has similar properties to quickly cooled glass. Here, too, deposited substances can easily be incorporated either from solution or as a suspension of particles.
HDC glass transition temperatures (Tg) are low, typically less than 70 ° C and unexpectedly unpredictable based on melting points. Typically, the tendency to crystallize from a cooling molten mass or when reducing the amount of solvent is low. Both the devitrification and the fluidity of the molten mass at temperatures close to Tg can be controlled using modifiers such as other sugar derivatives and some organic active ingredients. Tables 1 and 2 show the glass transition and melting temperatures of various HDCs suitable for use in the compositions of the invention, used either as individual derivatives or in composite glasses (the data provided in the examples illustrating the solutions of the invention were used).
Table 1
<td>Substance / Glass</td><td>Melting point, ° C</td><td>Glass transition temperature, ° C</td><td>Molecular weight</td>
<td>SHAC</td><td> 100-104</td><td> -6</td><td> 434,4</td>
<td>α-GPAC</td><td> 109-111</td><td> 14</td><td> 390,3</td>
<td>β-GPAC</td><td> 130-131</td><td> 17</td><td> 390,3</td>
<td>OGTA</td><td> 50-52</td><td> -10</td><td> 460,5</td>
<td>TOAC</td><td> 101-103</td><td> 50</td><td> 678,6</td>
<td>TOPR</td><td> 47-48</td><td> 3</td><td> 790,6</td>
<td>SOAC</td><td> 87-89</td><td> 25</td><td> 678,6</td>
<td>COAC</td><td> 224-226</td><td> 65</td><td> 678,6</td>
<td>ORE</td><td> 87-88</td><td> 55</td><td> 966,9</td>
Table 2
<td>Glass arrangement</td><td>HDC molar ratios in glass</td><td>Glass transition temperature, ° C</td>
<td> 1</td><td> 2</td><td> 3</td>
<td>TOAC</td><td> 100</td><td> 50</td>
<td>ORE</td><td> 100</td><td> 55</td>
<td rowspan="4">α-GPAC TOAC</td><td> 10 90</td><td> 47</td>
<td> 25 75</td><td> 44</td>
<td> 50 50</td><td> 32</td>
<td> 75 25</td><td> 22</td>
184 068 cd table 2
<td> 1</td><td> 2</td><td> 3</td>
<td>SOAC: TOAC</td><td> 25 75</td><td> 41</td>
<td>COAC: TOAC</td><td> 25:75</td><td> 55</td>
<td>TOPR: TOAC</td><td> 22:78</td><td> 37</td>
<td rowspan="4">ORE: TOAC</td><td> 10:90</td><td> 52</td>
<td> 25 75</td><td> 53</td>
<td> 50:50</td><td> 52</td>
<td> 75:25</td><td> 54</td>
Delivery substrates containing combinations of different HDCs allow new delivery substrates with high Tg regulation and other physicochemical properties such as viscosity and resistance to degradation in water.
Combined delivery systems.
Solid dose delivery systems containing HDC and carbohydrate and / or other glass forming substances in complex compositions and other combinations are called combined delivery systems.
At least two types of combined delivery systems are prepared by making complex compositions of HDC and carbohydrate substrates to produce delivery systems. In one case, the microspheres of the carbohydrate delivery system are suspended in the HDC delivery system. In the second case, the microspheres of the HDC delivery system are suspended in the carbohydrate delivery system. These combined delivery systems allow the release of at least two different located substances, one hydrophobic and one hydrophilic, with at least two different release rates.
Other combined delivery systems are produced by coating one delivery system with another. For example, the implantable carbohydrate delivery system may be coated with an HDC layer or HDC delivery system to provide delayed release of the substance deposited in the carbohydrate delivery system or subsequent release of various deposited substances. The variety of such characters is very large. The number of coatings is theoretically unlimited and can be determined by specialists in the field.
Combined delivery systems can also be made by extruding hollow cylindrical substrates containing a space free from the substrate or delivery system (carbohydrate, HDC or combinations thereof). Such compositions are particularly useful for the production of injectable or implantable devices.
Other components of delivery systems.
Other glasses.
The delivery systems may further comprise at least one physiologically tolerated glass. Suitable glasses include (but are not limited to): carboxylates, phosphates, nitrates, sulfates, acid sulfates, HDC and combinations thereof. Carboxylates have been used up to now where glasses that slowly dissolve in water were required, since many of them are only poorly soluble in water. Suitable such glasses include (but are not limited to) those described in PCT / GB 90/00497. Until now, the production of these carboxylic glasses has been carried out only by quickly cooling the molten mass. The elevated temperature necessary to melt the carboxylates strongly limits the carboxylates in their applicability in the production of glassy delivery substrates, especially for biologically active substances that are prone to heat sensitivity. Surprisingly, it has been found that carboxylate glasses can easily be prepared by evaporating a carboxylate-containing solvent
184 068 metal forming the glass and the deposited substance to be embedded. Methods for preparing substrates and solid dosage systems involve dissolving the carboxylate component in a suitable solvent and evaporating the solvent to obtain glassy glass. Mixtures of carboxylates can be used, as well as mixtures of other glass forming components, to produce new delivery systems.
Delivery systems can also be coated with one or more layers of physiologically tolerated glass having predetermined dissolution rates. This is especially effective in cases of impulse release of deposited substances. The compositions may also contain other water-soluble and metabolizable glass forming substances. Suitable glass forming substances include (but are not limited to) lactides and lactide / glycolide copolymers, glucuronide polymers and other polyesters, polyorthoesters and polyanhydrides.
Placed substances.
Examples of types of deposited substances that can be used in media include industrial chemicals such as dyes and perfumes, and biologically active medical and agricultural substances suitable for in vivo and in vitro use. Suitable biologically active substances include pharmaceuticals, therapeutic and preventive agents, and agrochemicals such as anti-pest agents and pheromones.
Suitable pharmaceutical agents include anti-inflammatory drugs, analgesics, anti-arthritis drugs, antispasmodics, antidepressants, antipsychotics, sedatives, anxiolytics, anti-drug agents, anti-Parkinson agents, cholinergic agonists, chemotherapeutic agents, immunosuppressants. antiviral, antibiotics, appetite suppressants, anti-emetics, anti-cholinergic agents, antihistamines, anti-migraines, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, anti-coagulants, diuretics, antihypertensives, cardiovascular drugs, opioids, etc.
Suitable therapeutic and preventative agents include (but are not limited to) any therapeutically effective biological modifier. Such modifiers include (but are not limited to) subcellular compositions, cells, bacteria, viruses and molecules including (but not limited to) lipids, organic compounds, proteins and peptides (synthetic and natural), peptide mimetics, hormones (peptides , steroids and corticosteroids), polymers of the amino acids D and L, oligo-saccharides, polysaccharides, nucleotides, oligonucleotides and nucleic acids, including DNA and RNA, protein-nucleic acid hybrids, small molecules and their physiologically active analogues. In addition, these modifiers may, be derived from natural sources or may be produced recombinantly or synthetically, and include analogs, agonists and homologs.
The term protein as used herein also refers to peptides and polypeptides. Such proteins include (but are not limited to) enzymes, biopharmaceuticals, growth hormones, growth factors, insulin, monoclonal antibodies, interferons, interleukins and cytokinins.
Organic compounds include (but are not limited to) pharmaceutically active chemicals. For example, representative organic compounds include (but are not limited to) vitamins, neurotransmitters, antibacterial agents, antihistamines, analgesics and immunosuppressants.
Suitable steroid hormones include (but are not limited to) corticosteroids, estrogen, progesterone, testosterone and their physiologically active analogs. Numerous steroid hormone analogues are known and include (but are not limited to) estradiol and tamoxifen. Numerous steroid hormones such as progesterone, testosterone and their analogues are particularly suitable for use in the composition of the invention, because they are not absorbed transdermally and, with the exception of a few analogues, decompose when administered orally. first pass hepatic mechanism.
The term nucleic acids as used herein includes all therapeutically effective nucleic acids known in the art, including (but not limited to) DNA,
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RNA and their physiologically active analogues. These nucleotides can encode individual genes and can be any transfer known in the recombinant DNA industry, including (but not limited to) plasmids, retroviruses and adenoviruses. Preferably, the nucleotides are administered in the form of a powder from a solid dosage system.
The compositions of the invention constituting solid dose delivery systems may contain preventative biologically active substances and carriers. Preferred compositions include immunogens such as those used in vaccines. Preferably, these compositions suspend immunogenic amounts of the immunogen, effectively acting either to immunize or to assist vaccination.
Suitable immunogens include (but are not limited to) live and attenuated viruses, antigens encoding nucleotide transporters, bacteria, antigens, antigens and auxiliaries, and haptens associated with carriers. Particularly preferred are immunogens effective for inducing an immune response against diphtheria, tetanus, pertussis, botulinum toxin, cholera, denga, hepatitis A, C and E, influenza hemophilnus b, herpes virus, Heliobacterium pylori, influenza, Japanese encephalitis , meningococci A, B and C, measles, mumps, papillomavirus pneumococci, childhood paralysis, rubella, rotavirus, respiratory virus, Shigella, tuberculosis, yellow fever and their combinations.
Immunogens can also be produced by molecular biology methods to produce recombinant peptides or fused proteins containing one or more parts of a protein derived from pathogens. For example, fused proteins containing a given antigen and cholera toxin B subunit have been shown to elicit an immune response to a given antigen. Sanchez et al. (1989) Proc. Natl. Acad. Sci. USA 86: 481-485.
The immunogenic compositions preferably contain a certain amount of excipients sufficient to increase the immune response to the immunogen. Suitable excipients include (but are not limited to) aluminum salts, spinacene mixtures (SAF-1), muramyl peptides, saponin derivatives, mycobacterial cell wall preparations, monophosphoryl lipid A, mycolic acid derivatives, surface-active nonionic block copolymers, Quil A, cholera toxin sub-unit B, polyphosphazenes and derivatives and immunostimulatory complexes (ISCOM) as described by Takahasi et al. (1990) Nature 344 '873-875. The mitogenic components of Freund's excipient can be used for veterinary use and for the production of antibodies in animals.
As with all immunogenic compositions, immunologically effective amounts of these immunogens should be determined empirically. Factors considered include immunogenicity whether a given immunogen will be complexed or covalently bound to a given excipient or carrier protein or other carrier, the mode of administration, and the number of immunizing doses to be administered. Such factors are known in the field of vaccines and assays can also be performed efficiently by immunologists without undue experimentation.
If the deposited substances and / or substrates contain carboxyl and amino, imine or guanidine groups, it is preferred that the delivery systems also contain at least one physiologically tolerated Maillard reaction inhibitor in an amount effective to significantly prevent condensation of amino groups and carbonyl reactive groups in a given composition.
The Maillard reaction inhibitor is known to those skilled in the art. This inhibitor is present in an amount sufficient to prevent or significantly prevent condensation of amino groups and reactive carbonyl groups.
Usually, amino groups are found in biologically active substances, and carboxyl groups are present in carbohydrates, but it can also be the opposite. However, amino groups and carbonyl groups may be intravitreal, occurring either in the biological substance or in the carbohydrate. Various classes of compounds are known which exhibit a suppressive effect on the Maillard reaction and are therefore used in the compositions described herein. These compounds, in general, are either competing or co-competitive inhibitors. Competing inhibitors include (but are not limited to
184 068 them) amino acid residues (both D and L), combinations of amino acid residues and peptides. Lysine, arginine, histidine and tryptophan are particularly preferred. Lysine and arginine are the most effective. There are many known non-competitive inhibitors. These include (but are not limited to) aminoguanidine and derivatives, 4-hydroxy-5,8-dioxoquinoline derivatives and appropriate Maillard inhibitors such as those disclosed in EP-A-0 433 679.
Dosage forms.
The compositions of the invention may be such delivery systems that are sized and shaped suitable for penetration through the epidermis and suitable for ballistic delivery. Appropriate substrate sizes are therefore in the micrometer range, preferably in the range of 1-5 micrometer for diameter and 5-150 micrometer for length, which allows penetration and delivery through the epidermis to the subcutaneous, intradermal, intramuscular and intravenous tissue. It should be understood that with such dimensions, the delivery systems may look macroscopically as if they were in powder form, regardless of their configuration at the microscopic level.
Preferred configurations of ballistic delivery systems are microneedles and microfibers. The production of microfibers is relatively simple and economical and gives durable delivery systems containing glassy substrates and substances contained therein. Additional stabilizers, buffers, glasses and polymers can also be added during the processing as shown herein. Many of the most labile biological molecules can tolerate high temperatures well (e.g. 60-100 ° C), if they are stabilized by drying in trehalose, provided that the majority of their surface is in contact with the ground. Temperatures of 70 ° C can stand for over a month (Colaco et al. (1992) Bio / Technology 10: 1007-1011), and higher temperatures for shorter periods. The results presented there indicate that the fluorescent protein dried trehalose can be stored at 100 ° C for at least a month without a detectable decrease in functional activity. Other substrates provide protection at lower temperatures than trehalose. The maximum temperature of protection must be experimentally and in the circle of specialists in a given field done without unnecessary experience.
The microfibers produced by the process of the invention exhibit a relatively high ratio of dimensions, i.e. length compared to the diameter, preferably in the range of 1-5 microns for diameter and 5-100 microns for length. Such a high ratio of dimensions ensures increased penetration to the end in ballistic delivery due to the tendency of the microfibers to run parallel to the ballistic injector barrel, as described in more detail below. Longer macrofibers can be injected using conventional ballistic percussion devices or a trocar. Alternatively, macroscopic glass needles with sufficient internal strength may be directly inserted through the skin for subcutaneous, intradermal or intramuscular administration of deposited substances.
Other preferred solutions of the delivery systems include homogeneous microspheres, preferably of a narrow size distribution. This configuration is particularly useful when increased control of the penetration depth of the delivery system is desired. Such control is beneficial e.g. for intradermal, intramuscular and intravenous delivery of vaccines to the basal epidermis, to bring the antigen adjacent to the star cells of the spinous epidermal layer to elicit an optimal immune response.
Hollow fibers can also be used in the composition of the invention to deliver localized substances. Very fine, hollow needles can be made by drawing hollow billets in a furnace zone that locally softens the vitreous substrate. These needles can be filled with finely powdered, stabilized compound, by introducing this fine powder during the melting or drawing process. Hollow fibers can also be made of thermoplastic organic polymers and / or carbohydrates and / or HDC, which can themselves or slowly dissolve in water and / or metabolize.
Alternatively, the hollow substrate, consisting of a poorly water-soluble glass or plastic, is filled and optionally coated.
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Complex compositions of substrates and other poorly water-soluble substances may also be present in the solution of the invention. For example, complex substrate compositions with water-insoluble glasses such as phosphate, nitrate or carboxylate glasses, or metabolizable plastics such as lactide or lactide-glycolide copolymers will give slower eroding substrates for delayed release of biologically active substances.
Methods for producing delivery systems.
Provided the exposure time is limited, the deposited substances mixed with dry substrates can be heated to fluidize the glass, which can then be drawn or spun as fibers without damaging the product. The fibers can either be pulled from billets, cooled to solidify and then wound onto a drum, or they can be spun through small holes in a rapidly rotating cylinder that is heated above the melting point of the substrate. These fibers are inherently brittle and can easily be cut, broken, crushed or chopped to short lengths to produce long cylindrical rods or needles. By changing the diameter of the fibers produced, you can get needles that change from microneedles to macro-needles, i.e. from the thickness of a few micrometers to fractions of a millimeter. It has been found that cotton candy machines are suitable for the production of microfibers with small diameters. Although optimal conditions need to be determined experimentally for each substrate, such determinations are easy for specialists.
A variety of methods can be used to prepare the compositions of the invention in the form of microspheres, depending on the intended use of the delivery vehicles. Suitable methods include (but are not limited to) spray drying, freeze drying, air drying, vacuum drying, fluidized bed drying, milling, co-precipitation and supercritical fluid evaporation. In the case of spray drying, freeze drying, air drying, vacuum drying, fluid bed drying and supercritical liquid evaporation, the components (carbohydrate and / or HDC and / or other glass forming components, deposited substances, buffers etc.) are first dissolved in suitable solvents or suspends them in these solvents. In the case of milling, glasses made from these components either by evaporation of the solvent or by rapidly cooling the molten mass are ground in dry form and processed by any method known in the art. In the case of co-precipitation, these components are mixed in an organic medium and processed as described below.
Spray drying can be used to load the substrate with a localized substance. The ingredients are mixed in a suitable solvent and dried using precision nozzles to produce extremely uniform droplets in the drying chamber. Suitable spray drying devices include (but are not limited to) Buchi, NIRO, APV and Lab-plant spray dryers, used according to the manufacturers' instructions. Numerous carbohydrates are not suitable for use in spray drying, because the melting points of these carbohydrates are too low, which means that the dried amorphous substances attach to the sides of the drying chamber. In general, carbohydrates with a melting point lower than the spray drying chamber operating temperature are not suitable for spray drying. For example, palatinite and lactitol are not suitable for spray drying under conventional conditions. Determination of the suitability of carbohydrates can therefore be made on the basis of known melting points or determined experimentally. Such terms are within the reach of specialists.
An alternative way of producing microspheres is to prepare a homogeneous emulsion of the aqueous and organic phases, the substance deposited in the substrate solution as the aqueous phase and the glass-forming substance in the organic phase, or vice versa. The emulsion drops are then dried to form a solid solution of the deposited substance and the substrate in the amorphous matrix of the glass forming substance. In a variant of this method, the emulsion can be formed from a deposited substance in a solid solution in a substrate and two different glass-forming substances and / or polymers, dissolved together in one solvent. or dissolved in two separate solvents. The solvent (s) are then removed by evaporation to give a double or polyhedron
184 068 microspheres. Suitable methods for producing polyhedron microspheres are described, for example, in Pekarek im (1994) Nature 367: 258-260; and US 4,861,627.
The delivery system can also be dried from an organic carbohydrate solution and a hydrophobic placement substance to form a glass containing a homogeneously distributed deposited substance in a solid solution of a very fine suspension in poly glass. These glasses can then be ground or micronized to obtain microparticles of uniformly defined sizes.
The deposited substance and substrate can also be co-precipitated to obtain high-quality powders. Co-precipitation is carried out by spraying, e.g. with a spray gun, various components and / or polymeric glass-forming substances in a liquid, such as glacial acetone, in which none of them dissolves.
Another embodiment of the delivery substrate is a hollow substrate, consisting of glass or plastic, poorly soluble in water, filled and possibly coated with glass with carbohydrate and / or HDC and the deposited substance. Thin, hollow fibers of poorly water-soluble inorganic or organic glasses can be drawn from the hollow bite, and the finely powdered carbohydrate delivery system can be introduced during the process into the hollow center of the bite, and thus into the hollow center of the fibers.
Complex compositions of substrates and other water-soluble substances may also be present. For example, complex substrate compositions with water-soluble glasses, such as phosphate glasses (Pilkington Glass Company) or metabolizable plastics, such as lactide or lactide-glycolide copolymers, will provide slower eroding substrates for delayed release of deposited substances. To prepare such complex compositions, it is possible to thoroughly mix finely powdered glass containing a deposited substance with finely powdered carboxylate glass and sinter together. Alternatively, if the metal carboxylate glass has a lower melting point than the delivery system, the system can be uniformly deposited as encapsulated in the carboxylate glass while rapidly cooling the resulting molten mass. This can be ground to obtain a fine powder with an intermediate solubility between the relatively fast solubility of the substrate and the slow solubility of the carboxylate glass.
Alternative, complex compositions include the use of homogeneous suspensions of a finely powdered glass delivery system, encapsulated in a carboxylate glass by drying from an organic solvent in which the carboxylate dissolves and the amorphous powder does not dissolve to form carboxylate glass. This may be the basis for obtaining fine powders. which would contain a delivery system that dissolves relatively quickly, embedded inside slowly dissolving carboxylate glass (i.e. comparable to conventional slow release systems). Impulse release forms can be obtained either by repeating encapsulation cycles using glasses with different dissolution rates, or by mixing powders of a series of complex compositions with a desired range of release characteristics. It should be noted that glasses may also be drawn or spun to obtain microfibers or microneedles that would be slow release implants. It should be understood that any composition of the delivery system should be such that it is capable of releasing the deposited substance upon administration, and should not overly affect the stability of the administered substance.
Delivery substrates can be loaded with a localized substance by drying a solution of this localized substance containing enough substrate to form glass during drying. Drying can be by any of the methods known to those skilled in the art, which methods include, but are not limited to, freeze drying, vacuum drying, spraying, on a belt, air or in a fluidized bed. The dried material can be ground to a fine powder before further drying. processing this material using polyol glass or making a complex composition.
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Depending on the type of curing medium used, different dosing schedules can also be obtained. The delivery medium may provide for the rapid release of an intense dose of the deposited substance after administration if the delivery system is readily soluble. Complex compositions of substrates with glasses and plastics that are slowly water-borne, such as phosphate, nitrate or carboxylic glasses, and plastics and polyamide-glycolide, glucoronide or aolihydroxlip-matrix can provide slower dissolving substrates for slower release and prolonged dosage effects. By using hollow, slowly dissolving in water substrates, filled and coated quickly with roaauus / healing carbohydrate glass and / or HDC charged with the deposited substance, it is also possible to achieve the effects of shock and booster doses. Glass coatings charged with a deposited substance will dissolve quickly, giving the initial dosage effect. There will be no dosing when the hollow portion of the outer surface of the substrate dissolves, but after the initial shock dose there will be a booster dose of internal filling when the hollow outer font is moved by dissolution. This form of impulsive uwalmoplo is particularly preferred for the tuning of immunogenic compositions. If multiple-tuning effects are desired, delivery substrates can be constructed with any combination of layers of unnodified substrate and substrate loaded with deposited substances.
The delivery of more than one deposited substance can also be obtained by using a delivery system consisting of multiple coatings or layers of a substrate charged with various substances or mixtures thereof. Administration of solid dose dosing systems, the compositions of the present invention, can be used in conjunction with other, conventional treatment and co-administration of other therapeutic, preventive or diagnostic substances.
Suitable delivery methods for localized substances include (but are not limited to) topical, transdermal, transmucosal, oral, gastrointestinal, subcutaneous, ocular, intramuscular, intravenous, and inhalation (nasopharyngeal and pulmonary, including trans-bronchopulmonary and trans-vesicular) . Topical administration occurs e.g. by applying a dressing comprising the delivery system distributed therein, or by directly administering the delivery system to the cuts or open wounds. Creams or ointments containing slowly released beads or microspheres of the delivery system distributed therein are suitable for use as, e.g., topical ointments or wound filling agents.
Compositions for transdermal administration are preferably powders of delivery systems in the form of microneedles or microplates of uniform sizes. Larger, macuoscopic forms of needles and beads of delivery systems have also been established for subcutaneous implantation and prolonged drug delivery. The particle sizes should be small enough to cause only minimal skin damage during administration. Powdered forms of the delivery systems may be microneedles about 10-1000 micrometers in length and 1-150 micrometers in diameter. These powders can be packaged in single-dose, sealed and sterile packaging.
Suitable methods of intradermal administration include (but are not limited to) direct stroke and ballistic delivery, using trocar and liquid injection. For direct stroke access, precise macro-needles can be produced by methods well known in the inorganic glass industry, such as are used to make optical fibers. These needles can be stored in a precisely shaped, closed, used plastic container and directly inserted through the skin using a syringe. Ballistic administration is preferred because it is relatively painless. Typically, the delivery system is accelerated with a helium or other gas shock wave and shot into the epidermis. A suitable ballistic delivery device is described in PCT / GB 94/00753. A suitable liquid injector delivery device is the Medi-ject device [Diabetes Care (1993) Ib, 1479-1484]. Such a device - a liquid injector - is especially
184 068 useful for delivery systems with larger macro-needles that can also be delivered using conventional ballistic percussion devices or trocars.
During transdermal administration, the permeation rate of the delivery system can be controlled to some extent not only by the ballistic microinjector described below, but also by the shape and size of the powder particles. For example, if relatively uniform and less permeation is required, microspheres may be more suitable for practical use. On the other hand, if greater penetration is desired, then microneedle configurations may be more beneficial.
Due to the fact that the ratio of dimensions (i.e. length to diameter) is high for microneedles, they have larger masses than spherical particles of the same diameter. If they can be introduced by colliding with the skin to the end, their larger mass will give them a greater momentum of angularity at the same speed and thus they will penetrate deeper into the tissues. If the accidentally oriented microneedles are placed in the laminar gas stream, they will orient themselves in the direction of air flow, and in the case of a ballistic injector with pulses given by gas, this will ensure that the microneedles hit the skin at a right angle, ensuring penetration.
Delivery systems suitable for mucosal delivery include (but are not limited to) mucosal adhesion plates, films or powders, oral lozenges, pessaries and rings, and other vaginal or cervical delivery devices.
Compositions suitable for gastrointestinal administration include (but are not limited to) pharmaceutically tolerable powders, tablets, capsules and pills for consumption, and suppositories for rectal administration.
Compositions suitable for subcutaneous administration include (but are not limited to) various implants. Preferably, these implants are macroscopic in shape of discs, balls or cylinders to facilitate their insertion and may be fast or slow release implants. The entire implant dissolves in tissue fluids, so removal of the implant is unnecessary. In addition, implants do not contain synthetic polymers and are metabolized
Compositions suitable for ophthalmic administration include (but are not limited to) microsphere and macrosphere compositions, and saline drops, creams and ointments containing these microspheres and macrospheres, and rounded rods that conveniently fit into the lower conjunctival vault underneath the lower eyelid.
Compositions suitable for administration by inhalation include (but are not limited to) powdered forms of delivery systems. Preferably, these powders have a particle size of 0.1 to 10 microns. More preferably, the sizes of these particles are from 0.5 to 5 micrometers. Most preferably the particle sizes are from 1 to 4 microns. In particular, for pulmonary administration, the preferred particle sizes are 2.5-3 microns.
Carbohydrate-supplying powders preferably also contain effective amounts of physiologically tolerated molecular water pump (MWPB) buffer. MWPB is a physiologically tolerable salt that regulates water loss in the composition such that at ambient humidity the water vapor pressure of the crystallization water is at least 2000 Pa at 20 ° C and is not disturbed when forming the glass substrate. An effective amount of MWPB is such an amount, e.g. 50 mole% potassium sulfate, which reduces hygroscopicity sufficiently to prevent significant clumping. Sodium sulfate and calcium lactate are the preferred salts, and potassium sulfate is the most preferred.
Composite HDC delivery systems are particularly useful in inhalation dosage forms. For example, 10% (w / v) mixed delivery systems (aGPAC / TOAC are resistant to 95% relative humidity (RH), but they recrystallize on contact with liquid water and thus release all deposited substances into embedded traffic. This is particularly important for inhaled powders, as these powders can favorably devitrify and release deposited substances when in contact with water in the vesicles, but do not release them in the moist tracheal airways.
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The inventive compositions in the form of powders can be administered by means of nebulizers and evaporators filled with these powders. There are various devices suitable for use in the delivery of powders by inhalation. See e.g. Lindberg (1993) Summary of Lecture at Management Forum, 6-7 December 1993 Creating the Future for Portable Inhalers. Further devices usable herein include (but are not limited to) the devices illustrated in the following documents WO 9413271, WO 9408552, WO 9309832 and US 5,239,993.
Various other solid dose delivery systems are suitable for delivering a wide range of non-medical localized substances. For example, HDC glass, having incorporated agricultural substances, is dry during storage, even in tropical countries, but when in contact with liquid water on the surface of plants or soil releases antiseptics or biological regulation agents. HDC 'glass after incorporation of enzymes is useful as an additive to laundry detergents, because it stabilizes the enzymes even in high humidity conditions, and yet releases these enzymes immediately after contact with water.
A description of the figures in the drawings is given below.
Figure 1 is a graph showing the particle size distribution of micron trehalose glass powder suitable for administration by inhalation. Figure 1 is described in Example II.
Figure 2A is a graph showing a narrow particle size distribution of the glass trehalose powder / buffer salt of a molecular water pump (MWPB). Figure 2B is a graph showing the absorption of water by various glass powders of trehalose / MWPB and trnhalop / bed chloride after storage at ambient temperature and different relative humidity. Figure 2B shows: 51% relative humidity and MWPB (<sup>x</sup>), 80% relative humidity and MWPB (|), 51% relative humidity and chloride glass (□) and 80% relative humidity and chloride glass (X). Figure 2 is described in the example 'II.
Figure 3 is a graph showing a narrow particle size distribution of trehalose glass powder obtained by spray drying in a Laplant spray dryer. Figure 3 is described in Example II
Figure 4 is a graph showing a comparison of narrow particle size distributions of trehalose glass powders (0.5 M trehalose / 0.5 M calcium lactate) obtained in two different spray driers (Lab-Plant (□) and Buchi (a) as shown). Figure 4 is described in Example II.
Figure 5A is a graph showing the horseradish peroxidase resistance to acetone obtained by drying this enzyme from trehalose. Average values for cases are presented: without solvent (o), without solvent and without trehalose (O), acetone and trehalose (not squared at the bottom) and acetone without trehalose (squared at the top). Figure 5b is a graph showing the resistance of alkaline phosphatase on acetone, obtained by drying this enzyme with trehalose. In Figure 5, non-blacked circles mean no contact with solvent and trehalose, blackened circles means no contact with solvent and no trehalose, squares that are not blacked at the bottom mean average acetone and trehalose, and squares that are not blacked above mean mean acetone without trehalose. Figure 5 is described in Example III.
Figure 6 is a graph showing MB9 release from selected glassy metal carboxylate films. The squares represent the aluminum caproate film (100-200 microns), where the release precedes the dissolution of the film. The circles indicate a layer of calcium neocaprate (1-2 mm), where the release occurs after the film dissolves. Figure 6 is described in Example VII.
Figure 7 is a graph showing the release rate of the encapsulated Acid Blue 129 dye from an α-D-glucose pentacetate (α-GPAC) glass disc. Figure 7 is discussed in Example VIII.
Figure 8 is a graph showing the release of MB9 from a glass disc (6 mm x 2.5 mm) trehalose octacetate (TOAC) in PBS solution. Figure 8 is discussed in Example IX.
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Figure 9 is a graph showing the release of MB9 from TOAC / RUDA (trehalose octacetate / raffinose elevenacetate) matrix in deionized water. Different concentrations mean: 95% TOAC, 0.61% by weight of dye (□); 75% TOAC, 1.17% by weight of dye (O), 50% TOAC, 2.09% by weight of dye (a); TOAC alone, 1.39% by weight of dye (◊); and RUDA alone, 4% by weight of dye (V). Figure 9 is described in Example IX.
Figure 10 is a graph showing changes in Tg (glass transition temperature) versus TOAC mole% in a composition consisting of two HDCs. Squares represent trehalose octane acetate / sorbitan hexane acetate (TOAC / SHAC). The wheels indicate TOAC / RUDA lenses. Triangles denote trehalose octacetate / α-glucose pentacetate (TOAC / a-GPAC). Figure 10 is described in Example IX.
Figure 11 is a graph showing the average% MB9 release to PBS from selected TOAC / RUDA glass beads (n = 4). Squares represent 10% RUDA. The wheels represent 50% RUDA. Triangles mean RUDA itself. Figure 11 is described in Example IX.
Figure 12 is a graph showing Mb9 release (1% by weight) from composite TOAC compositions + 25% SOAC (□) and 25% COAC (♦) (n = 5). Figure 12 is described in Example IX.
Figure 13 is a graph showing MB9 (1 wt.%) Release from TOAC / a-GPAC in the following ratios: 90:10 (□), 75:25 (·), 50:50 (a) and 25:75 (V) (n = 4). Figure 13 is described in Example IX.
Figure 14 is a graph showing the release of MB9 from TOAC (□) and TOAC / TOPR (25% by weight) (·) (n = 5). Figure 14 is described in Example IX.
Figure 15 is a graph showing MB9 release (1% by weight) from TOAC (□) alone and TOAC and xPdO (5%) (·) (n = 5). Figure 15 is described in Example IX.
Figure 16 is a microscopic photograph of a thin film of glass with a complex composition, containing 10% trehalose in TOAC, dried from dimethylformamide (DMF). Figure 16 is described in Example X.
Figure 17 is a microscopic photo of the composite composition of Figure 16 at higher magnification. Figure 17 is described in Example X.
Figure 18 is a microscopic photo of a composite glass containing 10% trehalose in TOAC with methyl green and oil red O, dried from DMF. Figure 18 is described in Example X.
The inventive solutions are illustrated in the following examples.
Example I. Methods for producing solid glassy delivery systems based on microfibrous carbohydrate.
a) Preparation of carbohydrate microfibers
Glassy shaped lenses were prepared by drying under reduced pressure (10.6 Pa) for 16 hours, 20% solutions of trehalose, lactitol, palatinite or α-glucopyranosyl-1-6-sorbitol (GPS) containing MWPB and 1 mg / ml fluorescent algae protein, phycoerythrin. These moldings were ground in a home coffee grinder to give a coarsely ground powder that was used to fill the spinning head in a Kandy K1 Kandy Floss cotton candy machine (document GB 1 533 012). Then the engine was started and the powdered, glassy sugar was heated with the heating element set to a value between 5 and 9. The average residence time in the spinning head was from 2 to 10 minutes. Process continuity was maintained by continuous head filling.
The fibers produced were ground in a home coffee grinder. The obtained results are presented in Table 3, in which the average dimensions of the needles produced are given. The data show that for all three sugar glasses, as a result of the lowering of the heating element setting, smaller needles are obtained. During trehalose processing, setting 6 gave microneedles with an average diameter of 15 micrometers, and at setting 9, the microneedles had an average diameter of 40 micrometers. GPS processing at a setting of 9 gave microneedles with an average diameter of 15 microns. The microneedles formed from glasses containing buffer salts remained dry at ambient temperatures and humidity. Microneedles containing phycoerythrin retained biological activity as determined by fluorescence
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Table 3
<td>Analysis of the dimensions of mlórininłęó</td><td></td><td></td>
<td></td><td>Length (pm)</td><td>Width (pm)</td>
<td>Average</td><td> 192,60</td><td> 43,35</td>
<td>Standard error</td><td> 12,53</td><td> 2,33</td>
<td>Median</td><td> 167,5</td><td> 37,5</td>
<td>Value mhkal · aa</td><td> 137,5</td><td> 47,5</td>
<td>Standard deviation</td><td> 123,44</td><td> 22,91</td>
<td>Sample variance</td><td> 15237,75</td><td> 524,72</td>
<td>Rarities</td><td> 16,17</td><td> 2,55</td>
<td>slant</td><td> 3,35</td><td> 1,45</td>
<td>Compartment</td><td> 862,5</td><td> 115</td>
<td>Minimum</td><td> 67,5</td><td> 10</td>
<td>Maximum</td><td> 930</td><td> 125</td>
<td>Sum</td><td> 18682,5</td><td> 4205</td>
<td>Quantity</td><td> 97</td><td> 97</td>
<td>Confidence level (95,000%)</td><td> 24,57</td><td> 4,56</td>
b) Manufacture of two-component bedding and microfibers carbohydrate / organic matter.
A glassy mass was formed by drying meat / trehalose, sodium acetate and water (5: 1.1) under reduced pressure (10.6 Pa) for 16 gok / lg. This mass was ground in a home-made coffee grinder to give a coarsely ground powder that was used to fill the spinning head in the Random Floss Kando K1 machine. Then the engine was started and the powdered, glassy two-component product: carbohydrate / organic matter was heated with the heating element set to a value between 5 and 9. As in the case of pure vitreous trehalose, as a result of lowering the value of the heating element setting, microtubes with smaller diameters were obtained. The glassy masses of quusoleic mixtures can be designed as needed, obtaining masses with significantly different tensile properties compared to the corresponding glassy masses of pure trehalose. The average residence time in the spinning head was also between 2 and 10 minutes. Process continuity was maintained by continuous head filling. The obtained results show that differences in melting points and times of solubilization of these vitreous masses and in the physicochemical properties of microneedles can be obtained by changing both the carbohydrate molecules and the organic substance, as well as their proportions.
Example li. Methods for the production of solid, powdered glassy carbohydrate delivery systems.
a) Injection of the kgtncgy component into -oklihts / ogartcho carrier on a low carbon, to form microglossy powders.
Glassy masses were formed by drying 20% solutions of trehalose, lacitol, palatinite, α-D-glucopyranosyl-1 -> mannitol (GPM) or α-D-gluóopIragozyl-1-> 6-sorbitol (GPS) containing equimolar amounts of MWPB and protein freeze-drying technique at 10.6 Pa for 16 hours. These masses were pulverized in a Trost type grinder. Particle size measurements in micrograils were performed in the apparatus
184 068 laser Malvern Mastersizer. The results of the measurements showed that in micronized powders obtained from the original solution of 0.5 M trehalose and 0.5 M calcium lactate there is a monodisperse particle size distribution, with an average particle diameter of 1.1 microns (Fig. 1). Powders containing MWPB maintained free flow properties, showed no change in particle size, did not clump, did not absorb water under conditions of long-term storage at ambient temperature and humidity (Fig. 2A and Fig. 2B).
b) Introduce the active ingredient into a glassy carbohydrate based carrier to form spray dried powders.
20% trehalose solutions containing MWPB salts and protein (phycodrithrin) were dried in a Buchi or Lab-Plant spray dryer at a pump speed of 500-550 ml / hour and an inlet nozzle temperature of 180 ° C. Particle size was measured in a SympaTec laser apparatus. These spray dried powders had a monodisperse particle size distribution with a distribution peak narrow enough to be suitable for effective use as powder particles used in ballistic devices. In those shown in fig. 3 the results of particle size analysis of the spray dried powder obtained by spray drying a mixture of 0.5 M trehalose and 0.5 M calcium lactate in a Lab-Plant spray dryer shows an average particle diameter of 8.55 microns and a narrow peak of the resulting distribution.
A change in the average particle size can be achieved either by changing the composition of the spray dried mixture or the characteristics of the spray dryer nozzle. Figure 4 compares the results of particle size analysis of the spray dried powder as in Figure 3 with the spray dried powder prepared by drying the same mixture in a Buchi spray dryer using a different nozzle. Visible in fig. 4 the particle size distribution peak also has a narrow range, but the average particle size is currently 7.55 microns ·· '.
These data show that the particles obtained in various spray drying processes are equally well suited for use in orzhdowek compositions at ambient temperature and ambient humidity (Fig. 2A and Fig. 2B).
b) Incorporation of the active ingredient into a glassy support based on a stabilizing polyol to form spray dried powders.
20% trehalose solutions containing MWPB salts and protein (phycoerythrin) were dried in a Buchi or Lab-Plant spray dryer at a pump speed of 500-550 ml / hour and at an inlet nozzle temperature of 180 ° C. Particle size was measured in a SympaTec laser apparatus. These spray-dried powders had a monodisperse particle size distribution with a distribution peak narrow enough to be suitable for effective use as particles contained in the powder used in ballistic devices. In those shown in fig. 3 the results of particle size analysis of the spray dried powder obtained by spray drying a mixture of 0.5 M trehalose and 0.5 M calcium lactate in a Lab-Plant spray dryer shows an average particle diameter of 8.55 microns and a narrow peak of the resulting distribution.
A change in the average particle size can be achieved either by changing the composition of the spray dried mixture or the characteristics of the spray dryer nozzle. Figure 4 shows a comparison of the particle size analysis results of the spray dried powder as in Figure 3 with the spray dried powder prepared by drying the same mixture in a Buchi spray dryer using a different nozzle. Visible in fig. 4 the particle size distribution peak also has a narrow range but the average particle size is currently 7.55 microns.
These data show. that the particles obtained in various spray drying processes are equally well suited for use in compositions intended for ballistic delivery. It should be noted that the possibility of changing the particle size results in the possibility of preparing compositions with different penetration properties. This is particularly important in cases of intradermal, intramuscular or intravenous delivery, since penetration is a function of the momentum of the particle and distribution is a function of the particle size distribution.
c) Introduction of the active ingredient into a glassy support based on a stabilizing polyol, by drying from organic solvents.
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A solution of 50 mg / ml cyclosporin A (CSA) in a mixture of ethanol and water (1: 1) containing 20% trehalose was air-dried at ambient temperature to form a transparent trehalose glass containing CSA in solid suspension or in solid solution. This vitreous mass was ground to powder as described in Example 1. This powder retained the properties of free flow at ambient temperature and humidity. The addition of this powder to water caused trehalose to dissolve and a homogeneous, aqueous CSA suspension was formed.
d) Incorporation of the active substance into a vitreous support based on a stabilizing polyol by co-precipitation.
20% trehalose, lacitol, palatinite, GPM or GPS solutions containing MWPB and protein (phycoerythrin) were dried by spraying into a refrigerated acetone / dry carbon dioxide freezing bath system. Precipitated powders were separated by centrifugation or filtration and air dried to remove residual solvent. These powders also show a monodisperse particle size distribution and powders prepared with the addition of buffer salts remained dry at ambient temperature and humidity.
e) Preparation of a complex, glassy carrier of a hydrophobic active substance in a stabilizing polyol by drying from organic solvents.
Two different solvent systems were used to make vitreous composite masses ··. In the first case, cyclosporin A was dissolved in anhydrous ethanol and an equal volume of water was slowly added, whereby the cyclosporin precipitated with each addition of water could be released. Then trehalose in a 50% (v / v) ethanol solution, added in the amount needed to achieve a final 50% w / v concentration. Complex glass masses were obtained by evaporation of a mixed solvent on a hot plate at 70 ° C. In the second case, cyclosporin A and trehalose were dissolved in DMF and a glassy mass was also obtained by evaporation as described above. In both cases a slightly opalescent glassy mass formed. Water drops were applied to such glassy films to test the ro / release / release properties.
The obtained results indicate that these glass masses behave significantly differently. Glasses made of DMF did not absorb water and had a definitely hydrophobic surface. Gradually they formed cloudy patches and clumps of precipitated cyclosporin A if they were in contact with water. Glasses made of 50% ethanol were hydrophyte. They dissolved quickly in water and after dissolving the mist very fine particles of cyclosporin were released. This second glassy mass appeared to contain CSA either in the form of a fine, solid suspension or solid solution in a trehalose glass from which CSA is released as a precipitate after the trehalose has dissolved. This system represents a very useful dosage form for cyclosporin A, with high bioavailability due to a homogeneous and very fine format after release.
The different behavior of these vitreous masses of identical composition after drying from different solvents indicates an interesting and useful way to accurately control the patterns of different glass masses during evaporation of the solvent. Because CSA is more soluble in DMF than trehalose, complex glassy masses containing 10-120% CSA in trehalose made from this solvent tend to form hydrophyte trehalose cores and hydrophobic CSA shells. Conversely, after evaporation of 50% ethanol, the first losses of ethanol in the form of a 97% azeotrope cause CSA to leave the solution and surround it with trehalose syrup, which then solidifies as a continuous phase, giving CSA in a solid glassy trehalose emulsion.
Example III. Protection of proteins against organic solvent and elevated temperatures by drying in trehalose.
a) Protection of PCR and alkaline foseatfzy prase with acetone, by / on the trehalase.
0.1 mg / ml solution of horseradish aeraxase or 1 mg / ml solution of elicit phosphatase and 4 mg / ml bovine serum albumin yuy / it in loflli / atts FTS type, with or without the addition of 50% trehalose. The lyophil / ator was used as a vacuum dryer to dry the meat
184 068 without freezing them. A specified volume of solvent was added four times and the solution was evaporated to dryness. These residues were dissolved in 5 ml of water and the enzyme activity was determined by serial dilution using commercial reagent kits. The alkaline phosphatase assay kit was obtained from Sigma Chemical Co. and the horseradish peroxidase assay kit was obtained from Kirkegaard & Perry Laboratories, Inc. As shown in Fig. 5A and Fig. 5B, trehalose dried enzymes were more resistant to acetone than dried trehalose-free enzymes.
b) Protection of phycoerythrin against organic solvents by drying in trehalose.
The 400 µg / ml phycoerythrin solution was freeze dried in a Labconco freeze drier with or without 20% trehalose. The dry protein powder was exposed to various solvents for 72 hours. Phycoerythrin gave fluorescence in acetone, acetonitrile, chloroform and methanol. In pyridine, fluorescence persisted for a period of 24-48 hours, after which, within up to 72 hours, the compound began to moisten and lose fluorescence. The powder dissolved in dimethyl sulfoxide but the phycoerythrin fluorescence persisted.
c) Protection of phycoerythrin against 100 ° C by drying in trehalose.
The 400 µg / ml phycoerythrin solution was freeze dried in an FTS freeze dryer, with or without 20% trehalose. The dried protein was stored at 100 ° C for one month without loss of activity.
Example IV Preparation of a glassy, solid dose delivery system with a deposited substance incorporated into a glassy mass composed of a stabilizing polyol and / or hydrophobically derivatized carbohydrate (HDC) and / or carboxylate.
a) Co-forming a glassy, solid delivery system based on complex stabilizing polyol and glassy organic masses by evaporation.
Trehalose microparticles containing MB9 were prepared by spray drying as described in Example IIb. The dried solution contained 0.39 M trehalose and 0.14 M calcium lactate and 0.5% MB9. These particles were coated by adding them to a saturated solution of zinc palmitate (ZnCns) in toluene and cooling from 60 ° C to 30 ° C. The ZnCi6 film deposited on the particles. The product was filtered under reduced pressure to remove excess ZnCl2, washed with acetone and air dried. The resulting powder did not wet in water for at least three days (the particles floated on water without sinking or releasing MB9 and then slowly released the dye into the water). Thus, water-soluble powders can be prepared in a water-impermeable form by coating with metal carboxylates, such as ZnCl 6, to provide slow-release systems. It should be noted that the coating material is most likely in crystalline form and not in glassy form. Thus, the solid phase in which the deposited substances are suspended need not be in the vitreous phase in order for it to be impermeable to water.
b) Co-forming a glassy, solid delivery system based on glassy, stabilizing polyols, containing the active ingredient and glassy organic masses, by evaporation.
Powdered glassy trehalose containing phycoerythrin was added to a mixed carboxylate glass, namely to a 1: 1 mixture of sodium octanoate and zinc ethylhexanoate, dissolved in an excess of chloroform and evaporated in a stream of nitrogen at room temperature to give a carboxylate glass containing phycoerythrin powder in solid suspension or in solid solution. The glassy mass thus formed remained insoluble in water for at least 48 hours. Phycoerythrin powder retained its fluorescence properties in both the initial organic solution and the final glass.
c) Co-forming a glassy, solid delivery system based on glassy stabilizing polyols, containing the active ingredient and glassy organic masses by co-melting
Preformed organic glass prepared by rapidly cooling the melt of a mixture of sodium octanoate and zinc ethylhexanoate (1: 1) was softened at 95 ° C and powdered trehalose glass containing phycoerythrin was added to the alloy. The resulting mixture was immediately cooled on an aluminum block previously cooled to 15 ° C.
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Clear carboxyl glass containing microcapsules of phycoerytype powder retained biological activity. as demonstrated by the preservation of fluoues / entity properties. By suppressing the type and proportions of carbohydrate and organic residues in these co-formed vitreous masses, glasses with different slow release characteristics can be obtained, which was determined on the basis of different settling times in water.
d) Co-forming a glassy, solid delivery system based on glassy stabilizing polyols, containing the active ingredient and glassy hydrophobic carbohydrate derivatives by evaporation.
Release systems were prepared by spray drying in a Buchi B-191 spray dryer. Preformed, spray dried trehalose particles with dye MB 9 (1%) with a size of 6 μm (0.264 g) were suspended in a solution of trehalose octaocton, TOAC (4 g) and azobenzene (0.029 g) in 100 ml of dichloromethane and spray dried at the nozzle temperature 40 ° C. A turbid yellow hydrophobic powder was obtained consisting of TOAC glass with an azoCepzep yellow dye incorporated, with a milky glass bottle of trehalose glass containing blue MB9 dye. This complex delivery system carrier was characterized by delayed release of the water-soluble MB9 blue dye with intense color upon immersion in an aqueous solution.
e) Co-for-glassy, solid delivery system based on glassy stabilizing polyols containing active ingredient and plastics by evaporation.
Powdered trehalose glass containing phycoerythrin, prepared according to Example 1, was added to a forest solution dissolved in an excess of chloroform and evaporated under a stream of nitrogen at room temperature to give a solid block containing phycoerythrin powder in solid solution. This phycoerythrin powder showed fluorescence in both the initial organic solution and the reformed solid pleNiglas, which remained water impermeable even after 4 weeks. Similar results were obtained using the polyester dissolved in dichloromethane and the polyurethane dissolved in dimethyl sulfotape.
Example V. Production of hollow needles filled with delivery systems.
The end of a bundle of glassy trehalose tubes with internal holes filled with powdered trehalose glass containing phycoerythrin, prepared according to example 1, was melted in a zone furnace and the fibers were drawn on a metal drum rotating at a constant speed. The hollow fibers formed contained a finely powdered trehalose stabilized compound. They could be cut to any size. Such hollow fibers can also be made of a biodegradable thermoplastic material or of an organic compound or hydrophobically derivatized carbohydrate (HDC) and the diameter of the fiber production / h can be varied, filled needles with macro to micro needle sizes can be made, i.e. their thickness can be range from microns to millimeters. Hollow needles can be filled with any of the described active carriers for the active ingredient.
Example VI. Ballistic administration of solid active ingredient dose delivery systems.
Powdered vitreous masses were injected into the skin by means of recoil at supersonic speeds, using a shockwave / wave, created by the release of compressed gas. The powder was placed in a chamber attached to the large end of the funnel-shaped cavity and to the small end of this cavity a compressed gas cartridge was sealed sealed with Mylar polyester film. The supersonic (^ '^: ą shock wave was generated by breaking this Mylar film. Alternatively, self-timer controlled selenoid may be used to control helium release, which would allow operation at lower helium pressures. This is the principle used in the particle gun (PIG) developed by Finer, used for tuopsfoumovapowanie of plant tissues f ^ ain et al., Plant Cell Tissue and Organ Culture 33.237-246.1993).
Example VII. Manufacture of solid delivery systems based on organic glasses by solvent evaporation.
a) The production of scavengers / hokshulano-oxides is obtained by solvent stripping.
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Heósαgogiαn aluminum was dissolved in chloroform (0.5 g / 10 ml) together with a fine suspension of MB9, added in an amount of 1% by weight, used as indicator dye. A thin, amorphous film (100-200 pm thick) was formed by pouring onto silicone glass plates and evaporating the solvent in a stream of warm air. Release of the dye into distilled water was monitored for 5 hours. It is shown in Fig. 6. No clouding of these glasses was observed, the membranes remained transparent, although they became discolored as the dye diffused into the medium.
Amorphous membranes were also formed from calcium geodexagonate dissolved in chloroform (0.5 g / 10 mL) as described above. Dye release from these thicker films (1-2 nm thick) into distilled water was also monitored over 24 hours. This is shown in Fig. 6. Unlike aluminum membranes, dye release from calcium neokęóaogiag membranes occurred after dissolution of the membranes, as determined by Ca absorption spectroscopy.
b) Manufacture: complex, complex, doparch-based, glass-based glass containing active ingredients introduced into the carboxylate glass by evaporation.
Glucose glass films with MB9 dye incorporated in an amount of 1% by weight were melt-formed. These films were coated with thin (100 µm thick) amorphous metal carboxylate membranes by evaporation of a solution of carboxylate in chloroform (0.5 g / 10 mL). The metal carboxylates used were aluminum hexanoate and octanoate, calcium geocoalphonate, and magnesium isostearate and nękakaaogate magnesium. The dissolution of the film was monitored by releasing the dye into distilled water. Such release systems delayed the dye release by a time in the range of minutes to hours, with the exception of films formed with magnesium isosteariagage, delaying the dye release by 10 days.
Example VIII. Preparation of solid dosage systems based on hydrophobically derivatized carbohydrate (HDC).
A series of glassy HDC masses were made by melting and chilling. In the examples below, HDC components were from Aldrich Chemicals, with the exception of trehalose octane (TOPR), which was synthesized by the method described by Akoh et al. (1987). These components formed glazes with little or no decomposition. Fructose, sucrose and to some extent glucose melt with pronounced decomposition or with polymerization. An ester such as α-D-glucose pentaacetate is stable at its melting point and forms clear, colorless glass at high speed chilling. The greater stability of the ether and ester derivatives is an undoubted advantage in the micro-carbon balance of reactive organic substances such as pesticides and biocides.
HDC with particularly low melting points form a soft waxy glass when quickly cooled. It was shown that the NMR spectrum of the glassy (amorphous) αD-glucose tetraacetate is identical to the spectrum of the crystalline form of this compound.
The glassy mass formed from PD-glucose hegtaacetate is sparingly soluble in water and discs 20 mm in diameter and 2.5 mm in thickness made of this mass placed in flowing water lost about 33% of their original mass in 10 days. Another glass disk with similar dimensions was made from aD-glucose pentaacetate and placed in a liter of water changed once a day. After 7 days, the discs lost 20% of their original weight. The release rate from this glass enclosed in bubbles of this dye mass, acid blue, was a steel value as shown in Fig. 7. The dye release rate was higher on day one because the release was mainly from the surface of the discs.
Excellent recoveries of a number of organic substances enclosed in vesicles of these vitreous masses were obtained. Glassy discs of αD-glucose hentahctag containing 2% by weight of the substances listed in Table 4 were formed by melting, rapid chilling and subsequent milling. Phytochrome II is 5-chlorh-1,3-kihykrh-1,3,3-trimethyl-spiro [2H] -igol-2,3 '- [3H] -na: ft [^, 1-b] [1, 4] oxazin. The encapsulated substances were extracted with a suitable solvent such as methanol or water. The results are shown in Table 4.
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Table 4
<td>A substance enclosed in glass</td><td>Boiling point ° C</td><td>Temp. Melting point ° C</td><td>Application</td>
<td>Sour Yellow 65</td><td></td><td> >300</td><td>water-soluble dye</td>
<td>Acid Blue 129</td><td></td><td> >300</td><td>water-soluble dye</td>
<td>Red lasted 1</td><td></td><td> 161</td><td>no optical material</td>
<td>Mortar blue 9</td><td></td><td> >300</td><td>water-soluble dye</td>
<td>Hexad Ethyl waste</td><td> 168</td><td></td><td></td>
<td>Oktedd for ethyl</td><td> 207</td><td></td><td></td>
<td>Oksedlazdn</td><td></td><td> 90</td><td>insecticide</td>
<td>Azdbedzed</td><td> 293</td><td></td><td></td>
<td>melatonin</td><td></td><td> 117</td><td>veterinary hormone</td>
<td>FdtdeOadm II</td><td></td><td> 183</td><td>fdtdc0adm</td>
Acid blue 129 release rates were found to be dependent on the dissolution rate and shape of the glass discs. An insecticide such as oxadiazon dissolved easily and without difficulty in the melt of the glass in an amount of about 15% by weight.
Example IX. Melt forming and release properties of HDC-based glassy delivery systems.
a) Forming from seopu and whis twcici urs single-component mothers in zk) transparent glasses based on HDC.
In the following experiments, the delivery system was pre-formed either as a single material or as a composite composition.
This was done by thoroughly grinding the HDC components together, followed by careful, controlled melting in an oven in a temperature range of 120 ° C to 140 ° C at dormaldic pressure until alloying. These alloys were quickly cooled to a glassy mass by pouring onto brass plates. This vitreous mass was ground finely.
MB10 dye (1 or 5% by weight) was mixed with the ground glass mass before being re-melted at 140 ° C. Stop chilling to obtain small glassy beads (2.5 mm in diameter) that were used in controlled release experiments.
Codrelated release of the bulk dye was monitored by suspending three such beads in 25 ml or 50 ml deiodised water or a PBS solution at ambient temperatures (27-30 ° C) or at 37 ° C, as shown. The media were not mixed except for the batch mixer and exchanged for fresh media at set intervals (generally every 72 hours). One HDC and one HDC glass were made. The resulting composite HDC glasses are shown in Table 5. Dye release was determined by spectrophotometry (X max = 516 nm). The results are given in Figures 8 to 14. TOAC glasses show zero-order release characteristics. The use of other HDCs as glass modifiers in complex HDC forms allows these vitreous masses to be adjusted to meet the desired release characteristics.
Figure 8 shows the characteristics of zero order TOAC based delivery systems. The results given in Fig. 8 were obtained from TOAC glass disks (6 mm x 2.5 mm) containing uniformly dispersed MB9 dye in an amount of 2%
184 068 by weight. Release was determined at 25 ° C with gentle stirring and media replacement at specified intervals. Attention is drawn to the linear release of MB9 over 55 days. The results shown in Fig. 8 indicate that the transparent carrier system for release system containing pure HDC gives release rates of zero order active ingredients. The results presented in Fig. from 9 to 14 indicate fluctuations in release rates obtained by changing the proportion of different HDCs in the delivery systems, changing the length of the carbohydrate skeleton and changing the type of derivative on the carbohydrate skeleton. In either case, it is clear that the HDC-based delivery systems allow a wide range of release rates that can be matched to the deposited substance and its delivery.
Figure 9 shows the results obtained when in a release system the proportions of two different HDCs are different.
The release rate of MB9 determined from TOAC / RUDA (raffinose undecaacetate) matrices is shown in Figure 8. It appeared that the release rate is different for different compositions but is not directly dependent on the RUDA concentration. For example, the highest release rate was observed from masses containing 75% TOAC (25% RUDA) and the lowest release rate - from masses containing 95% TOAC. Thus, a suitable release rate from these delivery systems can easily be obtained experimentally.
Fig. 10 gives a comparison of the glass transition temperature (Tg) of three different HDC composite preparations together with the change in the amount of TOAC. Three different compositions were tested: TOAC / SHAC (sorbitol hexaacetate), TOAC / RUDA and TOAC / α-GPAC (α-glucose pentaacetate) increasing the molar percentages of TOAC. The results indicate that the Tg of these carriers increases with increasing molar percentages of TOAC in those composite forms that initially had a lower Tg, i.e. in TOAC / α-GPAC and TOAC / SHAC.
In Figure 11 the percent release of MB9 dye is compared from two different complex TOAC / RUDA compositions and from the RUDA form alone. RUDA has a biphasic release rate with an initial rapid release of about 60% of the dye over 5 days and a slow release of several remaining percent of the dye over the next 25 days. The release rate from a system based on RUDA alone is significantly modified in the presence of TOAC. The 50% RUDA system shows an almost linear release rate, higher than the 10% RUDA system release rate.
In Figure 12, the MB9 dye release rate from composite systems containing 75% TOAC and either SOAC (sucrose octaacetate) or COAC (cellobiose octaacetate) is compared to demonstrate the effect of carbohydrate skeletal change. The results indicate that the release rates can be changed in this way, with the composite TOAC / COAC system showing an increased release rate compared to the TOAC / COAC system.
In Figure 13, the MB9 dye release rate is compared from systems composed of two HDC components with different carbohydrate length, TOAC and α-GPAC. Release rates were not directly dependent on the percentage (weight%) of TOAC, with 50% TOAC being the lowest and 25% being the highest. In this case, too, the desired rates can easily be determined experimentally.
In Figure 14, the MB9 dye release rate is compared from two different HDC-based complex systems with the same carbohydrate but with other derivatives, TOAC and TOPR (trehalose octapropanoate). The addition of 25% TOPR to the TOAC-based delivery system has been shown to dramatically decrease the release rate of the deposited substance.
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Table 5
<td>Glassy system</td><td>MB weight percent</td><td>Temp.CC</td><td>Proportions (%)</td>
<td>EtOAc</td><td>1 and 5</td><td>room temperature, 37</td><td> 100</td>
<td>2 RUDA</td><td>1 and 5</td><td>room temperature</td><td> 100</td>
<td>3 TOAC / SOAC</td><td> 1</td><td>room temperature</td><td>75 (w)</td>
<td>4 TOAC / a-GPAC</td><td> 1</td><td>room temperature, 37</td><td>75 (w)</td>
<td>5 TOAC / COAC</td><td> 1</td><td>room temp</td><td>75 (w)</td>
<td>6 TOAC / TOPR</td><td> 1</td><td>room temperature</td><td>75 (w)</td>
<td>7 TOAC / e-GPAC</td><td> 1</td><td>room temp</td><td>75 (w)</td>
<td>8 TOAC / a-GPAC</td><td> 1</td><td>room temp</td><td>90.75.50.25 (mole%)</td>
<td>9. TOAC / RUDA</td><td> 1</td><td>room temperature</td><td>90.75.50.25 (mole%)</td>
b) Insertion of HDCs by rapid alloying.
Synthetic nortikzsteroIO, XPDO (described below) obtained in alloy
TOAC and rapid cooling with the emergence of s / nhytzgo, a permanent delivery system. Based on experiments with the release of MB9 into the aqueous solution, in these experiments the compatibility of the steroid with the glassy mesa, the subsequent steroid recovery and the effect of XPDO on the system properties of the delivery compared with the release of MB9 into the aqueous solution were examined. TOAC (3.21 g) was pre-melted at 150 ° C and then quenched to form glass. This mass was ground together with XPDO (0.15 g) and re-melted. The clear alloy was again quickly chilled to give a vitreous / encapsulated mass containing HDC and the active ingredient. Thermal analysis was performed in a different Rheometric Scientific (DSC) scanning method with a heating rate of 10 ° C / minute under α / ot atmosphere. The following samples were prepared:
1. TOAC / XPDO (5% lime)
2. TOAC / XPDO (d% by weight + MB9, (% wwggwyy
3. TOAC alone
4. TOAC / MB9 (2% by weight)
Tg = 50.6 ° C Tg = 50.9 ° C Tg = 50, 1 ° C Tg = 50.3 ° C
The release characteristics of these glassy solid HDC-based delivery systems were studied by monitoring the release of MB9 from TOAC / XPDO glasses, as shown in Figure 15. To analyze the stability of the active ingredient in these HDC-based glassy solid delivery systems, XPDO was recovered from of these samples by dissolving glass in acetonitrile and analyzing by HPLC. Full amount of substance deposited even after 4 weeks storage at 45 ° C.
Example X. Forming glassy, solid delivery systems based on HDC ar / z / evaporation ro / pus / c / ajniZa.
a) Form sketches HDC HDCZ I am solving roze uazczatΐll / a.
As described above, TOAC has been found to form a carrier with good delivery properties after rapidly cooling the melt. This delivery system has a low melting point and very little tendency to crystallize. Therefore, a number of experiments were carried out on TOAC glasses prepared by evaporation / dissolution on 3x1 inch sodium glass plates.
Dichloromethane (DCM) and chloroform are standard TOAC, which is also recognizable in other solvents, such as acetonyl. DCM was used for all subsequent experiments.
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Glass masses were prepared by evaporation of DCM on a hot plate set at 65 ° C with 25% TOAC solutions (crystals often deposited on the pipette tip from 50% solutions). Drying was carried out for 2 hours to ensure absolute dryness. Homogeneous glasses were made using an Eopeddorfk pipette, dakraolαj 100 μ 100 onto a movable plate placed on a hot plate and then about 50 μl was removed by using the cleaning-expelling space of this pipette. The glasses were very clear and adherent at the beginning but gradually recrystallized during the month at room temperature with a relative humidity of 50-60%.
Glassy trehalose masses, prepared similarly by evaporating water from a 50% trehalose solution, were clear immediately after production, but gradually recrystallized over several weeks.
b) Introduction of the active ingredient into HDC glasses by solvent evaporation; powders suitable for administration by inhalation.
XPDO is a steroid anti-inflammatory drug. Chemically, it is 6α, 9α-difluoro-11β, 21-dihydroxy-16a, 17α-oropyl-methylenedioxy-4-pregddd-3.20-dlod. XPDO crystallizes in the form of spirals, which are packed into needles, losing long , intramolecular voids, binding water molecules in a way that resembles zeolites. This makes the steroid sufficiently hygroscopic to exclude its use in a dry powder inhaler, which is the preferred method of administration. In amorphous (diecristalline) form, XPDO is non-hygroscopic but chemically unstable. Studies on the stabilization of this compound with trehalose have failed and no nidhigroskooljndgo powder could be produced.
XPDO was therefore introduced into TOAC glass by dissolving both crystalline TOAC and XPDO in DCM and evaporating the solvent at 70 ° C on a hot plate. XPDO was used in the proportions of 10% and 20% of the total solid mass in the final TOAC glass. These glasses were completely anhydrous and transparent. Stored under relative humidity of 75%, 81%, 90% and 95% for 4 weeks, they showed no changes in the vitreous structure, such as recrystallization.
However, after immersion in water, the surface of this glass slowly recrystallized. After 15-30 minutes after adding water, TOAC microcrystals of pyramidal shape were visible under the microscope. Crystallization slowly progressed and in the next few minutes small clusters of typical needle-shaped XPDO crystals appeared. Neither the needle-like XPDO crystals nor the TOAC pyramidal crystals adhered to the glass below. They were therefore washed easily, revealing the fresh glass surface for further slow dissolution. The complete elimination of XPDO from TOAC crystals has proven that this molecule, previously introduced into the TOAC matrix glass, has now been released into the liquid phase.
c) Introduction of the active ingredient into HDC glasses by solvent evaporation; spray dried powders, suitable for administration by inhalation.
Studies were carried out using a synthetic XPDO corticosteroid dissolved in DCM. The solution was dried in a Buchi B-191 spray dryer at a nozzle temperature of 40 ° C. A fine, amorphous, white powder was formed containing XPDO in a solid solution. The content of XPDO introduced was 20% by weight. This powder was completely amorphous, which was confirmed by thermal analysis (Tg = 66 ° C).
XPDO was extracted from the spray dried powder for analysis by dissolving the powder in acetonitrile and then further diluting the acetonitrile solution with sodium phosphate buffer. The analysis was carried out by HPLC. Samples were set up for XPDO stability tests in spray dried molds at 45 ° C and stored over saturated zinc sulfate (relative humidity: 80-85%).
To test the release of XPDO into the sodium phosphate buffer, an amount of 0.0868 g of spray dried powder was shaken in 10 ml of this buffer for a minute. The suspension was filtered through a 0.2 Pm filter. HPLC analysis showed that XPDO is effectively released into the aqueous solution. The bioavailability of this steroid from the test delivery system was studied by immersion in a short time in an aqueous solution. Stability of the steroid in dried form
184 068 was spray tested in high humidity conditions at 45 ° C (both factors are important for the successful use of this form as an inhalation powder. The results showed resistance to high humidity, durability in glassy mass and good bioavailability in in vitro studies. In the analysis by HPLC, no signs of degradation of the spray-dried glassy powder were observed even after 4 weeks storage at 45 ° C and 85% humidity.
d) Introducing the deposited substance into the HDC glasses by solvent evaporation; slow-release cyclosporin A.
Cyclosporin (CSA, Sandimune ©) is a hydrophobic, cyclic peptide used as an immunosuppressant, especially in organ transplantation cases. It is given orally or intravenously. It is dissolved in alcohol for administration. In clinical practice, blood levels of the drug fluctuate significantly due to unstable absorption from the proximal small intestine (jejunum). This difficulty could be overcome if CSA were released at a constant rate over many hours in absorbable form.
CSA was introduced into the TOAC glass by dissolving both crystalline TOAC and CSA in DCM and evaporating the solvent at 70 ° C on a hot plate. CSA was used in the proportions of 5%, 10% and 20% of the total solids in the final TOAC glass. These glasses were perfectly clear and transparent as water. Maintained at 75%, 81%, 90% and 95% humidity for 4 weeks, they showed no structural changes such as recrystallization. After immersion in water, these glasses behaved like glasses containing XPDO, i.e., they slowly recrystallized as separate TOAC and CSA crystals.
e) Forming glassy solid carriers of delivery systems based on composite HDC glasses by solvent evaporation.
In addition to TOAC, two other hydrophobic modified saccharides, α-GPAC and TOPR in mixtures were tested to obtain mixed glass with better properties.
Mixed glasses of these HDC vapors were made by mixing the crystalline components in various proportions and then preparing glass masses either by evaporation of DCM solvent on a hot plate or by melting at 150 ° and fast chilling on a brass plate.
The obtained glasses were tested by two methods towards their usefulness as matrices for controlled release systems. The first trial evaluated their resistance to turbidity as a result of exposure to high humidity at room temperature. In the second test, they were immersed in water or in phosphate buffered saline (PBS), examining their solubility and degree of erosion by surface recrystallization.
One-component glass α-GPAC and β-GPAC could only be produced by rapid alloying. In cases of solvent evaporation, the solutions of these HDC always crystallized. One-component TOAC and TOPR glasses were easily manufactured by evaporation of solvents or rapid chilling but they were very sensitive to clouding in high humidity conditions, showing complete crystallization of these glass films on microscope slides and surface recrystallization of fast chilled discs kept overnight at a relative humidity of 75% up to 95%. These mixed glasses behaved as shown in Table 6.
Table 6
<td>% GPAC</td><td>% TOAC</td><td>% TOPR</td><td>Initial Form</td><td>After 24 hours storage in humid conditions</td>
<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>
<td></td><td> 100</td><td></td><td>glass</td><td>++++ crystallization</td>
<td> 10</td><td> 90</td><td></td><td>glass</td><td>glass</td>
184 068 cd table 6
<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>
<td></td><td> 90</td><td> 10</td><td>glass</td><td>glass</td>
<td> 50</td><td> 50</td><td></td><td>glass</td><td>glass</td>
<td> 90</td><td> 10</td><td></td><td>crystallization ++++</td><td>not marked</td>
<td> 80</td><td> 20</td><td></td><td>crystallization +</td><td>crystallization ++++</td>
<td> 90</td><td></td><td> 10</td><td>crystallization ++++</td><td>not marked</td>
The obtained results indicate that the influence of different relative humidity values is very simple. While glass from pure TOAC and some composite glass crystallized at all humidity values from 75% to 95%, other composite glass remained amorphous at all relative humidity values tested.
Compositions containing 10% α-GPAC and 10% TOPR in TOAC glasses and compositions with a TOAC: α-GPAC molar ratio of 50:50 were also tested. They were immersed in water, determining the turbidity rate in water. No studies on the effects of moisture have been performed. The first glass recrystallized within 20-30 minutes, while the second one formed a few small crystals after 4 hours. In the composition glass with 50:50 component proportions, no changes were observed for 4 days, indicating remarkably low solubility.
As a carrier for powder drug delivery systems for deep lung areas, glass containing 10% α-GPAC in TOAC has highly desirable humidity resistance properties up to 95%, such as may occur in the inhaler and in the air flow in which, at the same time, rapid recrystallization occurs in water, e.g. in the liquid layer surrounding the alveoli.
TOAC glasses without or with the addition of 10% or more α-glucose hegtaoctag or trehalose octahrohoglycan have a wide range of resistance to ambient humidity and dissolution rates enabling them to some extent adapt to the requirements for controlled-release drugs dispersed in these glasses.
f) Wprowapz-mle saiad inka aatywacgo ne / localized composition Iki ^ eł<sup>1</sup> i / Dh SP with slow release by solvent evaporation.
For maximum usability, the slow release properties of HDC should be adapted to both hydrophobic and hydrophilic molecules. The former can easily be prepared in a solid solution of one of the HDCs either by evaporation of the solvent or by direct melt dissolution and subsequent rapid cooling. Hydrophyte particles are not directly soluble in HDC.
A very useful way has now been found to introduce hydrophilic substances into very Jękgorhkgzm, a useful distribution in HDC matrices. This process is well illustrated by the use of trehalose as a hydrophilic substance and TOAC as a hydrophobic matrix. DMF and DMSO are good solvents for both natural and modified trehalose. After evaporation to a dry residue of 10% trehalose and 90% TOAC, a glass of matte or opalescent appearance in DMF. Under the microscope, Jeknorokgy scattering of spherical, glassy mini-cylinders of Je'dna Cowzchch in a continuous matrix (Fig. 16 and Fig. 17) became apparent. By rough eyepiece measurement with a thread mesh the diameter of these micro beads was determined to be about 4 pm.
The identity of the two phases was confirmed by introducing a small amount of intensely hydrophobic lipid pigment, oil red O together with a small amount of hydrophyte dye, methylene green in DMF solution prior to glass production. As expected, the hydrophobic oil red O only entered the continuous phase, which was the TOAC phase, while the hydrophyte methylene green only entered the discontinuous, homogeneous trehalose particles, making them visible (Figure 18). Thus, composite, manufactured glass had a structure of very homogeneous and stable glass in a glassy solid emulsion either
184 068 in a solid suspension, not a solid solution, such as was seen in glasses containing deposited hydrophobic substances, XPDO, CSA or oil red O.
If the same mixtures of trehalose and TOAC were evaporated from the solution in DMSO, the appearance of this composite glass was different. In this case, the glassy mass was more transparent. and under the microscope, the discontinuous trehalose phase occurred in two forms. One form was a very fine suspension of extremely small trehalose particles homogeneously dispersed in a continuous matrix. The second form consisted of larger spherical trehalose beads clustered in a group in the center of this composite glass.
Without entering into any theoretical considerations, it appears likely that the different formulas observed reflect the differences in the solubility of these two carbohydrates in the solvents used, which causes them to separate from the solution at different stages of solvent evaporation. The evidence confirming this explanation was found during experiments with the production of composite glasses in the opposite orientation, i.e. vitreous masses in which the hydrophobic substance is finely dispersed in a hydrophilic continuous matrix.
g) Toxicity of HDC nightlist masses.
The toxicity of the saturated TOAC solution in deionized water (0.42 g in 20 ml) was determined in in vitro tests on the African monkey kidney Vero cell line, either at a 10-fold serial dilution or by adding TOAC powder directly to the cell culture medium. No toxic effects were observed during the weekly culture and cell division remained normal.
Inside 1
<img file="PL184068B1_D0001.tif" />
Inside 2
184 068
<img file="PL184068B1_D0002.tif" />
Hours
FIG. 2B
The volume decomposes
<img file="PL184068B1_D0003.tif" />
FI G.3
184 068
<img file="PL184068B1_D0004.tif" />
FI 0.4
absorbance
<img file="PL184068B1_D0005.tif" />
184 068
5.0-1
absorbance
40FI G.5B
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356 ~ <S, 4Ś9
37.6
dilution
184 068% release. The average percentage of MB9 release
<img file="PL184068B1_D0007.tif" />
Time (hours)
6 discloses
<img file="PL184068B1_D0008.tif" />
Time (days)
FIG.7
184 068
<img file="PL184068B1_D0009.tif" />
<img file="PL184068B1_D0010.tif" />
FI G.9
184 068
Average release percentage MB9 Glass transition temperature (° C)
<img file="PL184068B1_D0011.tif" />
<img file="PL184068B1_D0012.tif" />
Time (days) Fl G.11
184 068
Average percentage of MB9 release. Average percentage of MB9 release
<img file="PL184068B1_D0013.tif" />
12 is an
<img file="PL184068B1_D0014.tif" />
Time (days)
FI G.13
184 068
<img file="PL184068B1_D0015.tif" />
FI Θ.14
<img file="PL184068B1_D0016.tif" />
FI G.15
184 068
<img file="PL184068B1_D0017.tif" />
Figure 16
184 068
<img file="PL184068B1_D0018.tif" />
FIG 17
184 068
<img file="PL184068B1_D0019.tif" />
F IG.18
184 068
Decomposition density q 31 g Decomposition intensity (%)
<img file="PL184068B1_D0020.tif" />
FIG.1
Volume of distribution
<img file="PL184068B1_D0021.tif" />
.AND
UP Department of Publications. Circulation of 70 copies
Price PLN 6.00.
Contents12
34 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4 Sheet 5 Sheet 6 Sheet 7 Sheet 8 Sheet 9 Sheet 10 Sheet 11 Sheet 12 Sheet 13 Sheet 14 Sheet 15 Sheet 16 Sheet 17 Sheet 18 Sheet 19 Sheet 20 Sheet 21 Sheet 22 Sheet 23 Sheet 24 Sheet 25 Sheet 26 Sheet 27 Sheet 28 Sheet 29 Sheet 30 Sheet 31 Sheet 32 Sheet 33 Sheet 34
64 members in 24 offices
Priority claims12
| Document | Office | Kind | Date |
|---|---|---|---|
| 9415810 | United Kingdom | A | |
| 9415810 | United Kingdom | A | |
| 34902994 | United States of America | A | |
| 34902994 | United States of America | A | |
| 9501861 | United Kingdom | W | |
| 9501861 | United Kingdom | W | |
| 94349029 | – | – | – |
| 949415810 | – | – | – |
| 95GB9501861 | – | – | – |
| GB19940015810 | – | – | – |
| US19940349029 | – | – | – |
| WO1995GB01861 | – | – | – |
Members64
| Document | Office | Kind | |
|---|---|---|---|
| GB9415810D0 | United Kingdom | D0 | |
| CA2197982A1 | Canada | A1 | |
| WO9603978A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU3185195A | Australia | A | |
| FI970867A | Finland | A | |
| NO971688D0 | Norway | D0 | |
| NO971688L | Norway | L | |
| NZ290896A | New Zealand | A | |
| EP0773781A1 | European Patent Office (EPO) | A1 | |
| PL318898A1 | Poland | A1 | |
| SK27797A3 | Slovakia | A3 | |
| CZ47697A3 | Czechia | A3 | |
| EE9700062A | Estonia | A | |
| BG101278A | Bulgaria | A | |
| AU688557B2 | Australia | B2 | |
| MX9701394A | Mexico | A | |
| JPH10503769A | Japan | A | |
| AU7186498A | Australia | A | |
| HUT77777A | Hungary | A | |
| CN1204959A | China | A | |
| AU707605B2 | Australia | B2 | |
| US6290991B1 | United States of America | B1 | |
| EP1138319A2 | European Patent Office (EPO) | A2 | |
| EP1138337A2 | European Patent Office (EPO) | A2 | |
| US2001038858A1 | United States of America | A1 | |
| US6331310B1 | United States of America | B1 | |
| RU2177785C2 | Russian Federation | C2 | |
| US2002012687A1 | United States of America | A1 | |
| EE03593B1 | Estonia | B1 | |
| PL184068B1This record | Poland | B1 | |
| SK283026B6 | Slovakia | B6 | |
| EP1138319A3 | European Patent Office (EPO) | A3 | |
| US2003054040A1 | United States of America | A1 | |
| EP1138337A3 | European Patent Office (EPO) | A3 | |
| US6565871B2 | United States of America | B2 | |
| US6586006B2 | United States of America | B2 | |
| US2003147961A1 | United States of America | A1 | |
| EP0773781B1 | European Patent Office (EPO) | B1 | |
| AT252373T | Austria | T | |
| ATE252373T1 | Austria | T1 | |
| DE69531992D1 | Germany | D1 | |
| DK0773781T3 | Denmark | T3 | |
| US2004052825A1 | United States of America | A1 | |
| PT773781E | Portugal | E | |
| CN1152670C | China | C | |
| ES2208687T3 | Spain | T3 | |
| DE69531992T2 | Germany | T2 | |
| US6811792B2 | United States of America | B2 | |
| US2004219206A1 | United States of America | A1 | |
| EP1516615A2 | European Patent Office (EPO) | A2 | |
| US6893657B2 | United States of America | B2 | |
| US2005276759A1 | United States of America | A1 | |
| US2005276845A1 | United States of America | A1 | |
| US2005276846A1 | United States of America | A1 | |
| JP2006056898A | Japan | A | |
| US7056495B2 | United States of America | B2 | |
| CZ297431B6 | Czechia | B6 | |
| EP1516615A3 | European Patent Office (EPO) | A3 | |
| US2008193546A1 | United States of America | A1 | |
| NO326966B1 | Norway | B1 | |
| CA2197982C | Canada | C | |
| US7744925B2 | United States of America | B2 | |
| US7780991B2 | United States of America | B2 | |
| US7785631B2 | United States of America | B2 |
1 legal event, as the office reported them to INPADOC
Events
| Event | Code | |
|---|---|---|
| Decisions on the lapse of the protection rightsLapsedLAPS | LAPS |
Numbers
- Publication, DOCDB
- 184068
- Publication, EPODOC
- PL184068B
- Application
- 95318898
- Application, DOCDB
- 31889895
- Application, EPODOC
- PL19950318898
Titles2
- English
- SYSTEM SUPPLYING SOLID BODIES FOR CONTROLLABLE RELEASE OF PARTICLES BUILT IN INTO THEM AND METHOD OF OBTAINING SUCH SOLID BODIES
- Polish
- Kompozycja farmaceutyczna o wysokiej stabilności i sposób wytwarzania kompozycji farmaceutycznej o wysokiej stabilności
Classification
- CPC, 11
- A61K9/0036
- A61K9/0073
- A61K9/0021
- A61K9/006
- A61K9/0075
- A61K9/0092
- A61K9/145
- A61K9/1623
- A61K9/2018
- Y02A50/30
- A61K47/30
- IPC, 6
- A61K9 00
- A61K9 14
- A61K9 16
- A61K9 20
- A61K9 22
- A61K47 30
