Invented by Bruce J. Roser, Camilo Colaco, Mohammed A. Z. Jerrow, Julian Blair, Jaap Kampinga, James Lewis Wardell, John Alistair Duffy, Quadrant Drug Delivery Ltd
The Quadrant Drug Delivery Ltd invention works as followsThe present invention comprises solid dose delivery systems to administer guest substances. Preferred delivery systems can be used to deliver bioactive materials into subcutaneous, intradermal, and intramuscular tissue. The delivery system is sized and formed so that it can penetrate the epidermis. The delivery system comprises a glass vehicle that is loaded with the guest material and can release the guest material in situ at different controlled rates. “The present invention also includes methods for making and using solid dose delivery systems.
Background for Solid delivery system for controlled release molecules incorporated in them and methods to make same
Solid delivery systems can be used in many applications, including the controlled release of bioactive molecules such as enzymes, vaccines, and pharmaceutical agents. They are also useful for biological control agents like pesticides, fertilisers, and pheromones.
Solid dose delivery to biological tissues like mucosal and dermal tissues, as well as subcutaneous, intradermal, and pulmonary, offers several advantages over other methods, such as topical liquid applications, transdermal administration through so-called “patches” and hypodermic injection. Direct transdermal injection of solid doses can reduce the risk of infection, provide more accurate dosage than vials of multidoses, and eliminate or minimize the discomfort that is often associated with hypodermic infusion. “Several solid dose delivery methods have been developed, including those that use ballistic and transdermal delivery devices.
Topical delivery can be used for a wide range of bioactive materials, such as antibiotics to heal wounds. These topical creams, gels and ointments are all available in a variety of forms. Reapplication is necessary to maintain effectiveness. It is especially difficult to do this with burns and ulcers.
Devices for administering drugs via transdermal administration usually consist of laminated composites that have a reservoir layer containing the drug, with the composite adhering to the skin. No. 4,906,463. “However, transdermal drug delivery rates have not been optimized for many drugs, and those that are capable of it, neither.
In membrane-permeation-type controlled delivery, the drug is encapsulated in a compartment enclosed by a polymeric membrane that limits its rate of permeation. The reservoir can contain solid drugs or dispersion of solids in liquid or matrix dispersing media. The polymeric membrane can be made from either a nonporous homogeneous material, or a heterogeneous polymeric material. It may also be made using a semipermeable or microporous membrane. Encapsulation of a drug reservoir within the polymeric membrane can be achieved by molding, encapsulation or microencapsulation. The implants release the drugs through dissolution in the inner core, and diffusion slowly across the outer matrix. This type of implantable system is designed to release drugs at a relatively constant rate. Its drug release rate depends on either the rate of dissolution of the drug within the polymeric membrane, or the rate of diffusion across a semipermeable or microporous membrane. The outer matrix of the device does not dissolve. However, over time, the inner core can dissolve substantially.
Implants can be placed subcutaneously, by forcing the implant between the muscle and the skin. If the implants have not been dissolved by then, they are removed surgically. U.S. Pat. No. 4,244,949 describes an implant which has an outer matrix of an inert plastic such as polytetrafluoroethylene resin. Progestasert and Ocusert systems are examples of this type.
Other implantable therapeutic system involve matrix diffusion type controlled drug delivery. The drug reservoir is created by homogeneous drug dispersion in a lipophilic, hydrophilic or ionic polymer matrix. Dispersion of the drug in the matrix can be achieved by mixing the drug with either a viscous semi-solid or liquid polymer. The polymer is then cross-linked, or the drug and polymer are mixed at elevated temperatures. The polymer and/or drug particles can be dissolved in an organic solvent, followed by mixing the mixture and evaporating the solvent under high temperature or vacuum. This type of delivery system does not release drugs at a constant rate. This type of implantable system includes the Compudose implant and contraceptive vaginal rings. PCT/GB 1990/00497 describes glassy slow-release systems for the formation of implantable device. The implants described are bioabsorbable, and do not require surgical removal. The insertion method is surgical. These devices are also severely restricted in terms of the bioactive materials that can be used, as they must be resistant to heat or solvents to be incorporated into the delivery device.
In microreservoir dissolution-controlled drug delivery, the drug reservoir, which is a suspension of drug particles in an aqueous solution of a water-miscible polymer, forms a homogeneous dispersion of a multitude of discrete, unleachable, microscopic drug reservoirs in a polymer matrix. The microdispersion may be generated by using a high-energy-dispersing technique. This type of drug-delivery device releases the drug either by an interfacial separation or matrix diffusion controlled process. The Syncro-Mate C Implant is an example of a drug delivery device of this type.
Bioactive materials which cannot tolerate organic solvents should not be used in the manufacture of cast polymeric implant. Bioactive materials which cannot withstand high temperatures required to extrude polymer systems are not suitable for use. Bioactive materials that are unstable, especially over long periods of time, at body temperatures are not suitable for use.
A number of formulations are available for aerosolized administration to mucosal surface, especially?by-inhalation” (nasopharyngeal, pulmonary). By-inhalation compositions are generally composed of a liquid formulation containing the pharmaceutical agent, and a device that delivers the liquid aerosolized. U.S. Pat. No. No. 5,011,678 describes compositions suitable for a pharmaceutically-active substance, a biocompatible steroid amphiphilic and a biocompatible carbon propellant (hydro/fluoro). U.S. Pat. No. No.
One disadvantage of using aerosolized formulations, is that maintaining pharmaceutical agents in aqueous solutions or suspensions can cause aggregation. This leads to loss of bioavailability and activity. Refrigeration can partially prevent the loss of activity, but this reduces the usefulness of these formulations. This is especially true for peptides or hormones. Synthetic gonadotropin-releasing hormone (GnRH), such as nafarelin, or ganirelex antagonist, are designed to have high potency, increased membrane binding, and hydrophobicity. These compounds are hydrophobic enough to aggregate and form an ordered structure in aqueous solutions. Their viscosity increases with time. Bioavailability may be low in nasal or lung formulations. Powdered formulations can overcome many of these disadvantages. Powders of this size must be deposited in the deep alveolar spaces in the lungs. Powders with this particle size are prone to clump and absorb water, reducing the amount of powder deposited in deep alveolar spaces. Powders of larger particle sizes are ideal for the nasopharynx, but their tendency to clump reduces the surface area available for absorption by these membranes. There are devices that disaggregate clumps resulting from electrostatic interactions (e.g. the Turbohaler?) These devices do not break down moisture-induced clumps. “It would be beneficial to have powders that do not absorb moisture or clump together, increasing the pulmonary concentration.
Solid dosage delivery vehicles for transdermal, ballistic administration have also developed.” In U.S. Pat. No. A ballistic animal implant consisting of an outer polymeric shell encasing bioactive material for veterinary purposes is described in U.S. Pat. In U.S. Pat. No. A solid dose ballistic missile containing bioactive material without an external casing and a binder inert is disclosed under U.S. Patent No. 4,326,524. Delivery can be by explosion or compressed gas. U.S. Pat. also describes tranquilizing substances covered in gelatin and carried by ballistic projectiles to be implanted. No. 979,993. 979,993. These ballistic devices are however only suitable for large animal veterinary application due to the relatively high dose delivered.
Ballistic delivery on the cellular scale has also proven successful. Ballistic administration uses a supersonic gas wavefront to propel particles in an adjacent chamber. Nucleic acid adsorbed onto tungsten microprojectiles has been successfully delivered into living epidermal plants cells. See, Klein (1987) Nature 327:70-73. The particle inflow device (PIG) is a better-controlled device. Vain et al. Plant Cell, Tissue and Organ Culture, 33:237-246 (1993).
Devices that fire ampules with medication by using gas pressure have been described. U.S. Pat. No. No. A number of devices for injecting fluids are also described. U.S. Pat. Nos. Nos. Existing formulations for ballistic delivery are limited. Pharmaceutical powder formulations are not suitable for ballistic delivery. The particles of powders are irregular and vary in size, density, and shape. This lack of uniformity can lead to powder loss and deposit at the skin’s surface during administration. It also causes problems with control and consistency in the depth of delivery of subcutaneous and intradermal tissue.
It would be beneficial to have solid drug delivery systems with defined sizes, shapes, densities and dissolution rates for ballistic distribution to ensure a more uniform distribution. The shape of the vehicle can be adjusted to control or facilitate penetration of the epidermis, and the hard layers of skin. A small delivery system, coupled with a high-velocity delivery, will also improve comfort and minimize tissue injury. It is important that the solid dose delivery system be manufactured in a way that does not damage the guest substance or the delivery vehicle, nor reduce its efficacy. The guest substance must also remain stable within the vehicle or on it to ensure that the system can be administered effectively and stored. The manufacture of the solid-dose delivery vehicle, its loading with guest materials to obtain a system of solid-dose delivery and administration should be simple and inexpensive.
All references are hereby incorporated herein by reference.
The present invention comprises solid, glassy delivery vehicles that can be loaded with a variety of substances, or guests? to obtain solid delivery systems. Glassy delivery vehicles are chosen based on the guest substance and the desired delivery rate. There are many different types and rates of delivery. We also provide preferred guest substances, adjuvants, buffers and additional stabilizers. Delivery systems are available in a range of sizes and shapes to suit different modes of administration.
The invention consists of rapidly soluble solid dosage delivery systems containing a stabilizing Polyol (SP), and a guest material. These delivery systems are available in powders with homogeneous particles and larger implantable forms.
The invention further encompasses novel glassy vehicles formed from hydrophobically-derivatized carbohydrates (HDCs). These HDCs do not contain toxic substances and guests can be released from the systems over a long period of time. Release from HDC systems can be achieved by devitrification or dissolution, and/or through hydrolysis. “HDC delivery systems can be used to deliver hydrophobic substances like pesticides or pheromones. They are also suitable for peptides and peptide mimics. Antibiotics and organic pharmaceuticals including synthetic corticosteroids and bronchodilators, immunomodulators, and immunosuppressants such as cyclosporin A.
The invention also encompasses coformulations to create novel combination delivery system. Combination delivery systems are composed of HDCs in combination with SPs or other slowly water-soluble glassy materials such as carboxylate nitrate phosphate, to create solid dose delivery system with novel properties.Click here to view the patent on Google Patents.