A system by which a central hub and transport means, listing means, matching engine, and operating method will capture overstock and understock information from participating retailer or distributor nodes and create congruent matches, with subsequent shipments of one to the other to improve the inventory of both nodes.

The present invention relates generally to the field of product distribution, where imperfect stocking or manufacturing decisions can result in accumulations of excess inventory at some points, and deficiencies of inventory at other points. The present invention provides a system by which retailers and distributors can cost-effectively and profitably equalize inventory, facilitating the movement of items from geographic markets and participating nodes in which they are slow-moving to geographic markets and participating nodes in which they are faster moving, via a centralized transport system and transaction engine that acts as a virtual vendor.
There exists a spectrum of methodologies by which inventory is managed by multiple outlets, distributors, wholesalers, and manufacturers with multiple distribution points and channels, all intended to improve profitability of the overall system by improving the relationship between the cost of maintaining inventory and the revenue generated by that inventory. The systems and methods of the prior art attempt to manage inventory by forecasting and optimizing movement of inventory from manufacturer to consumer. These inventions are directed towards such things as systems and methods for managing the rate of use of inventory by a node in the system and calculating therefrom the proper time for ordering more inventory. And, systems and methods exist for moving inventory from storage to the sales floor, or as a return to the manufacturer, before the storage cost per item causes the retailer's profit to significantly diminish even further than any restocking charge imposed by the supplier (often called the "vendor").
United States Patent Application No. 2006/0195563 by Christopher Chapin, et al, entitled Peer to Peer Inventory Management System describes an inventory matching method and system by which overstock and understock inventory can be listed by similar retailers, and matches made enabling retailers with an overage of a given item to ship it to another retailer whose market seeks more than the normal supplier can deliver. That application describes a unique matching engine which can examine many thousands of listings by many thousands of nodes of a system, and efficiently make matches that solve congruent problems. However, that application requires that shipper and recipient become known to one another, and that the transaction include payment by the recipient to the shipper, and often that is inconvenient or impossible, particularly when those two nodes are also competitors or members of competing chains. That matching engine is exploited by the present invention, which addresses those deficiencies and permits transactions even between competitors.
U.S. Pat. No. 6,643,626, issued to Perri de Resende and titled Sales Point Business Method and Apparatus, generally describes remotely monitoring a display case having merchandise. The described purpose for remotely monitoring the display case is to assure that authorized users are accessing the merchandise, to monitor transactions involving the merchandise, and/or to provide security against theft, fire and other hazards. This invention allows for the remote monitoring of merchandise to detect the depletion of the merchandise, whether by desired or undesired means. The invention does not provide a means for managing the merchandise inventory amounts.
U.S. Pat. No. 6,405,177, issued to DiMattina and titled System for Securing Commercial Transactions Conducted On-Line, generally describes a system and method allowing on-line retailers to offer guaranteed financial services in addition to their goods. The financial services are such things as secure credit card transactions, price guarantees; guaranteed delivery and return policies and implied warrantee guarantees. The system for accomplishing this method comprises a purchaser-retailer transaction means, a single action ("one click") component, and a means for sending the financial services certificate to the purchaser. While this patent is related to selling an inventory and optimizes that process, it does not manage inventory.
United States Patent Application No. 2005/0075945, by Matsumoto et al. and titled Inventory Management and Ordering System, and Ordering Management System Using the Previous System, describes a system for managing a business inventory. The system monitors the quantity of an item inventory and the rate of use is determined so that future order dates can be predicted. Orders are placed based on the forecast, thereby keeping an adequate supply of an item. While this invention recognizes the need for inventory management, it focuses only on timely ordering of supplies to maintain an item on hand and provides no mechanism for rectifying errors.
United States Patent Application No. 2005/0033666, by Kurashige and titled Inventory Management Method and Program Product, generally describes a management server having an inventory database, a purchase database and a sales database. The server is designed to track certain inventory indicators and uses these indicators to move goods from inventory to sales. By tracking these indicators, inventory that is kept in storage can be moved to sales before the cost of the storage factored into each good diminishes the profits. It is desirable to keep products flowing from storage to the sales floor and in turn out the door. But, this does not address the problems of inventory that does not sell at one location, or inadequate inventory to meet demand at another.
United States Patent Application No. 2005/0004831, by Najmi et al. and titled System Providing for Inventory Optimization in Association with a Centrally Managed Master Repository for Core Reference Data Associated With an Enterprise, describes a system and method for developing an inventory plan for a supply chain. The supply chain is defined as the chain of participants beginning with suppliers including the manufacturers and vendors and ending with the consumer. The inventory plan is an optimized plan that assures that the members of the supply chain are able to predict proper inventory amounts based on a variety of defined metrics. If metrics reach a critical/problematic point, the plan is adjusted accordingly. New metrics can be added. This invention recognizes and addresses the problems with overstock and understock in a supply chain and attempts to develop a dynamic inventory plan that will prevent the occurrence of these problems. However, given the unpredictable nature of the consumer, this invention cannot address inventory problems that arise from an unexpected change in consumer demand, and does not provide a means by which inventory can be equalized between different nodes experiencing congruent problems (matching overstock and understock of the same inventory item).
At any level (manufacturer, distributor/wholesaler, or retailer), inventory excess is expensive, and there have evolved many business methods for dealing with the problem. The most visible is to discount the price from the planned one, motivating buyers in the chain to move the merchandise. A second solution is to return the inventory to the source—the manufacturer—and pay any imposed restocking charge. Both have the effect of reducing margins and therefore profits, but are better business method solutions than languishing and obsolescing inventory.
Another method for dealing with the problem is to package such obsolescing product, discount it, and ship it to off-price distributors and retailers, which has the same net effect of reducing margins and profits. Both of these steps have another effect that is highly negative and not as visible; branded merchandise appears for sale at a discount, which manufacturers (owners of such brands) work hard to prevent. Many brands are protected aggressively. There are often agreements between the distribution system and the manufacturer or importer intended to prevent such discounted sales, or transfers to distribution that is not pre-authorized by the manufacturer or importer, and violations of such agreements can cause termination of a sales franchise.
In the case of overstock, branded merchandise manufacturers often establish a buy-back program to help prevent discounting by authorized outlets, and to help prevent their merchandise from reaching discount outlets. Such returns come at a high price, however. First, they result in a credit against future orders, which does not help a cash-needy situation. Second, they are credited at a high discount compared to the original shipping invoice (15% or more, as a restocking charge). Third, retaining the right to sell a particular brand often requires maintenance of a certain volume of sales, and returns negatively impact that volume and can jeopardize retention of that sales franchise. Fourth, vendors/suppliers often control how the retailer can spend credits for returned merchandise.
Another business method that has emerged to deal with the problem is clandestine shipment by an authorized dealer in branded merchandise to an unauthorized dealer. This is usually a violation of the contract between the authorized dealer and the distributor or manufacturer, and sometimes occurs via nighttime transfers to trucks in alleys, but has the effect of converting excess inventory into ready cash. The risk is to the franchise held by the authorized dealer, but in the absence of trackable serial numbers that risk is small, and the result is a loss of brand protection.
Excess inventory is expensive, and its value decreases steadily. That decrease is often more rapid than the rate of sale of the stock, and waning sales revenue often will not replace the cost of buying the inventory in the first place. Tax authorities recognize the situation and permit deductions for obsolescing inventory, acknowledging that costly aspect of doing business in a supply-demand system where prediction is imperfect. A cost-effective business method that satisfies the problem would increase profit for every link in the supply chain.
For these reasons and more, all components of the system including manufacturers, wholesalers/distributors, and retailers seek ways and means to relieve the excess inventory problem.
One potential solution to a deficiency in inventory is to place an order for more. At the retail level, and sometimes at the wholesale/distribution level, this solution is often impractical. When the original imperfection in judgment resulted in one or two items selling out earlier than expected, or the unplanned success of a particular style or color of an item, it may not be cost-effective to place a re-order if there are minimum order quantities, or penalties when orders are below some threshold. Some items, in fact, may be orderable only in arrays that consist (as an example) of one gross of each color. When an item sells out in the two colors of a local university, for example, it may not be cost effective to order twelve gross, ten gross of which will languish along with the original shipment.
In many such cases, the deficiency remains unsatisfied because there is no method by which the order can be cost-effectively filled.
Further, re-order items may not be available at the factory or distributor level because they are back-ordered, closed out, or discontinued, resulting in lower profitability for the retailer whose inventory is comprised of partial size runs or limited color options, etc., making the product difficult to sell.
When all components of a distribution network are members of the same closed logistics system, and all are interconnected by inventory management software, communications, and logistics mechanisms (shipping means), software can be devised to (1) recognize inequities, (2) react to trigger points, (3) make recommendations to management, (4) monitor the logistical implementation of solutions, and (5) create data structures that suggest improvements to ordering protocols that lessen the likelihood of repetitive problems. There are prior art business methods by which closed/chain/franchise distribution systems can be optimized to reduce obsolescence, minimize investment in inventory, improve overall profitability, protect branding, and maintain brand franchises.
At the other extreme, a retailer with a franchise to sell protected branded merchandise will load excess merchandise onto a truck at night and ship it to another outlet, unauthorized by the brand manager, and despite any obligation to not do such illicit dealings. In a sense, this method is also "prior art".
Between these two points exist many different potential solutions, of which none works well enough to satisfy the preponderance of the inventory-balancing problems in the real world marketplace.
One problem with many existing inventory management systems is that they report to management when a given monitored item reaches a re-order level at a given location or storage point, but do not compare levels of different locations or storage points and report comparative levels.
Another problem with existing inventory management systems that monitor inventory levels at multiple sites is that they are not constructed to consider the value of the equalization of inventory between nodes (locations, or storage points, or distribution points).
Another problem is that many such systems do not provide a mechanism to recognize the cost of an overstock at one point, with aging and obsolescing inventory, with a simultaneous understock at a second point, with loss of sales due to nonavailability.
Another problem is that many such systems that do provide a mechanism that recognizes the importance of differential inventory levels, due to geographic preferences or errors made in placing orders, usually stop re-orders of obsolescing inventory and increase orders of understocked inventory, thus correcting the imbalance over time but in the least profitable manner.
Another fundamental problem with all such existing inventory management systems is that they apply exclusively to members of an integrated organization and not to transients or otherwise unaffiliated business units, and therefore the beneficiaries of such systems are only those who are part of that organization. For example, such a system that addresses the national distribution of product X might have the potential to do so for the organization that "owns and operates" the system, but not for the sole-site business that might benefit from its use, even if that sole-site's participation might assist the organization that operates the system by reducing its logistics costs.
One of the problems with known inventory balancing methods is that they normally affect ordering processes, reducing the input of an item that is stagnating and increasing the input of an item that is selling at unexpectedly high levels. This creates a substantial lag between the detection of a problem and the beginning of a solution, and the nature of the retail supply chain is such that lag is costly as it represents either stagnating inventory (cash that is not productive) or absent inventory (lost opportunity).
Another problem with known inventory balancing methods is that they are generally single-node, involving one business entity at a time, and can use only the flow rates at that location to correct the problem.
While many of the prior art inventory management and equalization solutions may be suitable to one degree or another for the particular limited requirements they address, they are not optimum or generalized solutions for broad and diverse multi-node retail, wholesale, and distributor markets. Nor do they meet the needs of transients passing through the system to satisfy inventory imbalance requirements, and are not sufficiently flexible to be adaptable to the needs of many potential users.
In view of the foregoing disadvantages inherent in the known types of inventory balancing, particularly as they might apply to cost-effectiveness, the present invention provides a new approach that overcomes deficiencies appearing in the prior art, and creates a new category of inventory balancing system with certain advantages and characteristics not available from those appearing in the prior art.
The main objective of the present invention is to provide an inventory balancing system, in a form, at a cost, and with such functionality as to improve the performance of the retail supply chain.
Another objective of the present invention is to provide a means by which overstock inventory that cannot be cost-effectively returned to the supplier or cannot be returned at all can be listed in an online database, while understock inventory that cannot be acquired from that same supplier can be similarly listed, and matches made to solve the problem of all participants.
Another objective of the present invention is to utilize a software matching engine that sorts through large numbers of such listings by many diverse and otherwise not coordinated nodes, to make matches whereby the same item is overstock in one location and understock in another location.
Another objective is to permit communication with a hub, comprised of a transportation means or Carrier that can efficiently pick up the overstock inventory and deliver it to the location where that same item is needed, in a manner that permits intimate cooperation between members of a chain, and also enables competing shippers and receivers to remain ignorant of the other's identity or location.
Another objective is to provide an accounting means by which the process is reported to central management of a chain, or when participants are not members of the same chain the account of the shipper is credited when the overstock inventory is picked up, and the account of the receiver is debited when that inventory is delivered.
Another objective is to provide a new source of revenue to the hub, which can impose a service charge on the shipping node (comparable to a restocking charge) and a shipping charge to the receiving node (comparable to the charge that the receiving node would pay if the shipment came from the original vendor).
Other objects and advantages of the present invention will become obvious to the reader and it is intended that these objects and advantages be within the scope of the present invention.
To the accomplishment of the above and related objects, this invention may be embodied in the forms illustrated in the accompanying specification and drawings. However, the specification and drawings are illustrative of the basic concepts only; there are many possible configurations and derivatives lying within the intended scope of the invention.


Bioerodible polyorthoesters useful as orthopedic implants or vehicles for the sustained delivery of pharmaceutical, cosmetic and agricultural agents contain hydrogen bonding groups and xcex1-hydroxy acid-containing groups.

1. Field of the Invention
This application relates to polyorthoesters. In particular, this invention relates to bioerodible polyorthoesters containing new diketene acetals and xcex1-hydroxy acid-containing groups.
2. Description of the Prior Art
Interest in synthetic biodegradable polymers for the systemic delivery of therapeutic agents began in the early 1970""s with the work of Yolles et al., Polymer News 1, 9-15 (1970) using poly(lactic acid). Since that time, numerous other polymers have been prepared and investigated as bioerodible matrices for the controlled release of therapeutic agents.
U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646 disclose biodegradable or bioerodible polyorthoesters. These polymers are formed by a reaction between an orthoester (or orthocarbonate) such as 2,2-diethoxytetrahydrofuran and a diol such as 1,4-cyclohexanedimethanol. The reaction requires elevated temperature and reduced pressure and a relatively long reaction time. Drugs or other active agents are retained in the polymer matrix to be released as the polymer biodegrades due to hydrolysis of the labile linkages.
U.S. Pat. No. 4,304,767 discloses polymers prepared by reacting a polyol with a polyfunctional ketene acetal. These polymers represent a significant improvement over those of U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646, since synthesis proceeds readily at room temperature and atmospheric pressure, and the resulting polymers have superior properties.
Further polymers are disclosed in U.S. Pat. No. 4,957,998. These polymers contain acetal, carboxy-acetal and carboxy-orthoester linkages, and are prepared by a two-step process beginning with the reaction between a polyfunctional ketene acetal and a compound containing a vinyl ether, followed by reaction with a polyol or polyacid.
Still further polymers of a similar type are disclosed in U.S. Pat. No. 4,946,931. The polymers are formed by a reaction between a compound containing a multiplicity of carboxylate functions and a polyfunctional ketene acetal. The resulting polymers have very rapid erosion times.
Despite the ease with which the orthoester linkage hydrolyses, polyorthoesters known in the prior art are extremely stable materials when placed in an aqueous buffer, or when residing in the body. This stability is attributable to the extreme hydrophobicity of the polyorthoesters which severely limits the amount of water that can penetrate the polymer. To achieve useful erosion rates, therefore, acidic excipients must be physically incorporated into the polymer. While this allows control over erosion rates, the physically incorporated acidic excipient can diffuse from the polymer matrix at varying rates, leaving a matrix that is completely depleted of excipient while the polymer still has a very long lifetime remaining.
U.S. Pat. No. 5,968,543 (Heller et al.) describes polyorthoesters containing xcex1-hydroxy acid-containing groups. The polyorthoesters are formed from the reaction of a diketene acetal such as 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) with at least 0.1 mol % of an xe2x80x9cxcex1-hydroxy acidxe2x80x9d diol and 0-99.9 mol % of one or more of a xe2x80x9chardxe2x80x9d diol and a xe2x80x9csoftxe2x80x9d diol (as those terms are used in the patent). These polyorthoesters are stated to have greater bioerodibility than similar polyorthoesters not containing the xcex1-hydroxy acid ester-containing groups, and to have the bioerodibility controllable by variation in the concentration of the xcex1-hydroxy acid ester-containing groups.
U.S. Pat. No. 4,549,010 (Sparer et al.) describes polyorthoesters containing functional groups which produce hydrogen bonding.
The disclosures of the documents listed in this section and elsewhere throughout this application are incorporated herein by reference.
In a first aspect, this invention is polyorthoesters of formula I:
where:
R is a bond, xe2x80x94(CH2)axe2x80x94, or xe2x80x94(CH2)axe2x80x94Oxe2x80x94(CH2)axe2x80x94; where A is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
R* is a C1-4 alkyl;
n is an integer of at least 5; and
A is R1, R2, R3, or R4, where
R1 is:
where:
p is an integer of 1 to 20;
R5 is hydrogen or C1-4 alkyl; and
R6 is:
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R7 is hydrogen or C1-4 alkyl;
R2 is:
R3 is:
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R8 is hydrogen or C1-4 alkyl;
R9 and R10 are independently C1-12 alkylene;
R11 is hydrogen or C1-6 alkyl and R12 is C1-6 alkyl; or R11 and R12 together are C3-10 alkylene; and
R4 is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
in which at least 0.1 mol % of the A units are R1.
In a second aspect, this invention is controlled release pharmaceutical compositions comprising:
(a) an active agent; and
(b) as a vehicle, the polyorthoester described above.
In a third aspect, this invention is a method of treating a disease state treatable by controlled release local administration of an active agent, in particular treating pain by administration of a local anesthetic or treating cancer by administration of a chemotherapeutic or antineoplastic agent, comprising locally administering a therapeutically effective amount of the active agent in the form of the pharmaceutical composition described above.
In a fourth aspect, this invention is methods of using the polyorthoesters of the first aspect of the invention as bioerodible implants.
In a fifth aspect, this invention is methods of preparation of the polyorthoesters of the first aspect of the invention and the controlled release pharmaceutical compositions of the second aspect of the invention.
It has now been discovered that polyorthoesters useful as orthopedic implants or vehicles for the sequestration and sustained delivery of drugs, cosmetic agents and other beneficial agents can be prepared in such a manner that the rate and degree to which they are hydrolyzed by contact with bodily fluids at normal body temperature and pH can be controlled without addition of exogenous acid. This discovery resides in the incorporation of esters of short-chain xcex1-hydroxy acids such as esters of glycolic acid, lactic acid or glycolic-co-lactic acid copolymer into the polyorthoester chain and variation of the amount of these esters relative to the polyorthoester as a whole.
In the presence of water, these esters, when incorporated into the polyorthoester chain, are readily hydrolyzed at a body temperature of 37xc2x0 C. and a physiological pH, in particular at a pH of 7.4, to produce the corresponding xcex1-hydroxy acids. The xcex1-hydroxy acids then act as an acidic excipient to control the hydrolysis rate of the polyorthoester. When the polyorthoester is used as a vehicle or matrix entrapping an active agent, the hydrolysis of the polyorthoester causes release of the active agent.
In addition, the mechano-physical state of the polyorthoester may also be controlled. This is achieved by the inclusion of the residues of certain diols in selected proportions relative to the polyorthoester as a whole. For example, a high content of the residue of trans-1,4-cyclohexane-dimethanol or a similar xe2x80x9chardxe2x80x9d diol relative to a xe2x80x9csoftxe2x80x9d diol (definition of which is given below) produces a relatively rigid polymer chain and a more solid substance, and by decreasing the trans-cyclohexanedimethanol content relative to the xe2x80x9csoftxe2x80x9d diol, the polyorthoester will change progressively through the stages of a rigid thermoplastic, a soft thermoplastic, a low melting solid to an ointment-like (viscous liquid) material, and any stage in between.
The polyorthoesters of the present invention are prepared by condensation reactions between diketene acetals and polyols, preferably diols, and the variation in mechano-physical state and rate of hydrolysis (bioerodibility) is achieved by the selection and use of combinations of different types of diols.
Definitions
xe2x80x9cActive agentxe2x80x9d includes any compound or mixture of compounds which produces a beneficial or useful result. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. Examples of active agents are pharmaceutical, agricultural or cosmetic agents. Suitable pharmaceutical agents include locally or systemically acting pharmaceutically active agents which may be administered to a subject by topical or intralesional application (including, for example, applying to abraded skin, lacerations, puncture wounds, etc., as well as into surgical incisions) or by injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection. Examples of these agents include, but not limited to, anti-infectives (including antibiotics, antivirals, fungicides, scabicides or pediculicides), antiseptics (e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride, nitrofurazone, nitromersol and the like), steroids (e.g., estrogens, progestins, androgens, adrenocorticoids, and the like), therapeutic polypeptides (e.g. insulin, erythropoietin, morphogenic proteins such as bone morphogenic protein, and the like), analgesics and anti-inflammatory agents (e.g., aspirin, ibuprofen, naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors, and the like), cancer chemotherapeutic agents (e.g., mechlorethamine, cyclophosphamide, fluorouracil, thioguanine, carmustine, lomustine, melphalan, chlorambucil, streptozocin, methotrexate, vincristine, bleomycin, vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin, tamoxifen, and the like), narcotics (e.g., morphine, meperidine, codeine, and the like), local anesthetics (e.g., the amide- or anilide-type local anesthetics such as bupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and the like), antiangiogenic agents (e.g., combrestatin, contortrostatin, anti-VEGF, and the like), polysaccharides, vaccines, antigens, DNA and other polynucleotides, antisense oligonucleotides, and the like. The present invention may also be applied to other locally acting active agents, such as astringents, antiperspirants, irritants, rubefacients, vesicants, sclerosing agents, caustics, escharotics, keratolytic agents, sunscreens and a variety of dermatologics including hypopigmenting and antipruritic agents. The term xe2x80x9cactive agentsxe2x80x9d further includes biocides such as fungicides, pesticides, and herbicides, plant growth promoters or inhibitors, preservatives, disinfectants, air purifiers and nutrients.
xe2x80x9cAlkylxe2x80x9d denotes a linear saturated hydrocarbyl having from one to the number of carbon atoms designated, or a branched or cyclic saturated hydrocarbyl having from three to the number of carbon atoms designated (e.g., C1-4 alkyl). Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and the like.
xe2x80x9cAlkylenexe2x80x9d denotes a branched or unbranched saturated divalent radical having from one to the number of carbon atoms designated (e.g., C1-C12 alkylene). Examples of alkylene include methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), isopentylene (xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94), n-octylene (xe2x80x94(CH2)8xe2x80x94) and the like.
xe2x80x9cBioerodiblexe2x80x9d and xe2x80x9cbioerodibilityxe2x80x9d refer to the degradation, disassembly or digestion of the polyorthoester by action of a biological environment, including the action of living organisms and most notably at physiological pH and temperature. A principal mechanism for bioerosion of the polyorthoesters of the present invention is hydrolysis of linkages between and within the units of the polyorthoester.
xe2x80x9cComprisingxe2x80x9d is an inclusive term interpreted to mean containing, embracing, covering or including the elements listed following the term, but not excluding other unrecited elements.
xe2x80x9cControlled releasexe2x80x9d, xe2x80x9csustained releasexe2x80x9d, and similar terms are used to denote a mode of active agent delivery that occurs when the active agent is released from the delivery vehicle at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon application or injection. Controlled or sustained release may extend for hours, days or months, and may vary as a function of numerous factors. For the pharmaceutical composition of the present invention, the rate of release will depend on the type of the excipient selected and the concentration of the excipient in the composition. Another determinant of the rate of release is the rate of hydrolysis of the linkages between and within the units of the polyorthoester. The rate of hydrolysis in turn may be controlled by the composition of the polyorthoester and the number of hydrolyzable bonds in the polyorthoester. Other factors determining the rate of release of an active agent from the present pharmaceutical composition include particle size, acidity of the medium (either internal or external to the matrix) and physical and chemical properties of the active agent in the matrix.
xe2x80x9cMatrixxe2x80x9d denotes the physical structure of the polyorthoester which essentially retains the active agent in a manner preventing release of the agent until the polyorthoester erodes or decomposes.
xe2x80x9cSequestrationxe2x80x9d is the confinement or retention of an active agent within the internal spaces of a polyorthoester matrix. Sequestration of an active agent within the matrix may limit the toxic effect of the agent, prolong the time of action of the agent in a controlled manner, permit the release of the agent in a precisely defined location in an organism, or protect unstable agents against the action of the environment.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease). For the purposes of this invention, a xe2x80x9cdiseasexe2x80x9d includes pain.
A xe2x80x9cunitxe2x80x9d denotes an individual segment of a polyorthoester chain, which consists of the residue of a diketene acetal molecule and the residue of a polyol.
An xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d unit denotes a unit where A is R1, i.e. in which the polyol is prepared from an xcex1-hydroxy acid or cyclic diester thereof and a diol of the formula HOxe2x80x94R6xe2x80x94OH. The fraction of the polyorthoester that is xcex1-hydroxy acid containing units affects the rate of hydrolysis (or bioerodibility) of the polyorthoester, and in turn, the release rate of the active agent.
xe2x80x9cHardxe2x80x9d, xe2x80x9csoftxe2x80x9d, and xe2x80x9chydrogen bondingxe2x80x9d units denote individual units of the polyorthoester, the contents of which relative to the polyorthoester as a whole determine the mechano-physical state of the polyorthoester. xe2x80x9cHardxe2x80x9d units are units where A is R2, xe2x80x9csoftxe2x80x9d units are units where A is R3, and xe2x80x9chydrogen bondingxe2x80x9d units are units where A is R4.
xe2x80x9cVehiclexe2x80x9d and xe2x80x9ccarrierxe2x80x9d denote an ingredient that is included in a composition such as a pharmaceutical or cosmetic preparation for reasons other than a therapeutic or other biological effect. Functions served by vehicles and carriers include transporting an active agent to a site of interest, controlling the rate of access to, or release of, the active agent by sequestration or other means, and facilitating the application of the agent to the region where its activity is needed.
The polyorthoesters are of formula I:
where:
R is a bond, xe2x80x94(CH2)axe2x80x94, or xe2x80x94(CH2)axe2x80x94Oxe2x80x94(CH2)axe2x80x94; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
R* is a C1-4alkyl;
n is an integer of at least 5; and
A is R1, R2, R3, or R4, where
R1 is:
where:
p is an integer of 1 to 20;
R5 is hydrogen or C1-4 alkyl; and
R6 is:
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R7 is hydrogen or C1-4 alkyl;
R2 is:
R3 is:
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R8 is hydrogen or C1-4 alkyl;
R9 and R10 are independently C1-12 alkylene;
R11 is hydrogen or C1-6 alkyl and R12 is C1-6alkyl; or R11 and R12 together are C3-10 alkylene; and
R4 is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
in which at least 0.1 mol % of the A units are R1.
The structure of the polyorthoester of the present invention, as shown in formula I, is one of alternating residues of a diketene acetal and a diol, with each adjacent pair of diketene acetal residues being separated by the residue of one polyol, preferably a diol.
In the presence of water, the xcex1-hydroxyacid containing units are readily hydrolyzed at a body temperature of 37xc2x0 C. and a physiological pH, to produce the corresponding hydroxyacids. These hydroxyacids then act as acidic catalysts to control the hydrolysis rate of the polyorthoester without the addition of exogenous acid. When the polyorthoester is used as a delivery vehicle or matrix entrapping an active agent, the hydrolysis of the polyorthoester causes release of the active agent.
Polyorthoesters having a higher mole percentage of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units will have a higher rate of bioerodibility. Preferred polyorthoesters are those in which the mole percentage of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units is in the range of about 1 to about 50 mole percent, more preferably from about 2 to about 30 mole percent, for example from about 5 to about 30 mole percent, especially from about 10 to about 30 mole percent.
Preferred polyorthoesters are those where:
n is an integer of 5 to 1000;
R5 is hydrogen or methyl;
R6 is:
xe2x80x83where s is an integer of 0 to 10, especially 1 to 4; s is an integer of 2 to 30, especially 2 to 10; and R7 is hydrogen or methyl;
R3 is:
xe2x80x83where x is an integer of 0 to 10, especially 1 to 4; y is an integer of 2 to 30, especially 2 to 10; and R8 is hydrogen or methyl;
R4 is selected from the residues of aliphatic diols of 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, interrupted by one amide, imide, urea, or urethane group; and
the proportion of units in which A is R1 is 1-50 mol %, preferably 2-30 mol %, more preferably 5-30 mol %.
While the presence of any of these preferences results in a polyorthoester that is more preferred than the same polyorthoester in which the preference is not met, the preferences are generally independent, and polyorthoesters in which a greater number of preferences is met will generally result in a polyorthoester that is more preferred than that in which a lesser number of preferences is met.
Expressed in terms of mole percent of the xe2x80x9chardxe2x80x9d or xe2x80x9chydrogen bondingxe2x80x9d unit relative to the polyorthoester as a whole, preferred polyorthoesters for liquid or ointment-like compositions are those in which the xe2x80x9chardxe2x80x9d or xe2x80x9chydrogen bondingxe2x80x9d unit constitutes about 20 mole percent or less. Likewise, preferred polyorthoesters for more solid compositions are those in which the xe2x80x9chardxe2x80x9d or xe2x80x9chydrogen bondingxe2x80x9d unit constitutes from about 60 mole percent to about 99.9 mole percent.
Polyorthoesters having a higher content of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d unit will have a higher rate of bioerodibility. Preferred polyorthoesters are those in which the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units constitute preferably from about 1 to about 50 mole percent, more preferably from about 2 to about 30 mole percent, for example from about 5 to about 30 mole percent, especially from about 10 to about 30 mole percent.
With respect to the individual xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d unit, p is preferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2; R5 is preferably hydrogen or methyl; and in the above definitions of R6, s is preferably 2 to 12, more preferably 2 to 6 and most preferably 2; and t is preferably 4 to 12, more preferably 4 to 6 and most preferably 6.
With respect to the individual xe2x80x9chardxe2x80x9d unit, HOxe2x80x94R2xe2x80x94OH is preferably trans-cyclohexanedimethanol.
With respect to the individual xe2x80x9csoftxe2x80x9d unit, in the definitions of R3, x is preferably 2 to 12, more preferably 2 to 6 and most preferably 2; y is preferably 4 to 12, more preferably 4 to 6 and most preferably 6; R8 is preferably hydrogen; R9 and R10 are preferably identical, more preferably an unbranched C4-C12 alkylene and most preferably an unbranched C6-C12 alkylene; R11 is preferably hydrogen, and R12 is preferably methyl.
Preparation of the Polyorthoesters
The polyorthoesters are prepared according to the methods described in U.S. Pat. Nos. 4,549,010 and 5,968,543. Specifically, the polyorthoesters are prepared by the reaction of a diketene acetal of formula II:
where L is hydrogen or a C1-3 alkyl, with a diol of the formula HOxe2x80x94R1xe2x80x94OH, and optionally at least one diol of the formulae HOxe2x80x94R2xe2x80x94OH, HOxe2x80x94R3xe2x80x94OH, and HOxe2x80x94R4xe2x80x94OH.
The rigidity or flexibility of the polyorthoester is determined by the proportions of the xe2x80x9chardxe2x80x9d and xe2x80x9chydrogen bondingxe2x80x9d units and xe2x80x9csoftxe2x80x9d units in the polyorthoester structure, with greater rigidity achieved by including greater proportions of the xe2x80x9chardxe2x80x9d and xe2x80x9chydrogen bondingxe2x80x9d units in the polyorthoester.
The bioerodibility of the polyorthoester is determined by the proportion of the hydrolyzable xcex1-hydroxy acid ester groups, with greater bioerodibility achieved by including greater proportions of the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units.
Thus, both characteristics of the resulting polyorthoester prepared from the reaction between the diketene acetal of Formula II and a mixture of the diols, are controlled by the ratio of quantities of the two to four types of diols in the diol mixture.
It is also understood that the present invention encompasses cross-linked polyorthoesters which are prepared by employing one or more polyols having more than two hydroxy functional groups. Such cross-linked polyorthoesters may be prepared preferably by first reacting the diketene acetal with a mixture of diols comprising a diol of the formula HOxe2x80x94R1xe2x80x94OH and optionally at least one diol of the formula HOxe2x80x94R2xe2x80x94OH, HOxe2x80x94R3xe2x80x94OH, and HOxe2x80x94R4xe2x80x94OH, followed by addition of the polyol(s) having more than two hydroxy functional groups. Alternatively, the polyol(s) having more than two hydroxy functional groups may be added simultaneously with the diol of the formula HOxe2x80x94R1xe2x80x94OH and other diols. Polyols having more than two hydroxy functional groups suitable for the preparation of the cross-linked polyorthoesters may be the straight or branched chain type, including polyhydroxyl compounds such as 1,2,3-propanetriol, 1,2,5-pentanetriol, 1,2,6-hexanetriol, 1,3,5-pentanetriol, 1,2,4-butanetriol, 1,4,7-heptanetriol, 1,5,10-decanetriol, 1,5,12-dodecanetriol, 1,2,3,4,5,6-hexane-hexol and the like. Other representative polyols of the type are described in U.S. Pat. No. 4,304,767. The reaction conditions (e.g., suitable solvents and reaction temperatures) and procedures for the preparation of the cross-linked polyorthoesters are similar to those described above for the preparation of the polyorthoesters employing only the diols, and are also described in U.S. Pat. Nos. 4,304,767 and 5,968,543.
The preparation of the diketene acetals of formula II is disclosed in Crivello et al., J. Polymer Sci., Part A: Polymer Chemistry, 34, 3091-3102 (1996); and will be known to a person of ordinary skill in the art. A typical method is the condensation of a bis(diol) of formula III:
with two equivalents of a 2-halocarboxaldehyde dialkyl acetal, such as 2-bromoacetaldehyde diethyl acetal, followed by dehydrohalogenation to give the diketene acetal. The condensation of a glycol with diethylbromoacetals is described in Roberts et al., J. Am. Chem. Soc., 80, 1247-1254 (1958), and dehydrohalogenation is described in Beyerstedt et al., J. Am. Chem. Soc., 58, 529-553 (1936).
The diketene acetals may also be prepared by the isomerization of divinyl acetals. The isomerization of the double bond is described in Corey et al., J. Org. Chem., 38, 3224 (1973). The divinyl acetals may be prepared by the condensation of the bis(diol) of formula III with two equivalents of a vinylic aldehyde, such as acrolein or crotonaldehyde, or their dialkyl acetals, such as acrolein dimethyl acetal, and such condensation reactions are well known. Thus, for example, 2,2xe2x80x2-divinyl-4,4xe2x80x2-bis(1,3-dioxolane) is prepared from the reaction of erythritol with acrolein in benzene/p-toluenesulfonic acid; and is subsequently isomerized to 2,2xe2x80x2-diethylidene-4,4xe2x80x2-bis(1,3-dioxolane) with tris(triphenylphosphine)ruthenium(II) chloride.
The bis(diol) of formula III where R is a bond is erythritol. The bis(diol) of formula III where R is xe2x80x94(CH2)axe2x80x94 may be prepared by the oxidation of an xcex1,xcfx89-diene, such as 1,3-butadiene or 1,5-hexadiene, with an oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or by other methods known in the art, to give the bis(diol). The bis(diol) of formula III where R is xe2x80x94(CH2)bxe2x80x94Oxe2x80x94(CH2)cxe2x80x94 may be prepared by the reaction of an xcfx89-hydroxy-xcex1-olefin, such as allyl alcohol, with an xcfx89-haloalkyloxirane, such as epichlorohydrin, to form an xcfx89-epoxy-xcex1-olefin with the backbone interrupted by an oxygen atom, such as 2-allyloxymethyloxirane, which is then oxidized with an oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or by other methods known in the art, to give the bis(diol).
The diols of the formulae HOxe2x80x94R1xe2x80x94OH, HOxe2x80x94R2xe2x80x94OH, HOxe2x80x94R3xe2x80x94OH, and HOxe2x80x94R4xe2x80x94OH are prepared according to methods known in the art, and as described, for example, in U.S. Pat. Nos. 4,549,010 and 5,968,543. Some of the diols are commercially available. The diol of the formula HOxe2x80x94R1xe2x80x94OH that comprises a polyester moiety may be prepared by reacting a diol of the formula HOxe2x80x94R6xe2x80x94OH with between 0.5 and 10 molar equivalents of a cyclic diester of an xcex1-hydroxy acid, such as lactide or glycolide, and allowing the reaction to proceed at 100-200xc2x0 C. for about 12 hours to about 48 hours. Although particular solvents are not required for this reaction, organic solvents such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and methylbutyl ether may be used. The preparation of diols, in particular the diol of the formula HOxe2x80x94R3xe2x80x94OH is generally disclosed in Heller et al., J. Polymer Sci., Polymer Letters Ed., 18, 293-297 (1980), by reacting an appropriate divinyl ether with an excess of an appropriate diol. Diols of the formula HOxe2x80x94R4xe2x80x94OH include diols where R4 is Rxe2x80x2CONRxe2x80x3Rxe2x80x2 (amide), Rxe2x80x2CONRxe2x80x3CORxe2x80x2 (imide), Rxe2x80x2NRxe2x80x3CONRxe2x80x3Rxe2x80x2 (urea), and Rxe2x80x2OCONRxe2x80x3Rxe2x80x2 (urethane), where each Rxe2x80x2 is independently an aliphatic, aromatic, or aromatic/aliphatic straight or branched chain hydrocarbyl, especially a straight or branched chain alkyl of 2 to 22 carbon atoms, especially 2 to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and Rxe2x80x3 is hydrogen or C1-6 alkyl, especially hydrogen or methyl, more especially hydrogen. Some representative diols of the formula HOxe2x80x94R4xe2x80x94OH include N,Nxe2x80x2-bis-(2-hydroxyethyl)terephthalamide, N,Nxe2x80x2-bis-(2-hydroxyethyl)pyromellitic diimide, 1,1xe2x80x2-methylenedi(p-phenylene)-bis-[3-(2-hydroxyethyl)urea], N,Nxe2x80x2-bis-(2-hydroxyethyl)oxamide, 1,3-bis(2-hydroxyethyl)urea, 3-hydroxy-N-(2-hydroxyethyl)propionamide, 4-hydroxy-N-(3-hydroxypropyl)butyramide, and bis(2-hydroxyethyl)ethylenedicarbamate. These diols are known to the art in reported syntheses and may are commercially available. Representative diols of the formula HOxe2x80x94(CH2)nxe2x80x94NHCOxe2x80x94(CH2)mxe2x80x94OH where n is an integer of 2 to 6 and m is an integer of 2 to 5 are made by the reaction of 2-aminoethanol, 3-aminopropanol, 4-aminobutanol, 5-aminopentanol, or 6-aminohexanol with xcex2-propiolactone, xcex3-butyrolactone, xcex4-valerolactone, or xcex5-caprolactone. Representative diols of the formula HOxe2x80x94(CH2)nxe2x80x94NHCOOxe2x80x94(CH2)mxe2x80x94OH where n and m are each integers of 2 to 6 are made by the reaction of the same aminoalcohols just mentioned with cyclic carbonates of the formula
such as ethylene carbonate. Bis-amide diols of the formula HOxe2x80x94Axe2x80x94NHCOxe2x80x94Bxe2x80x94CONHxe2x80x94Axe2x80x94OH are prepared by the reaction of a diacid, optionally in activated form, such as the diacyldihalide, with two equivalents of a hydroxy-amine. Other methods of preparation of the diols of the formula HOxe2x80x94R4xe2x80x94OH are known in the art.
Once made, the diol of the formula HOxe2x80x94R1xe2x80x94OH, and the diol(s) of the formulae HOxe2x80x94R2xe2x80x94OH, HOxe2x80x94R3xe2x80x94OH, and HOxe2x80x94R4xe2x80x94OH in the desired proportions are mixed with the diketene acetal of formula II, typically in a slightly less than 1:1 (e.g. 0.5:1-0.9:1) ratio of total number of moles of diketene acetal to total number of moles of diols, in a suitable solvent at ambient temperature. The condensation reaction between the diketene acetal and the diols is carried out under conditions which are described in, for example, U.S. Pat. Nos. 4,304,767, 4,549,010, and 5,968,543, and are well known to those skilled in the art; and will also be readily apparent from the structures of the reactants themselves. Suitable solvents are aprotic solvents, such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone, ethyl acetate, pyrrolidone, tetrahydrofuran, and methylbutyl ether, and the like. Catalysts are not required for this reaction, but when used, suitable catalysts are iodine in pyridine, p-toluenesulfonic acid; salicylic acid, Lewis acids (such as boron trichloride, boron trifluoride, boron trichloride etherate, boron trifluoride etherate, stannic oxychloride, phosphorous oxychloride, zinc chloride, phosphorus pentachloride, antimony pentafluoride, stannous octoate, stannic chloride, diethyl zinc, and mixtures thereof); and Brxc3x8nsted catalysts (such as polyphosphoric acid, crosslinked polystyrene sulfonic acid, acidic silica gel, and mixtures thereof). A typical amount of catalyst used is about 0.2% by weight relative to the diketene acetal. Smaller or larger amounts can also be used, such as 0.005% to about 2.0% by weight relative to the diketene acetal. Once the reaction is complete, the reaction mixture is allowed to cool and concentrated by rotoevaporation under vacuum. The concentrated mixture may be further dried under vacuum at an elevated temperature.
The polyorthoesters may also be prepared by reaction of the diketene acetal with the chosen diol(s) under similar reaction conditions, but in the presence of a xe2x80x9cchain stopperxe2x80x9d (a reagent that terminates polyorthoester chain formation). Suitable chain stoppers are C5-20 alkanols, especially C10-20 alkanols. The chain stopper is preferably present in from 1-20 mol % based on the diketene acetal. The polyorthoesters thus prepared have lower molecular weights with a lower molecular weight dispersion than those prepared by the reaction of the diketene acetals with only diols.
It is also understood that the present invention encompasses cross-linked polymers which are prepared by employing one or more polyols having more than two hydroxy functional groups. Such cross-linked polymers may be prepared preferably by first reacting the diketene acetal with a mixture of diols comprising a diol of the formula HOxe2x80x94R1xe2x80x94OH and optionally diols of the formulae HOxe2x80x94R2xe2x80x94OH, HOxe2x80x94R3xe2x80x94OH, and/or HOxe2x80x94R4xe2x80x94OH followed by addition of the polyol(s) having more than two hydroxy functional groups. Alternatively, the polyol(s) having more than two hydroxy functional groups may be added simultaneously with the diol of the formula HOxe2x80x94R1xe2x80x94OH and other diols. Polyols having more than two hydroxy functional groups suitable for the preparation of the cross-linked polymers may be the straight or branched chain type, including polyhydroxyl compounds such as 1,2,3-propanetriol, 1,2,5-pentanetriol, 1,2,6-hexanetriol, 1,3,5-peiitanetriol, 1,2,4-butanetriol, 1,4,7-heptanetriol, 1,5,10-decanetriol, 1,5,12-dodecanetriol, 1,2,3,4,5,6-hexane-hexol and the like. Other representative polyols of the type are described in U.S. Pat. No. 4,304,767. The reaction conditions (e.g., suitable solvents and reaction temperatures) and procedures for the preparation of the cross-linked polymers are similar to those described above for the preparation of the polymers employing only the diols, and are also described in U.S. Pat. No. 4,304,767.
The invention includes polyorthoesters which contain all four types of units as well as polyorthoesters containing from only the xe2x80x9cxcex1-hydroxy acid containingxe2x80x9d units, or a mixture of these units with only one or two of the xe2x80x9chardxe2x80x9d, xe2x80x9csoftxe2x80x9d, and xe2x80x9chydrogen bondingxe2x80x9d units. It also includes polyorthoesters prepared from a mixture of units which contains two or more diols of the same type.
Uses of the Polyorthoesters
The present polyorthoesters can be used for any use in which bioerodible polymers are usable, such as vehicles for the sustained release of an active agent or as orthopedic implants.
To use the polyorthoester as a sustained-release vehicle, the active agent must be incorporated into a matrix of the polyorthoester or encapsulated within a capsule (or a xe2x80x9cmicrocapsulexe2x80x9d or xe2x80x9cnanocapsulexe2x80x9d, as those terms are sometimes used) of the polyorthoester. Methods for the preparation of sustained-release dosage forms using biodegradable polymers are well known in the art, as discussed in the references cited in the xe2x80x9cDescription of the Prior Artxe2x80x9d section of this application, and in other references familiar to those of ordinary skill in the art; so that a person of ordinary skill in the art would have no difficulty, having regard to that skill and this disclosure, in preparing sustained-release formulations using the polyorthoester of this invention. Suitable active agents include therapeutic agents such as pharmaceutical or pharmacological active agents, e.g. drugs and medicaments, as well as prophylactic agents, diagnostic agents, and other chemicals or materials useful in preventing or treating disease. The compositions of this invention are particularly useful for the therapeutic treatment of humans and other mammals, but may also be used for other animals. In addition, the sustained-release compositions of this invention may also be used for the release of cosmetic and agricultural agents, or for the release of biocides, such as fungicides or other pesticides, into an environment where prolonged release of the active agent is desired.
In the case of matrix formulations, the polyorthoester is first mixed with the active agent. High homogeneity may be achieved by mixing the polyorthoester in its heat softened state with the active agent, followed by lowering the temperature to harden the composition. Alternatively, the polyorthoester can be dissolved in an appropriate casting solvent, such as tetrahydrofuran, methylene chloride, chloroform or ethyl acetate, and the active agent can then be dispersed or dissolved in the polyorthoester solution, followed by evaporating the solvent to achieve the finished composition. Another method is grinding a solid polyorthoester material into powder which is then mixed with a powdered active agent. The active agent may also be incorporated into the mixture of monomers before polymerization provided that it is stable under the polymerization conditions and does not interfere with the polymerization reaction. If the active agent is one that is unstable at elevated temperatures (e.g. above 40xc2x0 C.), or in the presence of organic solvents or organic solvent/water mixtures, such as a protein, then special preparation techniques may be required to minimize the exposure of the active agent to damaging conditions. Such techniques are disclosed in, for example, U.S. Pat. Nos. 5,620,697 (Txc3x6rmxc3xa4lxc3xa4 et al., assigned to Orion-Yhtyma Oy and Leiras Oy), which discloses ultrasonic melting to form matrix-type pharmaceutical compositions, and 5,518,730 (Fuisz, assigned to Fuisz Technologies, Inc.), which discloses melt-spinning, both of which techniques are designed to minimize the exposure of the polymer and active to elevated temperatures. Other methods are disclosed in the patents and literature references cited elsewhere in this application.
An alternate method for the incorporation and release of sensitive therapeutic agents is to use bioerodible polyorthoesters that have physical properties tailored for this incorporation. For example, the polyorthoester may be chosen so that it is semi-solid and has an ointment-like consistency, rather than being fully solid. Thus, a polyorthoester may be chosen that has a very high viscosity at normal body temperature of 37xc2x0 C. so that little if any deformation takes place at that temperature. However, the viscosity of the polyorthoester may decrease substantially at temperatures no higher than 45xc2x0 C., or preferably by 40xc2x0 C., so that injection of the material may be possible at a temperature at which the active agent retains its activity.
The composition obtained from any of the above methods can be readily processed into a variety of shapes and forms for implantation, insertion or placement on the body or into body cavities or passageways. For example, the polyorthoester composition may be injection molded, extruded or compressed into a thin film or made into devices of various geometric shapes or forms such as flat, square, round, cylindrical, tubular, disc, ring and the like. Rod- or pellet-shaped devices may be implanted through a trocar, such as is known for Norplant(copyright) implants, and these or other shapes may be implanted by minor surgical procedures. Alternatively, a device may be implanted following a major surgical procedure such as tumor removal in the surgical treatment of cancer.
The polyorthoester composition may also be injected by syringe subcutaneously or intramuscularly as particles of 0.1xcexc to 1000xcexc, preferably 0.5xcexc to 200xcexc, and more preferably 1xcexc to 150xcexc suspended in a pharmaceutically acceptable injection base. Liquid vehicles useful for suspending the drug-polyorthoester composition for injection include isotonic saline solution or oils (such as corn oil, cottonseed oil, peanut oil and sesame oil) which, if desired, may contain other adjuvants.
Another injectable dosage form may be prepared from an active agent mixed in with a polyorthoester of the present invention which has an ointment-like consistency. Such a dosage form may be administered by injection with or without a solvent.
The polyorthoester composition administered by either injection or implantation undergoes bioerosion in the body into non-toxic and non-reactive materials. By controlling the number of hydrolyzable bonds in the polyorthoester, the active agent may be released at a desired rate. Implants prepared from the present polyorthoesters in which the polyorthoester constitutes the matrix containing an active agent also have the advantage that they do not require removal because of the bioerodibility of the polyorthoester.
In some cases, particles with cores of the pure active agent coated with various thicknesses of the present polyorthoester may be preferred for sustained delivery of the active agent. Coating or encapsulation of discrete particles of the active agent may be accomplished by conventional methods which are all well-known to the person skilled in the art. For example, finely divided drug particles may be suspended in a solvent system (in which the drug is not soluble) containing the dissolved polyorthoester and other excipients, followed by spray drying. Alternatively, the drug particles may be placed in a rotating pan or a fluid-bed dryer and the polyorthoester dissolved in a carrier solvent is sprayed onto the drug particles until a suitable coating quantity is deposited on the particles to give a desired thickness. The coating may also be achieved by suspending the drug particles in a solvent system containing the dissolved polyorthoester followed by adding to the suspension a non-solvent causing the polyorthoester to precipitate and form a coating over the drug particles.
For the sustained release compositions, because the active agent will be released over a controlled period of time, the agent usually is present in an amount which is greater than the conventional single dose. The relative proportions of the active agent and the polyorthoester can vary over a wide range (e.g., 0.1 to 50 weight percent) depending on the therapeutic agent and the desired effect.
Sustained compositions of cosmetic and agricultural agents may also be prepared by any one of the methods as described above, using the polyorthoesters of the present invention.
The solid polyorthoesters (those containing a high percentage of the xe2x80x9chardxe2x80x9d unit and/or a high proportion of the xe2x80x9chydrogen bondingxe2x80x9d unit) are also useful for a variety of orthopedic applications. For example, they can be used as fracture fixation devices for repair of osteochondral defects, ligament and tendon reconstructions and bone substitutes. In addition, the fact that the present polyorthoesters permit simultaneous selection of both a desired level of their mechano-physical state and a desired rate of bioerodibility, also renders them attractive as grafts or scaffolds on which cells can be cultured in vitro prior to implantation to regenerate tissues. Tissues which can be regenerated using this approach include but not limited to, bone, tendon, cartilage, ligaments, liver, intestine, ureter and skin tissues. For example, the polyorthoesters may be used to regenerate skin for patients with burns or skin ulcers. Cartilages may be repaired by first isolating chondrocytes from a patient (or a donor), allowing them to proliferate on the scaffolds prepared from the present polyorthoester and re-implanting the cells in the patient.
The polyorthoester scaffolds or implants may further contain other biologically active substances or synthetic inorganic materials such as reinforcing filler material for enhancing the mechanical properties of the scaffolds or implants (e.g. calcium sodium metaphosphate fibers), antibiotics or bone growth factors to induce and/or promote orthopedic restoration and tissue regeneration.
The compositions are also stable. The release rates of the active agent are not affected by irradiation for sterilization.
Particular Compositions and their Uses
Exemplary compositions of this invention, and their uses, include:
(1) compositions containing local anesthetics, optionally in combination with glucocorticosteroids such as dexamethasone, cortisone, hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone, flunisolide, fluoconolone acetonide, fluocinonide, triamcinolone, and the like, for the prolonged relief of local pain or a prolonged nerve blockade. This use is discussed further below;
(2) compositions containing cancer chemotherapeutic agents, such as those listed above under xe2x80x9cActive Agentsxe2x80x9d, for deposition by syringe or by injection into tumors or operative sites from which a tumor has been ablated, for tumor control or treatment and/or the suppression of regrowth of the tumor from residual tumor cells after ablation of the tumor;
(3) compositions containing progestogens, such as flurogestone, medroxyprogesterone, norgestrel, norgestimate, norethindrone, and the like, for estrus synchronization or contraception;
(4) compositions containing antimetabolites such as fluorouracil and the like, as an adjunct to glaucoma filtering surgery; compositions containing antiangiogenic agents such as combrestatin, for the treatment of macular degeneration and retinal angiogenesis; and other compositions for the controlled release of ophthalmic drugs to the eye;
(5) compositions containing therapeutic polypeptides (proteins), such as insulin, LHRH antagonists, and the like, for the controlled delivery of these polypeptides, avoiding the need for daily or other frequent injection;
(6) compositions containing anti-inflammatory agents such as the NSAIDs, e.g. ibuprofen, naproxen, COX-1 or COX-2 inhibitors, and the like, or glucocorticosteroids, for intra-articular injection;
(7) compositions containing antibiotics, for the prevention or treatment of infection, especially for deposition into surgical sites to suppress post-operative infection, or into or on wounds, for the suppression of infection (e.g. from foreign bodies in the wound);
(8) compositions containing morphogenic proteins such as bone morphogenic protein; and
(9) compositions containing DNA or other polynucleotides, such as antisense oligonucleotides.
Delivery of Controlled-release Local Anesthetics by Injection
Local anesthetics induce a temporary nerve conduction block and provide pain relief which lasts from a few minutes to a few hours. They are frequently used to prevent pain in surgical procedures, dental manipulations or injuries.
The synthetic local anesthetics may be divided into two groups: the slightly soluble compounds and the soluble compounds. Conventionally, the soluble local anesthetics can be applied topically and by injection, and the slightly soluble local anesthetics are used only for surface application. The local anesthetics conventionally administered by injection can also be divided into two groups, esters and non-esters. The esters include (1) benzoic acid esters (piperocaine, meprylcaine and isobucaine); (2) para-aminobenzoic acid esters (procaine, tetracaine, butethamine, propoxycaine, chloroprocaine); (3) meta-aminobenzoic acid esters (metabutethamine, primacaine); and (4) para-ethoxybenzoic acid ester (parethoxycaine). The non-esters are anilides (amides or nonesters) which include bupivacaine, lidocaine, mepivacaine, pyrrocaine and prilocaine.
Many of the local anesthetics are conventionally used in the form of their acid addition salts, as this provides solubility in aqueous injection media. However, because the presence of the large amount of acid within such a local anesthetic acid addition salt will result in more rapid degradation of the polyorthoesters and release of the local anesthetic, it is generally desirable to use the local anesthetics in free base form, or with only a small proportion of the acid addition salt present (addition of small quantities of the acid addition salt may provide enhanced release if desired).
The semi-solid injectable form of a local anesthetic of the present invention is prepared by incorporating the local anesthetic into the delivery vehicle in a manner as described above. The concentration of the local anesthetic may vary from 1-60 wt. %, preferably 5-30 wt. %, e.g. about 10 wt. %. The semi-solid composition is then filled into a syringe with a 18-25 gauge needle, and injected into sites that are painful or to be subjected to surgical procedures. The semi-solid injectable composition of the present invention can be used for controlled delivery of both slightly soluble and soluble local anesthetics.
Because the duration of action of a local anesthetic is proportional to the time during which it is in actual contact with nervous tissues, the present injectable delivery system can maintain localization of the anesthetic at the nerve for an extended period of time which will greatly prolong the effect of the anesthetic.
A number of authors, including Berde et al., U.S. Pat. No. 6,046,187 and related patents, have suggested that the co-administration of a glucocorticosteroid may prolong or otherwise enhance the effect of local anesthetics, especially controlled-release local anesthetics; and formulations containing a local anesthetic and a glucocorticosteroid, and their uses for controlled release local anesthesia, are within the scope of this invention.

Bioerodible polyorthoesters from dioxolane-based diketene acetals


In a method for operating a SOFC high-temperature fuel cell, wherein a hydrogen-containing fuel is converted internally in the fuel cell by an endothermic reaction at the anode thereof into a synthesis gas, which is converted by an exothermic reaction into electricity, fuel is supplied to the fuel cell, to cool the fuel cell, in an excess amount such that, with a predetermined average current density flow, the fuel utilization degree is below 40%, whereas the oxygen is supplied stoichiometrically corresponding to the amount of electricity generating requirements. No additional coolants are therefore reqired for the cooling of the fuel cell.

The invention relates to a method of operating a fuel cell, wherein a hydrocarbon containing fuel is converted in the fuel cell into a synthesis gas with which the fuel cell is operated to generate electricity.
A fuel cell comprises a cathode, an electrolyte, and an anode. An oxidant such as air is supplied to the cathode and fuel such as hydrogen is supplied to the anode.
Various types of fuel cells are known as, for example, the SOFC fuel cell disclosed in the printed publication DE 44 30 958 C1 as well as the PEM fuel cell disclosed in the printed publication DE 195 31 852 C1.
The SOFC fuel cell is also called high temperature fuel cell since its operating temperature is up to 1000xc2x0 C. In the presence of the oxidant oxygen ions are formed at the cathode of a high temperature fuel cell. The oxygen ions pass through the electrolyte and combine at the anode side with the hydrogen and/or carbon monoxide from the fuel. Electrons are released in the process whereby electric energy is generated. These electrochemical reactions are highly exothermic.
The operating temperature of a PEM fuel cell is about 80xc2x0 C. At the anode of a PEM fuel cell, protons are formed by means of a catalyst in the presence of the fuel. The protons pass through the electrolyte and combine at the cathode side with the oxygen from the oxidant to form water. In this process electrons are released whereby electrical energy is generated.
For achieving a large electrical power output generally, several fuel cells are interconnected by connecting elements electrically and mechanically. An example for such a connecting element is the bipolar plate known from DE 44 10 74 C1. With bipolar plates, fuel cells, which are connected electrically in series, are stacked on top of one another. Such an arrangement is called a fuel cell stack.
As fuel, among others, methane and methanol may be provided. The fuels mentioned are converted for example to hydrogen or hydrogen-rich gas by reformation or oxidation.
It is known from DE 195 198 47 C1 to reform a fuel-like methane internally that is directly at, or within, the anode of a SOFC fuel cell. Alternatively, fuel is reformed in the interior of a fuel cell stack that is in additional chambers of a fuel cell stack (integrated reformation). With the internal or respectively, integrated reformation reaction, the endothermic reformation reaction is to draw the required heat from the exothermic electrochemical reaction. In this way, high efficiencies are to be achieved.
The printed publication DE 196 46 354 A1 discloses that fuel such as methanol can be oxidized at the anode of a PEM fuel cell by means of a catalyst such as platinum whereby hydrogen is released. The effects are comparable with those of the internal or integrated reformation.
It is practically impossible to convert a fuel such as hydrogen and/or carbon monoxide in a fuel cell completely to an electric current. The exhaust gas, which leaves the anode space of a fuel cell, will always contain a rest of the electrochemically active fuels mentioned above. The experts however are striving to minimize this rest of fuel in the exhaust gas.
A measure herefor is the fuel utilization degree, which is defined as follows:       BN              xe2x80x83        [    %    ]    =      1    -                            (                                    2                                                              n                  .                                H2                                      +                          2                                                              n                  .                                CO                                      +                          8                                                              n                  .                                CH4                                              )                                  xe2x80x83                        exit                              (                                    2                                                              n                  .                                H2                                      +                          2                                                              n                  .                                CO                                      +                          8                                                              n                  .                                CH4                                              )                                  xe2x80x83                        entrance
Wherein {dot over (n)} indicates the respective mole flows in mol/h.
From EP 0 398 111 A a fuel cell arrangement is known, wherein O2 and ballast gases as well as fuel are introduced into the fuel cell in excess and the gases are partially recirculated. In this way, fuel utilization degrees of about 90% can be achieved.
In the carbonate fuel cell known from DE 690 06 458 T2 natural gas is reformed internally within cooling plates which are arranged within the fuel cell. The fuel utilization degree achieved in this way is about 85%.
It is further known to introduce pre-reformed fuel into a SOFC fuel cell with internal reformation. Fuels such as natural gas whose main component is methane is partially externally reformed. A mixture of methane and the hydrogen-rich synthesis gas obtained by the pre-reformation is supplied to a fuel cell. Within the fuel cell, the methane contained in the mixture is also converted to a hydrogen-rich synthesis gas. By the pre-reformation, the higher hydrocarbons are disintegrated. This occurs because they are disadvantageously chemically unstable and therefore disintegrate easily while forming carbon. Besides the higher hydrocarbons, also the methane itself reacts to form carbon particularly by thermal cracking of methane:
CH4(g)⇄2H2(g)+C(s)
This reaction takes place preferably at temperatures above 650xc2x0 C. (J. R. Rostrup-Nielson, Catalytic Steam Reforming, Springer Verlag, 1984). The carbon formation should preferably be avoided in the fuel cell.
An external procedure for generating hydrogen by catalytic reformation has the disadvantage of high heat input requirements. The required heat is provided for example by additional combustion of hydrocarbons. The process is therefore relatively expensive.
The endothermic reactions occurring in a fuel cell cannot compensate for the heat generated by the exothermic electrochemical reactions. In the state-of-the-art techniques, the heat balance in a fuel cell always provides for excess heat. A fuel cell therefore needs to be cooled by a coolant as it is shown for example in the printed publication DE 196 36 908 A1. In the high-temperature fuel cell substantial amounts of cooling air must be provided in order to remove the heat released by the electrochemical reactions as can be taken from the printed publications xe2x80x9cFuel Cell Systems L. Blomen, M. Mugerwa, Plenum Press 1993xe2x80x9d or xe2x80x9cOptimization of 200 KW SOFC co-generation plant, Part II: variation of the flow sheet; E. Riensche, J. Meusinger U. Stimming, G. Unverzagt; Journal of Power Sources 71 (1998), pp. 306-314xe2x80x9d. This results in large efficiency losses and increasing electric power generating expenses.
To cool a fuel cell requires energy. The efficiency of a fuel cell is reduced thereby. It would be advantageous to strive for an isothermal process wherein the heat budget of the fuel cell is balanced.
From the state of the art, combined processes are known wherein for example a fuel cell and a thermal power plant are coupled for the utilization of the excess heat of the fuel cell (DE 196 36 738 A1) or a fuel cell is coupled with a gas turbine (DE 40 32 993 C1).
A process for the manufacture of highly pure hydrogen or, respectively, synthesis gas which includes a fuel cell is also known from DE 196 36 068 C1. In this process, the isolated reaction space is brought for the reformation in thermal contact with the interior of a high-temperature fuel cell, which is operated at 300xc2x0 C., but preferably above 500xc2x0 C.
Based on the printed publication xe2x80x9cCh. Rechenauer, E. Achenbach, Dreidimensionale mathematische Modellierung des stationxc3xa4ren und instationxc3xa4ren Verhaltens oxid-keramischer Hochtemperatur-Brennstoffzellen (three-dimensional mathematical modelling of the stationary and instationary behavior of oxide-ceramic high temperature fuel cells) Jxc3xcl-2752xe2x80x9d known typical operating data of a single fuel cell are given in the following table:
It is the object of the present invention to provide a method with which utilization, particularly of the waste heat of a fuel cell possible, is improved.
In a method for operating a SOFC high-temperature fuel cell, wherein a hydrogen-containing fuel is converted internally in the fuel cell by an endothermic reaction at the anode thereof into a synthesis gas, which is converted by an exothermic reaction into electricity, fuel is supplied to the fuel cell, to cool the fuel cell, in an excess amount such that, with a predetermined average current density flow, the fuel utilization degree is below 40%, whereas the oxygen is supplied stoichiometrically corresponding to the amount of electricity generating requirements, while the temperature difference of the operating media between the entrance into, and the exit from, the anode space as well as into, and from, the cathode space is not more than 20xc2x0 C.
In accordance with the method, a hydrocarbon-containing fuel such as methanol, methane or ethanol is introduced into the interior of the fuel cell and is converted therein into a synthesis gas by endothermic reactions. The synthesis gas is converted to electricity partially by exothermic electrochemical reactions. The part of the synthesis gas, which could not be converted in the fuel cell into electricity can be collected in a container after leaving the fuel cell and/or can be supplied to a gas treatment unit which includes apparatus for cleaning and/or separating the gas and/or it can be utilized in an additional fuel cell for the generation of electricity. With an appropriate excess amount of fuel, no additional cooling of the fuel cell is required.
In contrast to the state of the art, the fuel to be reformed is supplied to the fuel cell in large excess. This is to be understood in such a way that, in comparison with the state of the art, substantially more of the fuel to be reformed is supplied to the fuel cell than the fuel cell can convert into electricity. The purpose is to avoid additional cooling of the fuel cell. The excess amount is therefore to be so selected that cooling of the fuel cell by air, which is not needed for the generation of electricity, or by other liquid or gaseous coolants is essentially avoided.
The heat removal in a fuel cell by endothermic reactions, in accordance with the invention, is approximated to the heat generation by exothermic reactions in an improved manner. Particular measures for cooling which have no other purpose, are reduced in this manner, or are, in the ideal case, totally eliminated.
A fuel cell, for example, is operated by pre-reformed natural gas. Herein, the material volume part of methane upon entering the fuel cell is, for example,  greater than 10%. A high excess in the sense of the invention is present in this fuel cell for example if, upon leaving the fuel cell, the mole content of hydrogen is at least 20% and the mole content of methane is less than 5%. A high excess in the sense of the invention is particularly then present if, at the exit of the fuel cell, the mole content of hydrogen is at least 40% and the mole content of the methane is less than 5%. The degree of fuel utilization is then below 40% preferably even below 30%. The amount of oxygen admitted (that is, air) is reduced practically to the minimum amount required for the generation of the electricity. No cooling by liquid or gaseous coolants (in addition to the operating media mentioned before) is required in an ideal case. A suitably controlled fuel excess has advantageous effects in combination with a minimized oxygen supply for an isothermic operation of the fuel cell such that inlet and outlet temperatures are approximately the same and a temperature gradient within the fuel cell is avoided. This can be realized for example with a metallic interconnector of steel (1.4742) of high heat conductivity.
The excess is preferably so adjusted that the heat resulting from the exothermic electrochemical reactions is utilized to at least 80%, preferably completely, for the endothermic methane reformation in the anode. The heat energy is utilized in this way substantially better in comparison to the state of the art. In the method according to the invention, the heat energy is utilized in a pre-planned manner for the generation of electricity as well as for the production of hydrogen and, respectively, synthesis gas.
Below the invention will be described in greater detail on the basis of the accompanying drawings.
As fuel natural gas is used to which water vapor is added at a rate at which the formation of carbon is excluded. In order to ensure a predetermined average area-specific current flow density in a single high temperature fuel cell stack, a theoretical minimum amount oxygen (air) is required which correlates with a stoichiometric minimum amount of fuel.
It is the aim to achieve an almost isothermic operation wherein, at the same time, the oxygen supply as much as possible stoichiometric.
The amount of oxygen admitted (for example, air) is for this purpose reduced to the stoichiometrically needed minimum. The possibly partially pre-reformed fuel gas, which is supplied at the anode side, is available in such an excess amount that a fuel utilization degree of less than 40%, preferably about 30% is obtained. The methane is converted catalytically within the high-temperature fuel cell, that is, immediately in, or at, the anode to hydrogen and carbon dioxide which however is not further converted electrochemically. With the endothermic methane reformation, the reaction heat released during the electrochemical reaction is consumed. The high temperature fuel cell stack is preferably so operated that the whole electrochemically generated energy is consumed by an internal methane reformation. The discharge gas, which has been enriched at the anode with hydrogen and carbon monoxide can be supplied to another high-temperature fuel cell stack or it may be utilized otherwise without the fuel cell. In this regard, it is for example advantageous to supply the gas from the fuel cell operation to gas cleaning or separation apparatus and/or gas storage installations. Also the gas may be subsequently combusted with the air conducted past the cathode (after-burner, boiler, furnace) so that an uncoupling of high-temperature heat is achieved, beyond the state of the art, which may be made available for use in a subsequent gas turbine and/or steam turbine power plant.
The introduction of combustion gas in excess provides for an efficient utilization of the electrochemical reaction heat and a greater uncoupling of high-temperature heat as this has been possible in connection with the state of the art processes.
Below the invention will be described in greater detail on the basis of the accompanying drawings.

Solid oxide fuel operating with an excess of fuel


A furnace consists of at least one wall-mounted burner tilted downward for feeding air-fuel mixture and of a prism-shaped ash hopper. Slopes of the walls of lower combustion chamber region define the slotted mouth of ash hopper. The bottom airflow device is located below the ash hopper mouth the wall opposite to the airflow nozzle of the bottom airflow device has a concave form. In accordance with said invention the bottom airflow device spans along the entire width of the ash hopper mouth. The concave wall in its upper region meets the ash hopper mouth and an imaginary plane being a continuation of said concave wall crosses the opposite slopes of the wall of ash hopper in its middle region. The axis of bottom airflow nozzle passes along the lower region of said concave wall and is directed to form a 0-to-45 degree angle between said axis and lower region of said concave wall. The concave wall may be tilted relative to horizon at the angle of 20-45 degrees. The bottom airflow device may comprise of two similar parts symmetrical to the vertical axis of combustion chamber. FIG. 1

The invention relates to the thermal techniques, namely, to furnaces fired with organic fuels. The invention may successfully be applied to firing pulverized fuels.
When designing furnaces, much attention is paid to the completeness of fuel combustion what is one of the defining factors for increasing their economic and environmental numbers. It is well known that the increased completeness of fuel combustion may be achieved by thoroughly mixing fuel with air at the increased combustion temperature. However the increased temperature within the combustion region leads to the increased nitrogen oxide emission at the expense of the so-called xe2x80x9cthermalxe2x80x9d nitrogen oxides resulted from oxidation of nitrogen present in ambient air. Besides, the increased flame temperature causes the slag buildup at the heat absorbing wall tubes and other negative consequences. To reduce temperature in the combustion region a number of techniques is introduced, such as the combustion products recirculation into the furnace, introduction of coarsely pulverized fuel, etc. At present the most effective way is the introduction of vortex furnaces providing maximum combustion temperatures at a relatively low level by increasing residence time of particles within active combustion regions.
Well known is the furnace (SU, A, 483559) consisting of the combustion chamber and the wall-mounted burner used for the air-fuel mixture supply. Tilted walls of the lower combustion chamber region formed the prism-shaped ash hopper with slotted mouth. Below the ash hopper mouth the bottom airflow device is installed. This device is designed, for example, as an air nozzle. At operation of such furnace the air-fuel mixture is fed through the burner and air is fed from below through the slotted mouth. As a result of the interaction of two reversely-directed flows a vortex zone is formed in the lower furnace region whereas the upper furnace region will have a straight-flow zone. Fine particles burn within the straight-flow zone and zones adjacent to the burners where as the middle-sized and coarse particles are separated into the vortex zone. Within the vortex region these particles burn our as a result of repeated circulation. As a size of the coarse particles diminishes these particles are blown out of the vortex zone and burned out within the upper straight-flow flame zone. An intense in-furnace recirculation of air mixture results in a considerable decrease and uniform temperatures within the entire vortex zone. To prevent the combustion of main portion of particles near the burner region and to carefully use the advantages of vortex furnaces, different approaches may be introduced, such as coarsely pulverized fuel with low content of finely pulverized particles, increased burner tilt angles and raised velocity of air mixture fed through the burner to improve the fuel particle separation into the vortex zone. Reduced fuel combustion velocity caused by lowering maximum combustion temperatures and coarsely pulverized fuel are supplemented by increased fuel residence time in the low temperature zone, that is, in the vortex zone. At the same time a considerable part of the vortex zone is a reducing oxygen-deficient region. It enables to lower the nitrogen oxide emission at the expense of oxide reducing.
Industrial tests of a boiler equipped with such burner confirmed considerable temperature and nitrogen oxide reductions in flue gases. However in cases of coarsely pulverized fuel combustion and when coal mills are in unsatisfactory conditions a fuel drop-off into ash hopper may increase. This may be a partial result of the wall tube surface structure when walls of many boilers are panels consisting of vertically mounted tubes between which small slots may be present. These slots may accumulate fuel particles. Fuel particles create so-called xe2x80x9cchainsxe2x80x9d. Having reached a critical mass and overcome the reverse airflow resistance, these chains drop into ash hopper. To fire the unburned fuel, the bottom airflow velocity should be increased. This causes higher maintenance costs for the forced and induced draft fans and intensification of the wall tube erosion. Besides, redundantly high velocities of the bottom airflow may distort the optimum vortex process aerodynamics that will result in higher unburned particle content in flue gas. More problems appear if wall tubes are not airtight. This is inherent to almost all older boilers. In this case the unburned particles pass between wall tubes and drop along the thermal insulation plates mounted behind the wall tubes down into ash hopper. In the ash hopper mouth the particles that have moved along that tilted wall where the bottom airflow nozzles are installed enter the flow injected from these nozzles. Some of them return to the active combustion region and the heaviest ones may drop off. It happens because the particles move in the direction counterwise to the bottom airflow direction. The process of returning fuel particles to combustion more effectively occurs when particles move towards the bottom airflow (for example, along a slanted surface). In this case the time required for air to react with a fuel particle and is quite sufficient in order to lower kinetic energy of the latter (the friction of a particle on the surface also contributes) and subsequently to direct it back to the combustion chamber. As for the particles that moved along the opposite slanted wall of ash hopper so they fully drop off. Heat losses resulted from the mechanical combustion incompleteness in the given furnace may considerably exceed the rated numbers. Therefore the economic numbers may be regretfully low. Also well known is the furnace described in the application PCT/RU93/00291. It was introduced to fire coarsely pulverized fuel. The furnace has a combustion chamber with slanted walls in the lower region forming the mouth below which there is the coarse particle treatment chamber equipped with the bottom airflow nozzle in its lower region. The coarse particle treatment chamber is a curved channel with the lower edge of the wall located opposite to the airflow nozzle and below the nozzle axis. The wall equipped with the bottom airflow nozzle has a region located above the opposite one. This region is directed toward the nozzle axis and the opposite wall. The wall opposite to the nozzle is curved and its upper edge is directed along the opposite slanted wall of the vortex chamber. At operation of this furnace the finely pulverized particles burn out near the burner itself and relatively coarse particles fall into the lower region of the vortex zone and enter the bottom airflow fed through the nozzle. The coarsest particles drop through the slotted mouth of ash hopper and, passing through the curved channel, reach the curved wall of the coarse particle treatment chamber. After the fuel particles have entered the curved channel its form provides the change in fuel particle movement in such a way that when caught by the bottom airflow, fuel particles are thrown toward the opposite wall, smashed and pulverized. Relatively fine particles resulted from such pulverization are fed with the airflow into the vortex zone where they burn out. Coarse particles again fall into the lower region and the cycle repeats itself.
Such furnace can be successfully introduced at firing fuel that is coarsely pulverized, highly moist or if a prolonged time for coarse fuel particle treatment is needed. In case when a finely pulverized and relatively dry fuel with low coarse particle content is used the above-mentioned furnace becomes inefficient since the costs for fan devices become unjustifiably high. Energy losses for repeated changes in airflow direction (including the cases of impacts on the opposite wall) are the main cause. In addition, if the fuels being used tend to form the slag buildup the presence of a long curved channel with relatively low cross-sections (necessary for the effective operation of the above-mentioned furnace) below the ash hopper mouth may cause some problems in operation of the boiler. These problems will occur as a result of frequent filling of the curved channel with coarse slag lumps formed at the adjacent walls. This may lead to the operation faults of the furnace or the entire boiler.
The base of the given invention was the task to build a furnace employing a bottom airflow device that provides the fuel particle return into the vortex zone with the purpose of compete combustion and lowering the slag blockage danger of the bottom airflow device with simultaneous increase of economic values. The given task is solved as follows. The vortex furnace consisting of a combustion chamber with at least one wall-mounted tilted burner, a prism-shaped ash hopper with a slotted mouth formed by the slanted walls of lower combustion chamber region and the bottom airflow device located below the ash hopper mouth. In addition the wall opposite to the bottom airflow device has the curved surface relative to the given device. The bottom airflow device spans along the entire width of the mouth and the above curved wall in its upper region is adjacent to the ash hopper mouth. This wall is built as the imaginary surface being its continuation crosses the opposite slanted wall of ash hopper in its middle region. The bottom airflow nozzle axis goes along the lower region of the curved wall and is directed upwards at the angle between the said axis and curved wall in its lower region equal to 0-45 degrees. Due to the location of the bottom airflow device along the entire width of slotted mouth the operation of such furnace provides the vortex zone formation practically in the entire volume of lower combustion chamber and prevents the possibility of fuel particle drop-off because of the irregular bottom airflow. The given tilt angle of the airflow nozzle provides the most efficient xe2x80x9cimpactxe2x80x9d angle for the fuel and slag particles to minimize energy losses. This provides the most successful furnace operation. The location of the upper curved wall region as described above is determined at first with regard to the erosion danger of wall tube twists in the ash hopper mouth and secondly to the possibility of tearing the bottom airflow off the slanted wall of ash hopper and subsequent transition to the so-called xe2x80x9cfountainxe2x80x9d regime at which the vortex process aerodynamics deteriorates and heat losses resulted from the unburned fuel abruptly grow. First of all the given design is aimed at shifting all particles that happened to drop into the ash hopper to the lower region of the curved wall. Having lost a portion of their kinetic energy as a result of the impact, these particles roll downwards affected by the upcoming bottom airflow that forces them back into the combustion chamber. The absence of xe2x80x9cnarrowxe2x80x99 regions excludes the collection of coarse slag lumps. It is expedient to form the lower region of the wall equipped with the bottom airflow device tilted to horizon at a given angle. As the angle between the bottom airflow nozzle axis and lower region of the curved wall has a defined number lightly weighted fuel particles are forced by the airflow into the vortex zone and slag particles drop off as a result of their weight. Fuel particles drawn to the curved wall have a different velocity and a different velocity vector. In case the wall tilt angle exceeds 45 degrees some fuel particles with higher velocity slightly lose their velocity on wall impact (a sliding impact occurs) and they can, having overcome the airflow resistance, enter the ash hopper increasing the unburned fuel losses. If the wall tilt angle is below 20 degrees then all fuel particles lose their velocity at this wall and are forced by the bottom airflow into the vortex zone for compete combustion. However at such tilt angle some heavier slag particles may gather and even provoke the filling of the bottom airflow device.
Orientation of the upper curved wall region is chosen on the base of the following. The bottom airflow coming from the ash hopper mouth must pick up fuel particles collected at the slanted wall. Therefore, the earlier the airflow nozzle axis crosses this slanted wall, the better. At the same time it is necessary to exclude the contact of this flow carrying abrasive particles (fuel, ash particles etc) with wall tube twists since these are the most dangerous points from the viewpoint of possible wall tube breakdowns since as wall tubes are twisted during fabrication their upper region become thinner (stretched). It is expedient for the bottom airflow device to have two similar parts symmetric with regard to the vertical axis of combustion chamber.