MXPA99007322A - Biocompatible compounds for pharmaceutical drug delivery systems - Google Patents

Abstract

Methods, compounds, and medicinal formulations utilizing biocompatible polymers for delivery of a drug, particularly for solubilizing, stabilizing and/or providing sustained release of drug from topical, implantable, and inhalation systems. Many of the methods, compounds, and medicinal formulations are particularly suitable for oral and/or nasal inhalation and use polymers of the formula -[X-R1-C(O)]- wherein each R1 is an independently selected organic group that links the -X- group to the carbonyl group, and each X is independently oxygen, sulfur, or catenary nitrogen.

Description

BIOCOMPATIBLE COMPOUNDS FOR PHARMACEUTICAL DRUG ADMINISTRATION SYSTEMS Description of the invention The present invention is concerned with the use of relatively low molecular weight biocompatible polymeric compounds for pharmaceutical drug delivery formulations and in particular with the use of such compounds as solubilization aids of medication and stabilization of medications and / or to provide sustained release of medication.

BACKGROUND OF THE INVENTION Biodegradable polymers have long been examined for their use to provide sustained release of drugs and have also been used to make biodegradable medical products. For example, it is known that polymeric esters of selected hydroxycarboxylic acids or their derivatives (eg, lactic acid, glycolic acid, p-dioxanone, etc.) are highly biocompatible with and biodegradable in the human body. Such polymers are degraded in their constituent hydroxycarboxylic acids, which are metabolized and eliminated from the body in periods that normally fluctuate from several weeks to several years. Consequently, compounds of this type have been used for such things as degradable sutures. preformed implants and sustained release matrices. However, the biodegradable polymers in use for such purposes typically have average molecular weights greater than 2000 and often as high as 50,000 to 250,000 (all molecular weights referred to herein are in Daltons). This results in biodegradation rates that are generally too slow for situations that require frequent application and / or where a biological half-life of less than a week to several hours is desired (eg, topical application to a wound). or for inhalation therapy). Certain relatively low molecular weight polymers having a number average molecular weight of less than about 1800 may have sufficiently short biodegradation times for many such purposes, but in general they have not been considered appropriate for most drug delivery systems. of sustained release. This is at least in part because the physical characteristics of these relatively low molecular weight polymers have been considered as unsuitable for many conventional drug delivery formats. For example, polylactic acids having a number average molecular weight of less than about 1000 with a normal molecular weight distribution (i.e., a distribution that is substantially unchanged from that obtained via polymerization) typically has a polydispersity (ie. , the ratio of molecular weight weights to number average molecular weight) greater than about 1.8, tend to have a glass transition temperature (Tg) lower than room temperature, which is about 23 ° C and are generally soft, waxy or sticky materials. Such materials are not generally suitable for making conventional, solid, preformed drug-containing structures, such as microspheres for sustained release of the medicament because the low vitreous transition temperature Tg prevents the material from maintaining its physical integrity. Also, the rate of release of the drug from and the percent loading of the drug to conventional low molecular weight biodegradable systems have not been generally considered sufficient to be useful for most drug delivery systems. Thus, formulations and methods for using biocompatible and preferably biodegradable polymers to provide a relatively short-term sustained release of drugs would be highly desirable. A particular area where sustained release is extremely useful and has still been difficult to obtain satisfactorily is in the context of drug inhalation therapy, such as with metered dose inhalers (MDI). Medications used for localized pulmonary administration, for example bronchodilators, are usually limited in their efficacy by the need for frequent administration. This is usually due to the rapid dissolution, absorption and metabolism of medications in the lungs. Many attempts have been made to provide sustained release of drugs to the lungs, as well as other sites, by entrapping or encapsulating the drug in preformed biodegradable microspheres. However, there are serious disadvantages when using preformed microspheres. First, it has generally been necessary to use polymers with a number average molecular weight of at least about 1800 and usually higher, such that the glass transition temperature Tg is high enough for the particles to remain discrete or at least separable before use. As indicated above, polymers of too high molecular weight will normally degrade too slowly to be useful in inhalation therapy due to the tendency of higher molecular weight materials to collect and accumulate in the lung parenchyma in continuous use . Second, the production of transformed microspheres is often difficult, inefficient, costly and may involve the use of materials that are physiologically and / or environmentally hazardous. Despite efforts to improve the processes, there are frequent problems for example with low and inefficient drug entrapment, particle aggregation, broad distributions of particle sizes and the presence of non-particulate materials. Hence, there is a substantial need for means for the preparation of microparticles which are appropriate for the administration of the pulmonary medicament and which will not accumulate in the lungs and even more preferably means for providing sustained release of the medicament without requiring the use of microspheres. preformed Another important issue concerning medicinal aerosol formulations such as MDI is whether the medicament is dissolved in the formulation or present as a micronized suspension of particles. Although there are advantages to using aerosol formulations where the drug is in solution, most commercially available DIs have the drug suspended in the propellant as a micronized dispersion. This is because in most cases the medicament is either not sufficiently soluble in the formulation to form a stable solution or if it is soluble, the medicament is too chemically unstable in its dissolved form. Thus, there is also a substantial need for biocompatible compounds that act as solubilization aids and / or chemical stabilizers or stabilizers for the medicament in medical aerosol formulations. U.S. Patent No. 5,569,450 (Duan et al.) Discloses that biocompatible oligomers such as oligohydroxycarboxylic acids are useful as dispersing aids to help maintain the particles as an appropriate suspension. However, they do not disclose formulations of such compounds that provide sustained release of the medicament or as a solubilization aid and / or stabilization of the medicament. In other non-inhalation contexts, biocompatible polymers have been used for various therapeutic systems, such as films that cover the skin that is "sprayed" which may have a drug included, however, in general, such systems are not considered to have physical characteristics. and biological / degradation appropriate for most applications of sustained release administration.

BRIEF DESCRIPTION OF THE INVENTION The methods, compounds and medicinal formulations of the present invention provide widely applicable means for the administration of a medicament. They are particularly useful for the solubilization of the drug and chemical stabilization, as well as for providing sustained release of the drug from a drug. drug delivery system, such as topical, implantable and inhalation systems. Additionally, means are provided for improving the physical and degradation characteristics of the biodegradable polymers and also for forming drug-polymer medicinal salts. Many of the methods, compounds and medicinal formulations are particularly useful for oral and / or nasal administration of the medicament, such as by inhalation of a metered dose inhaler.

Biocompatible Polymers All formulations of the present invention utilize one or more biocompatible and preferably biodegradable polymeric compounds. As used herein, "polymer" and "polymeric" are intended to include, unless otherwise indicated, homopolymers and block / random or messy copolymers (and oligomers) that include a chain of at least three or more monomeric structural units formed by polymerization reactions (for example, condensation polymerization or ring opening polymerization). Preferred biocompatible polymers are biodegradable and are preferably formed by condensation type polymerization. For some preferred embodiments, the biocompatible polymers are homopolymers, while for others they are copolymers. Preferably, the repetitive structural units contain amide units, ester units or mixtures thereof. Such preferred biocompatible polymers include at least one chain of units of the formula - [X-R1-C (0)] - wherein: each R1 is an independently selected organic group that links the group X to the carbonyl group and each X is independently oxygen, sulfur or catenary nitrogen. Such compounds can include chains having different R1 groups although for certain embodiments each portion of R1 is the same. The preferred group X is oxygen. Particularly preferred biocompatible polymers are relatively low molecular weight (PLA) polylactic acids. One reason they are preferred is because it is well known that lactic acid is endogenous in humans, highly biocompatible and therefore desirable from a regulatory approval point of view. Other biocompatible polymers are also useful in the methods and formulations according to the present invention. For example, it has been found that homopolymers and copolymers of lactic acid, glycolic acid, trimethylene carbonate, hydroxybutyric acid and p-dioxanone are all particularly useful in various embodiments of the present invention. In particular, polydioxanone and polylactic-co-glycolic acids are biocompatible and thus are also good candidates from a regulatory approval point of view. Sometimes it is also preferred that one or more chains of the biocompatible polymer can be capped at one end or both ends either by a monovalent, divalent or polyvalent organic portion (each valence of the coronation group is independently linked to a chain) that do not contain hydrogen atoms capable of forming hydrogen bonds or by a monovalent, divalent or polyvalent ionic group or a group containing no hydrogen atoms capable of forming hydrogen bonds. The choice of end groups can modify the performance of the polymer either in the formulation or biologically and the preferred choice will depend on the particular proposed application of the invention. A crown of the end of the preferred polymer is an acetyl group. Also, it should be noted that the various preferred quantities, molecular weights and ranges summarized below are provided for general guidance and are based primarily on poly-L-lactic acids in such a way that this should be taken into account when considering other polymers for use in the present invention. For example, polyglycolic acids are normally hydrolyzed faster, exhibit higher degrees of crystallinity and have higher melting points than polylactic acids. This should be taken into account when considering issues such as which polymer to use to get sustained or particular release. desired formulation characteristics. Furthermore, in the case of polylactic acids, the L form that occurs stably in nature is frequently preferred with respect to the D or DL forms because it is endogenous in humans. However, due to the amorphous nature of the DL compounds, there are applications where DL compounds (ie, mixtures of L and D isomers) are also sometimes preferred.

Low Polydispersity Compositions A first aspect of the invention, which may or may not be used in conjunction with other aspects discussed hereinafter, is concerned with improvements in the physical and degradation characteristics of biodegradable polymers. As indicated above, conventional polymeric compositions with the highly desirable property of relatively rapid biodegradation also commonly exhibit poor physical characteristics. They tend to be sticky, waxy and in general incapable of maintaining the physical integrity of the articles formed with them (for example, the microspheres are annealed together, the rollers conform to the shape of the container, etc.). However, it has been found that, contrary to conventional understanding, it is indeed possible to obtain the highly desirable combination of relatively rapid biodegradation and good physical characteristics with a biodegradable polymer of relatively low molecular weight. This surprising effect is carried out by limiting the polydispersity (ie, the ratio of the weight-average molecular weight to the number-average molecular weight) of the polymer to a relatively narrow range compared to the distribution that occurs in a normal manner (this is, the molecular weight distribution that normally occurs from conventional polymerization methods). It is hypothesized that this unexpected improvement is the result of several factors: the reduction of the amount of the high molecular weight component that degrades slowly from the polymer reduces the overall biological half-life of the polymer; while reducing the amount of the plasticizer low molecular weight compound of the polymer that raises the glass transition temperature Tg of the material. Also, the removal of the low molecular weight component seems to "sharpen" the transition between the fluid and non-fluid phases, that is, it raises the temperature of the beginning of the Tg (the point where stickiness and flow begin to appear) more close to the Tg of the midpoint. Thus, by limiting the polydispersity of the biodegradable polymer, the degradation characteristics can be improved without sacrificing and perhaps improving the physical characteristics of the composition. For example, by reducing the polydispersity of the polymer composition, a generally hard, non-tacky material can be produced and it degrades relatively quickly. With this aspect of the present invention it is thus possible to prepare medicinal compositions containing relatively low molecular weight medicaments which have a more rapid biodegradation and improved handling characteristics. This has potential application in virtually any context where a relatively biodegradable polymer is desired. For example, it can be used to make microparticles that contain -preformed medication and implants. As discussed below, the narrow polydispersity of the polymer may also provide benefits when dissolved in an MDI formulation to provide controlled release, solubilization and / or chemical stabilization of a medicament.

In order to provide rapid biodegradation and good physical characteristics, the biodegradable polymer preferably has a number average molecular weight of not more than about 1800 and more preferably not greater than 1500 (and in general not less than about 700) and a polydispersity of less than about 1.3 more preferably less than about 1.2 and more preferably less than about 1.15. The biodegradable polymer preferably comprises at least one chain of units of formula - [0-R1-C (O)] - wherein each R1 is an independently selected organic group that links the oxygen atom to the carbonyl group. More preferably, the biodegradable polymer is polylactic acid, polyglycolic acid or polylactic-co-glycolic acid and more preferably is poly-L-lactic acid. Some examples of uses for such biodegradable polymers having a relatively narrow molecular weight distribution include preformed medicament-containing powders and particles (e.g., microspheres), such as are used in dry powder inhalation systems, nebulizers, injection formulations, topical sprayings and suspension type MDI aerosol formulations, also as subcutaneous implants, dental medication administration packages and other medication administration systems. Polymers having such a relatively narrow molecular weight distribution can be prepared by any suitable means to limit polydispersity. A preferred technique is to use a supercritical fluid such as carbon dioxide, to fractionate the polymer. This useful technique is applicable to the biocompatible polymers described herein, as well as to other polymers in general.

Solubilization and / or stabilization of the medicament In another important aspect of the invention, biocompatible polymers are dissolved in medicinal formulations in order to help solubilize and / or chemically stabilize a medicament. A preferred embodiment of this aspect of the invention is a medicinal formulation suitable for nasal and / or oral inhalation, such as an MDI, which includes a propellant, a biocompatible condensation-type polymer, preferably comprising at least one chain of units of formula - [X-R1-C (O)] - wherein: each R1 is an independently selected organic group that links the group X to the carbonyl group and each X is independently oxygen, sulfur or catenary nitrogen and a therapeutically effective amount of a drug substantially completely dissolved in the formulation. Surprisingly, the biocompatible polymer, which is also substantially completely dissolved in the formulation, acts as a solubilization aid and / or as a chemical stabilization aid for many drugs. This is important because, as indicated above, many drugs are not sufficiently soluble in aerosol formulations or if they are soluble, they are chemically unstable in their dissolved form. Optionally, a cosolvent may also be present, which may help to solubilize either the medicament, the biocompatible polymer or both. Other excipients may also be included. It is also preferred in this aspect of the invention, although not required, that the biocompatible polymer have a relatively narrow molecular weight distribution, that is, polydispersity of less than about 1.8, preferably less than about 1.4, and more preferably less than about 1.2. This helps prevent the inclusion of larger polymers that could accumulate in the lungs over time due to repeated dosing. It may also allow a larger amount of the polymer to be completely dissolved in an aerosol formulation, which may be particularly important when a polymer is used as a drug solubilization aid because such use may require substantial amounts of the polymer to be dissolved. (for example, 1% or more of the formulation by weight).

For example, poly-L-lactic acid shows improved solubility in hydrofluorocarbon (HFC) propellants when the polydispersity is reduced.

Sustained release In another separate but related aspect of the invention, it has been found that medicinal formulations using the biocompatible polymers of the present invention are highly useful in providing sustained release of a medicament to the body. Such formulations include a medicament and a sufficient amount of biocompatible (preferably biodegradable) polymer which when administered is associated with the medicament (ie, medicament entrapped / encapsulated in a polymer matrix or as described hereinafter, as a medicament-polymer salt) to provide such sustained release of the drug as the polymer degrades and the medicament is released. This is useful in many drug administration contexts, such as solid and semi-solid implants and microspheres as well as for liquid injection and topical spray formulations. However, it is particularly useful and surprising in the context of medicinal aerosol formulations, such as for oral and / or nasal inhalation of a metered dose inhaler (MDI).

Such sustained release aerosol formulations include medicament and a sufficient amount of biocompatible polymer dissolved in a propellant to provide sustained release of the medicament when inhaled and may also include a cosolvent and other excipients. The medicament may be in the form of a micronized suspension or substantially completely dissolved in the formulation. The biocompatible polymer preferably comprises at least one chain of units containing amide and / or ester groups. Preferably, the biocompatible polymer comprises at least one chain of units of formula - [X-R1-C (O)] - wherein: each is an independently selected organic group that links the group X to the carbonyl group and each X is independently oxygen , sulfur or catenary nitrogen. It is particularly surprising to discover that when such biocompatible (preferably biodegradable) polymers are substantially completely dissolved in sufficient amounts in relation to the medicament for example in medicinal aerosol formulations and are administered to the body the medicament is released in a highly desirable sustained manner during a period that fluctuates for example from approximately 30 minutes to a day or more. The period of time for drug release depends on many factors including, for example, the amount, type and molecular weight of the biocompatible polymer used and the chemical and physical nature of the drug. The amount of polymer that will be sufficient to provide a desired sustained release profile can be determined on a case basis in case with little difficulty. In many situations, the polymer will comprise at least about 1% of the formulation to provide appropriate sustained release, although this will depend on the polymer used and the amount, type and physical and chemical form of the medicament. The polymer will generally be present in an amount of at least four times and often 10 to 100 times the amount of the drug on a weight-to-weight basis. In the case of suspension aerosol formulations, wherein the medicament is present as micronized particles, the amount of biocompatible polymer necessary to provide sustained release is in general substantially more than that which would normally be used as a dispersion aid for example. in the context of the US patent 5,569,450. In addition, although it may be preferable to use biocompatible polymers having, as described above, a relatively narrow molecular weight range (i.e., with a polydispersity of less than about 1.8 and preferably less than about 1.4 and more preferably less than about 1.2) is not required in accordance with all aspects of the invention, particularly in sustained release formulations. For example, when poly-L-lactic acids of normal polydispersity are used in a formulation for pulmonary administration, it is preferred that the number average molecular weight of the polymer be not greater than about 800 and more preferably not greater than about 600. Otherwise, depending on the frequency of administration, the highest molecular weight component present can accumulate in the lungs. Additionally, poly-L-lactic acids of normal polydispersity with molecular weights greater than about 800 may exhibit partial insolubility (depending on the percentage by weight, propellant used and the presence of cosolvent or other excipients) of the highest molecular weight fraction of the polymer. However, when poly-DL-lactic acids are used, such limitations are not generally found. When the poly-L-lactic acids of narrow molecular weight range (that is, those having a polydispersity of less than about 1.8 and preferably less than about 1.4 and more preferably less than about 1.2) are used, however, the number average molecular weight is preferably not greater than about 1300, and more preferably, for most applications, not greater than about 1000. For the poly-DL-lactic acid, although the solubility is not generally a However, it is desirable to use the lower polydispersity polymer due to the faster degradation. Molecular weight and polydispersity may be relatively higher in cases where frequent dosing or rapid bioabsorption is less important (eg, vaccine or nasal administration). The skilled artisan will recognize that these parameters will vary with each type of monomer used. The choice of polymer used will also be based on the capacity of the polymer, when administered, or to incorporate the drug into a matrix or as a salt (discussed later herein) and release thereof in a controlled manner. This depends on such factors as the molecular weight of the polymer, polydispersity, tendency towards crystallization and specific functionality, as well as the nature of the drug and the form it is in (eg dissolved or suspended). Thus, the system can be adjusted according to the particular requirements of the administration system. For example, where it is desired to provide an inhalation system of the therapeutic drug that requires only one dose per day, the amount of the biocompatible polymer, average molecular weight, polydispersity and other factors will preferably be selected such that the medicament is released from controllably and substantially all of the biodegraded polymer (such that the polymer matrix material is substantially undetectable at the site of administration) in a period of about 24 hours and in some cases preferably in a period of preference more than about 12 hours . This can be commonly carried out by using for example poly-L-lactic acid having an average molecular weight of about 1000 and a polydispersity of about 1.2, although these and several other factors, such as the amount of polymer used and the selection of comonomers (eg, use of L and D isomers, glycolic acid, etc.), can be adjusted as required for a particular situation. Also, significantly, the medicinal aerosol formulations described herein do not tend to form films, the presence of which would be highly undesirable in the pulmonary system. Rather, they form discrete particles spontaneously in the formulation leaving the valve of the aerosol container (eg, of a metered dose inhaler). This aspect of the invention is important in the context of providing sustained release microparticles and providing inhalable microparticles which are not for sustained release. Thus, a simple method for forming discrete particles of a medical aerosol formulation that is broadly applicable, cost effective and when an appropriate environmentally compatible propellant is used is also provided. The method includes the following steps: preparing a medicinal formulation by combining components comprising a propellant, a biocompatible polymer substantially completely dissolved in the formulation, a therapeutically effective amount of a medicament (preferably, substantially completely dissolved in the formulation) and optionally with a cosolvent and / or other excipient; placing the medicinal formulation in a device capable of generating an aerosol (preferably, an aerosol container equipped with a valve and more preferably a metered dose valve) and operating the device to form an aerosol of discrete particles that are sufficiently stable to avoid aggregation and film formation under conditions of use (for example, in inhalation, in topical application to a wound, etc.).

Medicinal Salts It has also been observed that certain biocompatible polymers, such as for example, low molecular weight poly-alpha-hydroxycxylic acids (PHA) can form salts with many medicaments. Such biodegradable low molecular weight polymers, in their salt form with a medicament, can provide sustained release of the medicament, aid in the solubilization of the medicament and chemically stabilize the medicament, without requiring the presence of matrix materials that control further release. Thus, another embodiment of the invention is a medicinal salt of a medicament and a biodegradable polymer of low molecular weight. The salt comprises: an ionic drug comprising at least one ammonium, sulfonate or cxylate group per molecule (preferably an ammonium group) and a biodegradable polymeric counter ion comprising at least one ammonium, sulfonate or cxylate group (preferably , cxylate group) and at least one chain of at least 3 units of formula - [0-R1-C (O)] - wherein each R1 is an independently selected organic moiety that links the oxygen atom to the cnyl group. Preferably, the hydroxyl end of the unbranched chain is esterified. Salt can be used to take advantage of various medicinal formulations, be it solid, semi-solid or liquid formulations. Preferred formulations include medicinal aerosol formulations suitable for oral and / or nasal inhalation such as MDI.

Such use of a bicompatible low molecular weight polymeric counter ion in a medicinal salt of a medicament can in many cases provide advantages over the use of a polymeric matrix in a non-ionic form. For example, the presence of a biocompatible polymer and the formation of such salts can provide a significant improvement in chemical stability with respect to the same formulation without a biocompatible salt-forming polymer. It can thus be seen from the foregoing that the present invention provides methods, compounds and medicinal formulations which represent a spectacular advance to provide improved solubilization and chemical stabilization of a medicament, as well as to provide sustained release of medicaments. This is particularly important in the field of administration of aerosolized medicaments, such as for inhalation. The biocompatible polymers described above, particularly the biodegradable polyesters and polyhydroxycxylic acids, can be used either as a drug or anti-ion containing matrix in solid, semi-solid or liquid formulations. Thus, among the improvements provided in the present invention are: a medicinal aerosol solution formulation comprising: (a) a biocompatible polymer dissolved substantially completely in the formulation; the biocompatible polymer comprises at least one chain of units and of formula - [X-R1-C (O)] - wherein: (i) each R1 is an independently selected organic group that links the -X- group to the cnyl group; and (ii) each X is independently oxygen, sulfur or catenary nitrogen; (b) a propellant; and (c) a medicament substantially completely dissolved in the formulation in a therapeutically effective amount. Preferably each X is independently oxygen or catenary nitrogen. Preferably, the biocompatible polymer is a biodegradable polymer having a number average molecular weight no greater than about 1200, more preferably not greater than about 800. Preferably, the biocompatible polymer has a polydispersity of less than about 1.2. In a further preferred embodiment, the biocompatible polymer chain comprises units derived from lactic acid and has an average chain length of about 5-16 units. The present invention also provides a sustained release medicinal formulation comprising: (a) a propellant; (b) a therapeutically effective amount of a medicament and (c) a sufficient amount of a biocompatible polymer dissolved substantially completely in the formulation to provide sustained release of the medicament; wherein the sustained release formulation results in discrete particles, which do not form film in the administration. Preferably the biocompatible polymer comprises at least one chain of units of the formula - [X-R1-C (O)] - wherein: (a) each R1 is an independently selected organic group that links the X group to the carbonyl group Y (b) each X is independently oxygen, sulfur or catenary nitrogen and is biodegradable having a biological half-life of less than about 10 days. The present invention also provides a biodegradable medicinal composition comprising: a therapeutically effective amount of a medicament and a biodegradable polymer comprising at least one chain of units of the formula: - [0-Rx-C (0)] - wherein: (a) each R1 is an independently selected organic group that links the -0- atom to the carbonyl group; and (b) the polymer has a number average molecular weight of no greater than about 1800 and a polydispersity of less than about 1.2. Preferably, the biodegradable polymer has a number average molecular weight of not more than about 1200. Preferably, the biodegradable polymer comprises units derived from precursors selected from the group consisting of glycolic acid, L-lactic acid, and D-lactic acid. The average chain length of the biodegradable polymer is preferably between about 5-20 units. In a further preferred embodiment, the medicinal composition has a glass transition temperature greater than about 23 ° C and is in the form of microparticles. The present invention also provides a medicinal salt composition comprising: (a) an ionic drug comprising at least one ammonium, sulfonate or carboxylate group per molecule; and (b) a biodegradable polymeric counter ion comprising at least one ammonium, sulfonate or carboxylate group and at least one chain of at least 3 units of formula - [0-Rx-C (O)] - wherein each R1 is an independently selected organic group that links the oxygen atom to the carbonyl group. The present invention further provides a metered dose inhaler for administering a sustained release medicinal formulation comprising: an aerosol container equipped with a metered dose valve and containing a sustained release medicinal aerosol formulation as described above suitable for nasal and / or oral inhalation. Preferably, the biocompatible polymer is a biodegradable polymer that biodegrades substantially completely over a period of about 12 hours. Preferably, the biocompatible polymer comprises at least one chain of units of formula [X-R1-C (0)] wherein: (i) each R1 is an independently selected organic group that links the -X- group to the group carbonyl and (ii) each X is independently oxygen or catenary nitrogen. In further preferred embodiments, the biocompatible polymer is biodegradable and comprises units derived from precursors selected from the group consisting of glycolic acid, L-lactic acid and D-lactic acid or has a polydispersity of less than about 1.2. In addition, the biodegradable polymer and medicine can form a salt. Additional aspects and specific features of the invention will also be apparent from the following detailed description and non-limiting examples of the invention.

DETAILED DESCRIPTION The present invention provides medicinal formulations containing a medicament and a biocompatible polymer. They can be solid, semi-solid or liquid. Preferred formulations are administered by oral and / or nasal inhalation, although formulations for administration via eg topical (eg, buccal, transdermal) spray administration can also be prepared. Additionally, compositions (for example those made with biocompatible polymers of low polydispersity and / or medicinal salt) capable of forming stable preformed solid objects, such as dry powders, microspheres, rollers, needles, can also be made for administration by injection, implant or other appropriate methods, also as oral and / or nasal inhalation.

As discussed later in this, medicinal formulations can be made with a variety of drugs, biocompatible polymers, propellants, cosolvents and other ingredients. Among the benefits provided by the invention, the biocompatible polymer can have improved physical and biodegradation properties due to low polydispersity, function as a solubilizer and / or chemical stabilization aid, provide sustained release and / or act as a counter ion to form a medicinal salt.

Medications The medicinal formulations according to the present invention contain a medicament either dispersed or dissolved in the formulation in a therapeutically effective amount (ie, an amount appropriate for the desired condition, route and mode of administration). As used herein, the term "medicament" includes its equivalents, "bioactive agent" and "medicament" and is intended to have its broadest meaning including substances proposed for use in diagnosis, cure, mitigation; treatment or prevention of diseases or to affect the structure or function of the body. The medications can be neutral or ionic. Preferably, they are suitable for oral and / or nasal inhalation. Administration to the respiratory system and / or lungs, in order to effect bronchodilation and to treat conditions such as asthma and chronic obstructive pulmonary disease is preferably by oral inhalation. Alternatively, to treat conditions such as rhinitis or allergic rhinitis, administration is preferably by nasal inhalation. Suitable medicaments include, for example, anti-allergens, analgesics, bronchodilators, antihistamines, antiviral agents, antitussives, anginal preparations, antibiotics, anti-inflammatories, immunomodulators, 5-lipoxygenase inhibitors, leukotriene antagonists, phospholipase A2 inhibitors, phosphodiesterase IV inhibitors. , peptides, proteins, steroids and vaccine preparations. A group of preferred medicaments include adrenaline, albuterol, atropine, beclomethasone bipropionate, budesonide, butyclocortipropionate, clomastine, cromolyn, epinephrine, ephedrine, fentanyl,. flunisolide, fluticasone, formoterol, ipratropium bromide, isoproterenol, lidocaine, morphine, nedocromil, pentamidine isoethionate, pirbuterol, prednisolone, salmeterol, terbutaline, tetracycline, 4-amino-alpha, alpha-2-trimethyl-lH-imidazo [4, 5-c] quiniolin-1-ethanol, 2,5-diethyl-10-oxo-l, 2,4-triazole [1, 5-c] pyrimido [5, -b] [1,4] -thiazine, 1 - (1-ethylpropyl) -l-hydroxy-3-phenylurea and pharmaceutically acceptable salts and solvates thereof and mixtures thereof. Particularly preferred medicaments include beclomethasone dipropionate, butyxocort propionate, pirbuterol, 4-amino-alpha, alpha, 2-trimethyl-1H-imidazo [4, 5-c] quinolin-1-ethanol, 2,5-diethyl-10- oxo-l, 2,4-triazole [1, 5-c] pyrimido [5, 4-b] [1,4] thiazine, 1- (1-ethylpropyl) -l-hydroxy-3-phenylurea and salts and solvates pharmaceutically acceptable thereof and mixtures thereof. For oral and / or nasal inhalation, formulations wherein the medicament is in solution and chemically stable are generally preferred; however, if suspensions are used, preferably the medicament is micronized (that is, in the form of particles having a diameter of the order of microns). More preferably, a therapeutically effective fraction of the medicament (typically, about 90% or more) is in the form of particles having a diameter of less than about 10 microns and more preferably less than about 5 microns. These particle sizes are also applied for the formulations (medicine and biocompatible polymer) used in dry powder inhalers. This ensures that the medication can be inhaled into the respiratory system and / or lungs. It will be recognized that such limitations do not necessarily exist for nasal inhalation. Preferably, the medicinal formulations according to the present invention include a medicament in an amount and in a form such that the medicament can be administered as an aerosol. More preferably, the medicament is present in an amount such that the medicament can produce its desired therapeutic effect with a dose of a conventional aerosol canister with a conventional valve, such as a metered dose valve. As used herein, a "quantity" of the drug can be referred to in terms of quantity or concentration. A therapeutically effective amount of a medication may vary according to a variety of factors, such as the potency of the particular drug, the route of administration of the formulation, the mode of administration of the formulation and the mechanical system used to administer the formulation. A therapeutically effective amount of a particular medicament may be selected by those of ordinary skill in the art in consideration of such factors. In general, a therapeutically effective amount will be from about 0.02 parts to about 2 parts by weight based on 100 parts of the medicinal formulation.

Biocompatible polymers Preferred biocompatible polymers are condensation-type homopolymers or block or random copolymers. Examples of such polymers may be derivatives of a hydroxy acid, a mercapto acid, an amino acid or combinations thereof, such as described in U.S. Patent No. 5,569,450 (Duan et al.). Other examples of such polymers may be derivatives of the condensation of a diol with a diacid, such as described in International Patent Publication No. WO 94/21228. Preferably, the repetitive structural units contain amide units, ester units or mixtures thereof. A preferred class of condensation polymer includes at least one chain of at least 3 units of formula - [X-R1-C (O)] - (formula I) wherein: each R1 is an independently selected organic group (which it can be linear, branched or cyclic) linking the group X to the carbonyl group and each X is independently oxygen, sulfur or catenary nitrogen. Preferably X is oxygen. In particularly preferred embodiments, at least 50% of the units include oxygen as X. Another class of preferred condensation polymers include at least one chain of at least 3 units of formula - [C (O) -R2-C ( O) -0-R3-0] - (formula II) wherein: each R 2 is an independently selected organic group (which may be linear, branched or cyclic) linking the carbonyl groups and each R3 is an independently selected organic group (which may be linear, branched or cyclic) that binds the oxy groups. In the above formulas I and II, preferably each R1, R2 and R3 is a straight chain, branched chain or cyclic organic group (preferably an alkylene or alkenylene group) containing 1-6 carbon atoms (preferably 2). -6 carbon atoms). Each R1, R2 and R3 may also contain heteroatom functional groups such as carbonyl groups, oxygen atoms, thiol groups or fully substituted catenary nitrogen atoms, wherein the nitrogen substituents are free of nucleophilic or hydrogen-donor bonding functional groups of hydrogen. R1 preferably contains about 1-4 catenary atoms. Each R1, R2 and R3 can also be an arylene group (for example 1, 4-phenylene) or an arylene group substituted by functional groups such as lower alkylene groups, lower alkoxy groups and halogens (preferably, by functional groups not containing hydrogen atoms capable of forming hydrogen bonds, such as lower alkyl or alkoxy groups). As used herein, the term "lower" when used in relation to alkyl, alkenyl, alkoxy, alkenylene, alkylene, etc. groups refers to such groups having 1-4 carbon atoms. Each R1, R2 and / or R3 may also be a combination of such arylene, alkenylene and alkylene groups, such as 1,4-xylylene. The chain (s) comprising (n) the units of formulas I or II may be linear, branched or cyclic. Such polymers (ie, those containing chain units of formulas I or II) may also optionally include one or more ionic groups, a group containing one or more hydrogen atoms capable of forming hydrogen bonds, or a group that does not contain hydrogen atoms capable of forming hydrogen bonds. For compounds containing at least one chain comprising units of formula I, the chain (s) comprise (s) units derived from a precursor hydroxy acid, precursor amino acid mercapto acid precursor or combinations thereof, such as those described in U.S. Patent No. 5,569,450 (Duan et al.). For compounds containing at least one chain comprising units of formula II, the chain (s) comprise (s) units derived from a precursor diacid and a precursor diol. The chains can be homopolymer chains(ie, those derived from a single such diacid-1 and diol) or copolymer chains (eg, chains containing randomly distributed units or blocks of units derived from any of two or more such diacids or diols). As used herein a chain "derived from" a particular precursor need not be prepared from the precursor; rather, this terminology is used to designate chains that have a structure that could be formally obtained by condensing the precursor. For example, units of formula II are commonly referred to as diol / diacid condensate units, although those do not need to be prepared by condensing a diol with a diacid. Rather, this terminology is used to designate chains having a structure which could in principle be obtained by a condensation reaction of a diacid with a diol. A hydroxy acid precursor can be any hydroxy acid, such as a hydroxycarboxylic acid or the corresponding lactone or cyclic carbonate, if any. It is preferred that the hydroxy acid be endogenous to the human body. Examples of suitable hydroxycarboxylic acids include straight chain carboxylic hydroxyalkyl (2 to 6 carbon atoms) acids such as hydroxyacetic acid, hydroxypropionic acids (eg, 2- or 3-hydroxypropionic acid), hydroxybutyric acids (eg 2-, 3-, or 4-hydroxybutyric), hydroxyvaleric acids (for example 2-, 3-, 4- or 5- hydroxyvaleric acid), hydroxycaproic acid (for example 2-, 3-, 4-, 5- or 6-) hydroxy caproic), branched chain carboxylic hydroxy (3 to 6 carbon atoms) carboxylic acids (eg, 2-hydroxydimethylacetic acid), malic acid, malic acid monoesters and the like. Preferably, the hydroxy acid is an alpha- or a beta-hydroxycarboxylic acid and more preferably an alpha-hydroxycarboxylic acid. Suitable lactones include lactides, 1,4-dioxanone (ie p-dioxanone), valerolactone and caprolactone. Suitable cyclic carbonates include trimethylene carbonate. A precursor amino acid can be any compound having an amino group, preferably a secondary amino group, at least one carbon atom removed from an acid group such as a carboxylic acid. Exemplary amino acids include secondary amino acids (sometimes referred to as "imino acids") such as sarcosine and proline. Similar to the hydroxy acids discussed above, it is preferred that the aminocarboxylic acid be endogenous to the human body. A precursor acid mercapto can be any compound comprising a thiol group and an acid group such as a carboxylic acid group. Exemplary mercapto acids include 2-mercaptopropionic acid, 3-mercaptopropionic acid, and mercaptoacetic acid. A diacid precursor can be any dicarboxylic acid, for example straight chain, branched chain or cyclic alkylene or alkenylene dicarboxylic acids wherein the alkylene or alkenylene portion optionally contains heteroatom functional groups such as carbonyl groups, oxygen atoms, thiol or nitrogen groups catenary (preferably, fully replaced). Examples of such dicarboxylic acids include oxalic acid, malonic acid, succinic acid, pentan-hexan- and heptan-dioic acids and cis- or trans-1, 2-cyclohexanedicarboxylic acid. Other diacid precursors include aromatic diacids. Examples of such aromatic diacids include phthalic acid, 1,4-benzenedicarboxylic acid, isophthalic acid, 2,3-furanedicarboxylic acid, 1,2-benzenediacetic acid and the like. Preferred diacids are oxalic acid and diglycolic acid. The anhydrides corresponding to a dicarboxylic acid are also suitable. Examples of such anhydrides include succinic anhydrides, diglycolic anhydrides and the like. A precursor diol can be any dihydric alcohol. Suitable precursor diols include straight chain alkylene or alkenylene diols, branched or cyclic optionally containing heteroatom functional groups such as carbonyl groups, oxygen atoms, thiol groups or catenary nitrogen (preferably fully substituted). Examples of such diols include ethylene or propylene glycol, 1,4-butanediol, 1,6-hexanediol and the like. Other precursor diols include polyoxyalkylene diols. Examples of such diols include polyethylene glycol, polypropylene glycol and block copolymers comprising polyoxyethylene units and polyoxypropylene units. Particularly preferred embodiments include polymers wherein the chains comprise units derived from a precursor hydroxy acid (preferably an alpha- or a beta-hydroxy acid and more preferably an alpha-hydroxy acid). More preferably, the chain comprises units derived from a precursor selected from the group consisting of glycolic acid, trimethylene carbonate, alpha- or beta-hydroxybutyric acid, p-dioxanone and lactic acid. Of these, lactic acid is particularly preferable, either in the isomeric form D, the isomeric form L or a mixture of both isomers. Of these, the L form is most preferred, although certain applications, the DL form has some advantages due to its amorphous nature and improved solubility for example in hydrofluorocarbon propellants such as HFC 134a and 227. One skilled in the art can select units for inclusion in the chains of biocompatible polymers with consideration of factors such as mode of administration, ease of metabolism, solubility or dispersibility, crystallinity, structural homogeneity, molecular weight, other components when used in medicinal formulations, etc.

Preferred biocompatible polymers as described herein contain at least one chain of units of formula I. In certain embodiments, the compound can include two or more chains arranged, for example, in connection with divalent and polyvalent capping groups or by inclusion of monomers that cause branching. A chain can be capped at one end or both ends by a monovalent, divalent or polyvalent organic moiety (each valence of the crown group is independently linked to a chain) that does not contain hydrogen atoms capable of forming hydrogen bonds. The chain may also be capped at one or both ends by a monovalent, divalent or polyvalent group, either an ionic group or a group containing hydrogen atoms capable of forming hydrogen bonds. Such groups do not necessarily need to terminate the compound; rather, they can join the chains. Examples of groups that do not contain hydrogen atoms capable of forming hydrogen bonds include organocarbonyl groups such as acetyl and alkoxy groups such as ethoxy. Examples of ionic groups include quaternary ammonium groups, sulfonate salts, carboxylate salts and the like. Examples of groups capable of forming hydrogen bonds include hydrogen when linked to a heteroatom terminus or terminus of a chain, also as acid functional groups, amides, carbamates and groups such as amino, hydroxyl, thiol, aminoalkyl, alkylamino, hydroxyalkyl, hydroxyalkylamino, sugar residues and the like. Such end groups are well known and can be easily selected by those skilled in the art and are described for example in U.S. Patent No. 5,569,450 and International Publication No. WO 94/21228. The choice of extreme groups (that is, coronary groups) can modify the performance of the polymer, either in the formulation or biologically. It is preferred for regulatory and biological reasons to minimize the complexity of the biocompatible polymer. However, for physical and chemical reasons it may be preferable to modify the biocompatible polymer with respect to increased stability, solubility of the propellant (for example in hydrofluorocarbon), affinity / solubility in water, interaction with the drug, etc. Such parameters often influence the release rates of the drug. Preferred biocompatible polymers as described herein contain a chain capped on the hydroxy terminus with an organocarbonyl group and more preferably with an acetyl group. Acylation can significantly improve the. stability and reduce the hydrophilicity and water solubility of biocompatible polymers.

Additionally, the preferred biocompatible polymers as described herein contain a chain capped at the carbonyl end with a hydroxyl group or with an alkoxy group, such as an ethoxy group. The esterification can improve the biocompatibility and reduce the hydrophilicity and water solubility of the polymers. Preferably, the biocompatible polymers described herein are also biodegradable. As used herein, a "biocompatible" polymer is one that does not generally cause significant adverse reactions (e.g., toxic or antigenic responses) in the body, either degraded in the body, remains for extended periods of time or it is excreted as a whole. A "biodegradable" polymer is one that degrades relatively easily under biological conditions. Normally, biodegradation occurs initially through hydrolytic degradation (ie, hydrolysis of polymers to smaller molecules). The biocompatible polymers described herein can have a wide variety of molecular weights. Normally, they must have a number average molecular weight no greater than about 5000 (for example, where n is approximately 70) because the polymers having a much higher number average molecular weight than these in general are not readily biodegradable. Depending on the particular mode and the purpose (s) of the biocompatible polymer used herein, the polymers described herein will preferably have a number average molecular weight of at least about 350 and more preferably at least about 500 and more preferably greater than about 600. In other words, the biocompatible polymers will usually have a preferred chain length of at least 5 and more preferably at least 8 units. For most embodiments of the polymers containing chains comprising units of formulas I or II, the chain length (ie, the average number of monomer units in the chain, often referred to as "n") is defined as not greater than about 70 such units, preferably not greater than about 25 of the units, more preferably not greater than about 16 of the units and more preferably not greater than about 11 of the units. Also, the chain length is defined by at least about 3 of the units and preferably by at least about 5 of the units. In some embodiments, it is preferable that the compound be substantially free of water-soluble polymers such that, for example, the polymer does not dissolve rapidly upon delivery to body tissue, such as the lungs, but rather degrades in a desired period of time. In general, polymers having less than 8 repeating units tend to be soluble in water, while polymers having 8 or more repeating units tend to be relatively insoluble, although the precise chain length varies of course with the nature of the repetitive units and the nature of the end units of the chain. These various preferred molecular weights and chain lengths are by necessity only general principles since there are many factors, as will be understood by those skilled in the art, such as the type of particular polymers, end-capping groups and the presence and type of others. ingredients (propellants, excipients, etc.) that can greatly affect the choice of molecular weight used. It is well known that polymers contain a distribution of chain lengths. A particularly preferred embodiment of the present invention has a narrow range of chain lengths, to thereby provide a biocompatible polymer having a relatively narrow molecular distribution, that is, low polydispersity. However, in certain embodiments a broad molecular weight distribution may be desirable. The skilled artisan will recognize which distribution is preferred for a given application based on the degree of solubility, physical characteristics, biological compatibility and degradation, formulation processability and performance factors (eg, solubilization capacity, release rate control). of the drug, life in storage, reproducibility of the dose, etc.) of the compound. For certain embodiments of the present invention, suitable biocompatible polymers preferably have a relatively narrow molecular weight distribution. In general, for such embodiments polydispersity (that is, the ratio of weight average molecular weight to number average molecular weight) is less than about 1.8, preferably less than about 1.6. This is particularly true for certain sustained release formulations that use higher molecular weight polymers. Preferably, the polydispersity is less than about 1.4, more preferably less than about 1.3, and more preferably less than about 1.15. This is particularly true where improved physical characteristics of the composition in solid form are desirable or for an improved solubility in, for example, an aerosol propellant. In contrast, the polydispersity of the conventionally produced poly-L-lactic acid having a number average molecular weight of about 1000 or more generally ranges from about 1.6 to 3 with a typical polydispersity greater than 2.2. This is significant because in certain applications a relatively narrow molecular weight distribution provides a material that has an optimized rate of biodegradation. In certain applications this results in an appropriate rate of drug release and improved storage and handling life characteristics in its bulk form. Although it may be preferable to use polymers (described below) that have a relatively narrow molecular weight range, is not required in accordance with all aspects of the invention. For example, when poly-L-lactic acids of normal polydispersity are used in a formulation for pulmonary administration, it is preferred that the number average molecular weight of the polymer is not greater than about 800. Otherwise, depending on the frequency of administration , the highest molecular weight component can accumulate in the lungs. When using poly-L-lactic acids of narrow molecular weight range (ie, those having a polydispersity of less than about 1.15), however, the preferred number average molecular weight is preferably not greater than about 1300 and more preferably, for most inhalation applications, no greater than about 1000. Those skilled in the art will recognize that these parameters will vary with each monomer used. For example, when poly-DL-lactic acids of normal polydispersity are used in a formulation for pulmonary administration, it is preferred that the number-average molecular weight of the polymer be not greater than about 1800 and more preferably not greater than about 1200. another way, depending on the frequency of administration, the highest molecular weight component present can accumulate in the lungs. When using poly-DL-lactic acids of narrow molecular weight range (ie, those having a polydispersity of less than about 1.15), however, the preferred number average molecular weight is preferably not greater than about 2000 and more preferably, for most applications, no greater than about 1600. In general, it is desirable to use the lower molecular weight biocompatible polymer which still provides for an appropriate incorporation of the drug into the polymer matrix in administration, together with the speeds of release desired. As already indicated, it is generally preferred that the biocompatible polymers of the present invention be biodegradable. Preferably, such polymers are sufficiently biodegradable in such a way that they have a biological half-life (eg, in the lungs) of less than about 10 days, more preferably less than about 4 days, even more preferably less than about 2 days. and more preferably less than about 1 day. For certain embodiments of the present invention, the biocompatible polymers are sufficiently biodegradable in use in such a way that the medicinal formulations containing them have a biological half-life of less than about 7 days. Preferably, for embodiments, such as those formulations capable of being inhaled, the biological half-life is less than about 2 days (more preferably, less than about 1 day, even more preferably less than about 12 hours and more preferably less about 6 hours). As used herein, "biological half-life" is the time required for half the mass of the material to disappear from the original site in vivo. For certain embodiments of the present invention, the biocompatible polymer has a glass transition temperature (Tg) such that the vitreous transition temperature of a composition including the biocompatible polymer, a medicament and additional optional excipients is greater than about 23 °. C. That is, the Tg of the biocompatible compound (preferably biodegradable) may itself be greater or less than about 23 ° C, whereas that of a mixture of the biocompatible polymer with a medicament and optional excipients is greater than about 23 ° C. . Preferably and advantageously, this Tg can be achieved without the aid of additional excipients in the polymer. Usually, such preferred biocompatible polymers are polymers having a polydispersity of less than about 1.15. Surprisingly, it has been found that when the bicompatible polymer is combined with a medicament, the Tg of the mixture is usually greater than that of the biocompatible polymer itself, which returns to a wider range of polymers in the medicinal formulation in general morphologically stable in the storage. In general, the Tg of the biocompatible polymer is such that the Tg of a composition including the biocompatible polymer, a medicament and optional excipients is less than about 100 ° C although it is often much smaller than this. Thus, certain preferred biocompatible polymers described herein may be combined with a medicament to form a polymer matrix that degrades rapidly, morphologically stable in storage which may be in the form of a dispersion or dry powder, for example. Such biocompatible polymers are preferably homopolymers having linear chains of units derived from an alpha-hydroxy carboxylic acid, such as L-lactic acid and preferably have a number average molecular weight greater than 700 and not greater than about 1500 and more than preference not greater than about 1200 and a polydispersity of less than about 1.15. In other words, the length (s) of the preferred average chain of the polymer is about 10-16 units. The optimum amount of the biocompatible polymer depends on its nature, what function it provides in the formulation and the nature of the drug with which it is used. A practical upper limit in aerosol formulations is based on the solubility of the polymer. The solubility levels of the individual biocompatible polymers are a function of the molecular weight and polydispersity of the polymer, as well as the chemical nature of the repeating units and end groups. In general, the solubilities of the polyhydroxycarboxylic acids (for a given molecular weight) increase as their tendency towards crystallization decreases. For example, poly-DL-lactic acid is generally more soluble than poly-L-lactic acid. For aerosol formulations, the biocompatible polymer is generally present in dissolved form in an amount from about 0.01 parts to about 25 parts by weight based on 100 parts of the medicinal formulation, preferably from about 0.1 parts to about 10 parts by weight based on 100 parts of the medicinal formulation and for some applications preferably from about 1 part to about 5 parts by weight based on 100 parts of the medicinal formulation.Method for producing narrowly distributed polymers Polymers according to the present invention having a narrow molecular weight range (eg, a polydispersity of less than about 1.3 and preferably less than about 1.15) can be prepared by using a method of fractionation of supercritical fluid. The solvent power of the supercritical fluids can be adjusted by changing the density of the supercritical fluid (via pressure / temperature), hence either the amount of solute or solubilized maximum molecular weight can be selected by adjusting the pressure / temperature conditions. This adjustment capability provides a substantial benefit with respect to the fractionation of normal liquid solvents. Thus, the present invention provides a method for producing a polymeric compound having, for example, a number average molecular weight of not more than about 1500 and a significantly reduced polydispersity (eg, less than about 1.3 and preferably less than about 1.15). . The method comprises sequentially exposing the polymeric compounds to a supercritical fluid flow under different pressure / temperature conditions. The particular type of supercritical fluid apparatus used is not limited so long as the biocompatible polymer has good contact with the supercritical fluid. Thus, for example, the fractionation can be effected by using a single vessel with increased pressure profile techniques or alternatively a series of pressure vessels with reduced pressure profile techniques can be used. The supercritical fluid is preferably selected from the group consisting of carbon dioxide, 1,1,1,2-tetrafluoroethane (also referred to as propellant 134a, HFC-134a, or HFA-134a), 1,1,1,2, 3,3,3-heptafluoropropane) also referred to as propellant 227, HFC-227, or HFA-227), nitrogen dioxide, ethylene, ethane, trifluoromethane, xenon or combinations of the foregoing. While a wide variety of supercritical fluids are useful in the present invention, it is preferred that they be non-reactive with the biocompatible polymer that is fractionated and non-toxic. More preferably, the supercritical fluid is carbon dioxide.

This method of fractionating the polymer by using supercritical fluid provides significant advantages. In addition to unexpected technical superiority, it also provides advantages over conventional solvent fractionation that has high costs, environmental disadvantages and that raises health concerns due to residual contamination.

Solubilization of the drug and chemical stabilization It has been found that in certain aerosol formulations the medicament is more soluble when a biocompatible polymer as described herein is present than when the biocompatible polymer is not present. Of course, this depends on a variety of factors, such as the type and amount of the medicament as well as the type and amount of the biocompatible polymer. In some instances, the solubility is improved by a relatively high concentration (eg, greater than 1% by weight) of a biocompatible polymer of relatively low molecular weight (eg average MW in number less than about 350). Alternatively, a low to moderate concentration (for example 0.01 to 1% by weight) of a biocompatible polymer of higher molecular weight, (for example PM average in number greater than about 600) may increase the solubility of some drugs. Also, it has been found that in certain formulations, the dissolved drug is chemically more stable (and thus has a longer shelf life) with a biocompatible polymer as described herein than when it is in a formulation without such a biocompatible polymer. For example, it is known that aerosol formulations of medicaments containing amine groups often have a relatively short shelf life.; however, when combined with an appropriate biocompatible polymer (for example one that is capable of forming a salt with the medicament containing amine dissolved in the formulation) the shelf life can be improved. It should also be noted that the same biocompatible polymer can help solubilize a given medicament if it is present in a relatively large amount (greater than about 1 part by weight based on 100 parts of the medicinal formulation) and still function as a dispersion aid. if present in smaller amounts (for example less than about 0.1 parts by weight based on 100 parts of the medicinal formulation). In general, longer chain polymers having a molecular weight of at least about 600 that strongly interact with the drug are good solubilizers or solubilizers at lower weight percentages of the formulation, while shorter chain polymers are preferred. having a molecular weight of less than about 350 normally function as solubilizers at higher weight percentages of the formulation. However, these are general descriptions only, since the specific parameters vary with each drug / polymer combination. For aerosol formulations wherein the biocompatible polymer acts as a solubilization and / or chemical stabilization aid, the number average molecular weight is preferably not greater than about 1500, more preferably not greater than about 1200 and more preferably not greater than about 800.

Sustained release aerosol formulations A preferred embodiment of the present invention is a sustained release medicinal aerosol formulation that includes a propellant, a medicament and a soluble biocompatible polymer. Such medicinal formulations are preferably suitable for nasal and / or oral inhalation. This means, among other things, that when administered from a metered dose inhaler it forms particles of an appropriate size for nasal and / or oral inhalation and does not normally form film. These particles are formed spontaneously as the formulation leaves the aerosol valve and the propellant evaporates. Hence, although the biocompatible polymers described herein can be used to make preformed sustained release microparticles (e.g., microspheres) by conventional means, the present invention also provides a method for automatically generating sustained release microparticles of an aerosol spontaneously after the valve actuation, without requiring any preformed microparticle. That is, the method includes the steps of: preparing a sustained release medicinal aerosol formulation by combining components comprising a propellant and a sufficient amount of a biocompatible polymer substantially completely soluble in the medicinal formulation to provide sustained release of the medicament and a medicament as a micronized suspension or substantially completely dissolved in the medicinal formulation in a therapeutically effective amount; placing the medicinal formulation in a device capable of generating an aerosol (preferably, an aerosol container equipped with a valve and more preferably an aerosol container equipped with a metered dose valve); and actuating the device to form an aerosol comprising particles that are sufficiently stable to prevent aggregation and film formation under conditions of use.

A sustained release formulation is one that releases the medication over an extended period of time (for example, as brief as about 60 minutes or as long as several hours and even several days or months), rather than substantially instantaneously in the administration. Typically, for a polymer matrix of a particular size, the sustained release characteristics are determined by the nature of the biocompatible polymer and the medicament. It is also determined by the relative amount of the biocompatible polymer to the medicament. A sustained release medicinal formulation includes a biocompatible polymer in an amount such that the period of therapeutic activity of the medicament is increased in relation to the activity of the same formulation with respect to the propellant and medicament but without the biocompatible polymer. Preferably, this increase is by a factor of at least about 1.5. Alternatively, for certain embodiments, it is preferred that the sustained release medicinal formulation include a biocompatible polymer in an amount such that the period of therapeutic activity of the medicament is prolonged by the presence of the biocompatible polymer for at least about 30 more minutes preferably for at least about 2 hours and more preferably for at least about 6 hours. When used in aerosol formulations, it will be understood by those of ordinary skill in the art that a direct comparison of the same formulation without the biocompatible polymer may not be possible due to formulation difficulties when the biocompatible polymer is absent. Thus, a conventional dispersant and / or co-solvent may need to be added in the medicinal formulation to provide an inhalable formulation by comparing the period of time during which the medicament is present at levels necessary to obtain a desired biological response. Nevertheless, such formulation changes can prevent a perfectly parallel comparison of release rates. The amount of biocompatible polymer (total mass in relation to the medicament) that will be sufficient to provide sustained release over a desired period of time depends on, among other things, the form of the medicament. In the case of aerosol formulations containing in medicine in the form of micronized particles (that is, dispersed in the formulation), the amount of the biocompatible polymer (preferably biodegradable polymer) which will generally be sufficient is at least sufficient to provide a substantially complete layer or coating around the micronized particles after leaving the aerosol valve. This amount is commonly considerably greater than the amount that is used when such polymers are used only as dispersion aids. It is commonly at least about a molar ratio of 1: 1 of the biocompatible polymer to the medicament. Preferably, the molar ratio of the biocompatible polymer to the medicament is greater than about 4: 1 on a molar basis. Alternatively, on a basis by weight there will commonly be at least a ratio of about 1: 1 of biocompatible polymer to the medicament. Preferably, on a basis by weight there will commonly be at least a ratio of about 4: 1 and more preferably at least about a molar ratio of 8: 1 of biocompatible polymer to the medicament. In case of aerosol formulations containing the drug in solution (this is substantially completely dissolved in the formulation), the amount of the biocompatible polymer (preferably, biodegradable polymer) sufficient to provide sustained release varies considerably. In general, at least about a molar ratio of 1: 1 of biocompatible polymer to medicament is desirable, although minor amounts can be used to provide partial sustained release (eg, biphasic release, etc.) and / or as an adjuvant. solubilization for the medicine. Alternatively, on a basis of weight per step, the ratio of the polymer to the medicament is generally between about 1: 1 and about 100: 1. Preferably, the amount of biocompatible polymer for sustained release of a medicament in dissolved form is usually from about a ratio of 2: 1 to about 30: 1 of the biocompatible polymer to the drug and more preferably about 4: 1 to about 15: 1 on a weight basis. Again, however, the desired amount may depend on many factors in which the desired release times, nature of the drug or agents involved, the nature and number of biocompatible polymers used, as well as the weight (s) are included. ) molecular (s) average of the biocompatible polymer (s) and their polydispersities. In general, the larger weight ratios of polymer to medicament will lead to slower release rates of the drug. Those skilled in the art will readily be able, based on the teachings herein, to incorporate and determine the various factors to suit a particular application of the invention. For sustained release aerosol formulations, the number average molecular weight is generally not more than about 5000, commonly not more than about 1800, preferably not more than about 1200, and more preferably not more than about 800. Also, it is generally preferred that the molecular weight is greater than about 600. In other words, the average chain length of the polymer is preferably less than about 25 units, more preferably between about 5-20 units and more preferably between about 8. -14 units. As well, it is generally preferred to use the lower polydispersity that still provides the desired release rate.

Medical drug-polymer salts Certain biodegradable polymers described herein may be combined with a medicament to form a medicinal salt. Thus, medicinal salts are provided which include an ionic drug that includes at least one carboxylate group, an ammonium group or sulfonate group per molecule and a biodegradable polymer counter ion that includes at least one ammonium or conjugate base derived from a group carboxylic or sulfonic acid (preferably, carboxylic acid group) and a chain of at least 3 units of formula - [0-R1-C (O)] - discussed above. Preferably, the ionic drug includes at least one ammonium group and the biodegradable polymer counter ion includes at least one carboxylate group. The ammonium group refers to any ionic portion derived from amine (for example, groups derived from primary, secondary, tertiary and heterocyclic amines by protonation, also as quaternary ammonium). The molecular weights, polydispersity and other characteristics of the biocompatible polymers previously described herein are also generally applied herein, wherein the biodegradable polymer acts as a counter ion. The polydispersity and the molecular weight of the biodegradable polymeric counterions are important variables to determine the profile of availability of the drug with the passage of time. This is particularly true if mixtures or combinations of biodegradable polymer counterions having different molecular weight distributions are used, to thereby form bimodal, trimodal, etc. formulations. Preferably, the biodegradable polymers that form the medicinal salt are linear chains and have a number average molecular weight of not more than about 1500 (more preferably about 500 to about 1000). The preferred polydispersity and molecular weight will of course vary with the desired drug release profile. More preferably, the biodegradable polymer used in the formation of the medicinal salt is derived primarily from alpha-hydroxy carboxylic acids containing only one carboxylate group. Additionally, the polymer is preferably esterified on the hydroxy end with a low molecular weight acyl group. The biodegradable salt-forming polymer is preferably present in at least a molar ratio of 1 to 1 in relation to the salt-forming medicament and more preferably in at least one equivalent in relation to the salt-forming groups of the medicament. Under certain circumstances it may be advantageous to include an excess of the biodegradable polymer. Additionally, it is within the scope of the present invention to include a smaller amount of the biodegradable polymer, in particular where the unbound or bound drug has different pharmacokinetic behavior than the salt form. The medicinal salts may be substantially soluble or substantially insoluble in a propellant used in a medicinal aerosol formulation. They can also be used in non-aerosol formulations. Also, a medicinal salt can be dispersed within a matrix comprising a second biocompatible polymer (preferably, a biodegradable compound) which will preferably have a higher molecular weight than that of the biocompatible polymer that forms the salt with the medicament. This dispersion can be either homogeneous or it can be heterogeneous in such a way that the discrete domains of the salt are formed within the matrix. Preferably, the second biocompatible polymer forming "" "matrix is biodegradable of formula - [X-R1-C (0)] - and has a number average molecular weight greater than about 1800. However, formulations having the medicament and the biodegradable salt-forming polymer without any additional biocompatible polymer matrix compound are generally preferred.

Propellants Preferred medicinal formulations according to the present invention include a propellant. Suitable propellants include, for example, a chlorofluorocarbon (CFC), such as trichlorofluoromethane (also referred to as propellant 11), dichlorodifluoro-methane (also referred to as propellant 12) and 1,2-dichloro-1,1,2,2-tetrafluoroethane (also referred to as propellant 114), a hydrochlorofluorocarbon, a hydrofluorocarbon (HFC) , such as 1, 1, 1, 2-tetrafluoroethane (also referred to as propellant 134a, HFC-134a or HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (also referred to as propellant 227, HFC-227 or HFA-227), carbon dioxide, dimethyl ether, butane, propane or mixtures thereof. Preferably, the propellant includes a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon or mixtures thereof. More preferably, a hydrofluorocarbon is used as the propellant. More preferably, HFC-227 and / or HFC-134a are used as the propellant. The propellant is preferably present in an amount sufficient to propel a plurality of doses of the medicament from an aerosol container, preferably a metered dose inhaler. Conventional aerosol containers, such as those of aluminum, glass, stainless steel or polyethylene terephthalate can be used to contain the medicinal formulations according to the present invention. Aerosol containers equipped with conventional valves, preferably metered dose valves, can be used to deliver formulations of the invention. The selection of the appropriate valve assembly commonly depends on the components in the medicinal formulation.

Co-solvent and other additives The medicinal formulations according to the present invention can include an optional cosolvent or mixtures of cosolvents. The cosolvent can be used in an effective amount to dissolve the medicament and / or the biocompatible polymeric compound. Preferably, the cosolvent is used in an amount of about 0.01-25% by weight based on the total weight of the formulation). Non-limiting examples of suitable cosolvents include ethanol, isopropanol, acetone, ethyl lactate, dimethyl ether, menthol, tetrahydrofuran and ethyl acetate. Ethanol is a preferred co-solvent, although it is believed that in at least some circumstances ethanol may tend to degrade the polymer and hence, isopropanol or a less nucleophilic solvent may be preferred. Other additives (ie, excipients), such as lubricants, surfactants and taste masking ingredients may also be included in the medicinal formulations of the present invention.

EXPERIMENTAL EXAMPLES The following experimental examples are provided to further illustrate various specific and preferred embodiments and techniques of the invention. However, it should be understood that many variations and modifications can be made as long as it remains within the scope of the present invention. All parts and percentages are by weight unless otherwise indicated. All materials were used as obtained unless otherwise indicated. Solvents and inorganic reagents were obtained from EM Science, Gibbstown, NJ. Lactic acid and lactides were obtained from Purac America Inc., Lincolnshire, IL. All other reagents were obtained from Aldrich Chemical Co., Milwaukee, Wl. In the preparations of the biocompatible polymers summarized hereinafter, the structure and the average number (n) of the repetitive units in a chain were determined by 1 H nuclear magnetic resonance spectroscopy. The number-average molecular weight NM and the weight-average molecular weight MW were determined by using gel permeation chromatography (GPC) or supercritical fluid chromatography (SFC). The GPC instrument used was a Hewlett-Packard 1090-LUSI equipped with a UV detector set at 254 nm and a refractive index detector (HP1037A). The set of columns consisted of 500 Angstrom columns by Jordi Associates, Bellingham, MA. The samples were dissolved in tetrahydrofuran at a concentration of approximately 25 mg solid / ml and filtered under pressure through a 0.2 micron alpha cellulose filter. An injection size of 150 μL was manipulated by a Hewlett-Packard 9816 computer with programming elements provided by Nelson Analytical, Cupertino, CA. The molecular weight data are based on a calibration with polystyrene standards. The SFC instrument used was a Dionex / Lee 602 (Salt Lake City, Utah) equipped with a flame ionization detector at 425 ° C. The column consisted of a 10-meter film, 25% cyanopropyl, 50 micron inner diameter, 0.25 micron film from Dionex / Lee Scientific Div., Salt Lake City, Utah. The samples were derived with diazomethane, dissolved in chloroform at an approximate concentration of 20 mg of solid / 1 ml and filtered under pressure through a polyvinylidene fluoride filter (PVDF) of 0.2 microns. Direct injection of 200 μL took 0.1 seconds. The conditions were isothermal (110 ° C) when using supercritical C02 as the carrier gas with a continuous elevation of 0.71 MPa / minute from 8.1 MPa to 42 MPa. The molecular weight data are calculated from the area of each individual polymer. The individual polymers were identified by comparison of retention times against well-characterized, nominally monodispersed PLA samples. The thermal properties (vitreous transition temperature, melting temperature and degradation temperature; Tg, Tm, Teg) were determined by using a modified differential scanning calorimeter (DSC) TA Instruments, New Castle, DE. A linear heating rate of 5 ° C / minute with a perturbation amplitude of ± 1 ° C was applied every 60 seconds. The samples were examined by applying a heating-cooling-cyclic heating profile that ranges from -144.5 ° C to 244.5 ° C. The vitreous transition temperatures (Tg) reported were taken at the midpoint in the change of thermal capacity over the transition stage and were evaluated by using the inversion of the signal curves. The aerosol average mass aerodynamic diameters were determined by using a quartz crystal microblaster (QCM) cascade impact device (model PE2AS / 202/207, California Measurements Inc., Sierra Madre, CA) as described in Pharmaceutical Research , 12, S-181, 1995.

E xamples 1-21: Preparation of biocompatible polymers Example 1 L-lactide (200 g, 1.39 moles) and water (150 ml, Millipore, Bedford, MA) were placed in a 1-liter 3-necked flask equipped with a mechanical stirrer , distillation head and thermometer. The reaction was heated to 80 ° C and stirred under the atmosphere of hydrogen overnight. Then the flask was placed under a vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 10.5 hours the reaction was cooled to a temperature of 80 ° C and 600 ml of chloroform was added with stirring. The organic layer was extracted twice with 200 ml of water in a separatory funnel and dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The polymer was transferred to a clean 3-necked 1000 ml flask equipped as described above and 200 ml of acetic anhydride was added. The solution was stirred at a temperature of 80 ° C overnight under a slow purge of hydrogen. After 12 or more hours the remaining acetic anhydride and acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 180 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum on a rotary evaporator. Chloroform (600 ml) is added and the resulting solution extracted twice with Millipore water (200 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvent were separated under a high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 8.8, NM = 860, PM = 1151. The product was then distilled at a pressure of 0.4 mm of mercury at 156 ° C (3x) in a still or falling film molecular distiller to remove certain low molecular weight polymers to result in acetyl-poly (L-acid). -lactic) with n = 9.0, NM = 933, PM = 1233 (using GPC).

Example 2 L-lactide (300 grams, 2.08 moles) and water (300 ml, Millipore) were placed in a 3-liter neck flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 6 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (300 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 hours or more, the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 230 ml of tetrahydrofuran / water (85/15; v / v) were added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Ethyl acetate (700 ml) is added and the resulting solution is extracted 2 times with Millipore water (200 ml) in a separatory funnel and then dried with MgSO. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.4. The product was then distilled at a pressure of 0.4 mm of mercury and a temperature of 110 ° C (lx), 156 ° C (3x) in a still or falling film molecular distiller to separate certain low molecular weight polymers resulting in acetyl -poly (L-lactic acid) with n = 8.6, NM = 685, MW = 859 (by SFC).

Example 3 L-lactide (300 grams, 2.08 moles) and water (300 ml, Millipore) were placed in a 3-liter neck flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (14 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 10 hours the temperature was raised to 160 ° C. After a total of 13 hours the reaction was cooled to 80 ° C and acetic anhydride (220 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 hours or more, the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 230 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Chloroform (700 ml) is added and the resulting solution is extracted twice with Millipore water (300 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 9.52. The polymer was dissolved in ethyl acetate at 16.5% solids and isopropyl alcohol is added until the solution starts to turn turbid. The solution was sealed and allowed to settle throughout the night during which time some of the polymers precipitate. The solution was filtered through a fritted glass funnel "c" when using Na2S04 as a filtration aid. The filtration was repeated using a fritted glass funnel "f". The product was then distilled at a pressure of 0.4 mm of mercury and a temperature of 110 ° C (4x) in a still or falling film molecular distiller to remove certain low molecular weight polymers to result in acetyl-poly (L-acid). -lactic) with n = 9.9, NM = 666, MW = 882 (by SFC).

Example 4 L-lactide (300 grams, 1.38 moles) and water (200 ml, Millipore) were placed in a 3-liter necked flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 6 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (200 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 or more hours, the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 180 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Chloroform (600 ml) is added and the resulting solution extracted twice with Millipore water (200 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.6. The product was then distilled at a pressure of 0.4 mm mercury at 190 ° C (3x) in a still or falling film molecular distiller to remove certain low molecular weight polymers to result in acetyl-poly (L-lactic acid) with n = 9.2, NM = 529, PM = 707 (using SFC).

Example 5 DL-lactic acid (300 grams, 2.38 moles) was placed in a 3-liter necked flask equipped with a mechanical stirrer, distillation head and thermometer.

Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 8 hours the reaction was cooled to 80 ° C to provide poly (DL-lactic acid) with n = 6.4. Then the product was placed under vacuum (0.7 mm of mercury) and the temperature was again raised to 140 ° C for 2 hours to provide poly (DL-lactic acid) with n = 11.4, NM = 925, MW = 1670 (by GPC).

Example 6 L-lactide (300 grams, 2.08 moles) and water (300 ml, Millipore) were placed in a 3-liter neck flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 8 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (300 ml) was added. The solution was stirred at 80 ° C overnight under a slow nitrogen purge. After 12 hours or more, the remaining acetic anhydride and acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 270 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum from a rotary evaporator. Chloroform (750 ml) is added and the resulting solution extracted 3 times with Millipore water (250 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.4. Then the product was distilled at a pressure of 0.4 mm of mercury and a temperature of 110 ° C (2x), in a still or falling film molecular distiller to separate the polymers with two or less repetitive units to result in acetyl-poly (L-lactic acid) with n = 8.1, NM = 592, MW = 751 (by SFC).

Example 7 L-lactide (300 grams, 2.08 moles) and water (300 ml; Millipore) were placed in a 3-liter necked flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 8 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (300 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 or more hours, the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 270 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature allowed to drop to 60 ° C. After 15 minutes, the reaction mixture was transferred to a round bottom flask and the tetrahydrofurane was removed under vacuum in a rotary evaporator. Chloroform (750 ml) is added and the resulting solution extracted 3 times with Millipore water (250 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.5. Then the product was distilled at a pressure of 0.4 mm of mercury and a temperature of 110 ° C (lx), 156 ° C (3x) and 212 ° C in a still or falling film molecular distiller to separate certain low weight polymers molecular to yield acetyl-poly (L-lactic acid) with n = 13, NM = 958, MW = 1077 (by SFC).

Example 8. Five batches of acetyl-poly (L-lactic acid), prepared as in Example 7 were combined and distilled at 0.4 mm of mercury at a temperature of 212 ° C (2x) in a still or falling film molecular distiller to obtain an acetyl-poly (L-lactic acid) with n = 11.5. As described in Example 22, 8.52 g of this polymer was then placed in a sample extraction cartridge connected to a sequentially fractionated dense gas (DGM) handling system. The C02 flow of supercritical fluid is initiated at a pressure of 27.5 Bar and a temperature of 60 ° C and 2.76 g of acetyl-poly (L-lactic acid) are separated and discarded. A second fraction was collected at a pressure of 37.5 Bar and a temperature of 60 ° C to obtain 2.96 g of acetyl-poly (L-lactic acid) with n = 12.8, NM = 982, MW = 1087 (by SFC).

Example 9 L-lactic acid (258 grams, 2.08 moles) and water (300 ml, Millipore) were placed in a 3-liter neck flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 16 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (200 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 or more hours, the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 300 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 40 ° C. After 30 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofurane was removed under vacuum in a rotary evaporator. Chloroform (300 ml) was added and the resulting solution was extracted with water then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solution was diluted with hexane until a second phase was formed. The chloroform layer was collected and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were separated under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 14, NM = 1118, MW = 2100 (through GPC).

Example 10 L-lactide (199 grams, 1.38 moles) and water (200 ml; Millipore) were placed in a 3-liter necked flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 6 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (200 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 or more hours the acetic anhydride and remaining acetic acid were removed under vacuum. After the acetic acid / acetic anhydride distillation was complete, 180 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature is allowed to drop to 60 ° C. After 15 minutes, the reaction mixture was transferred to a bottom flask round and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Chloroform (600 ml) was added and the resulting solution was extracted twice with Millipore water (200 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.4. Then the product was distilled at a pressure of 0.4 mm of mercury and a temperature of 110 ° C (lx), 156 ° C (3x) and 212 ° C (2x) in a still or falling film molecular distiller to separate certain low molecular weight polymers to result in acetyl-poly (L-lactic acid) with n = 9.07, NM = 829, MW = 1038 (by GPC).

Example 11 L-lactide (300 grams, 2.08 moles) and water (300 ml, Millipore) were placed in a 3-liter neck flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 6 hours the reaction was cooled to a temperature of 80 ° C and acetic anhydride (300 ml) was added. The solution was stirred at a temperature of 80 ° C overnight under a slow nitrogen purge. After 12 or more hours the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 230 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Ethyl acetate (700 ml) is added and the resulting solution extracted 2 times with Millipore water (200 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.4. Then the product was distilled at 0.4 mm of mercury and a temperature of 110 ° C (2x), 156 ° C (3x) in a still or falling film molecular distiller to separate certain low molecular weight polymers to result in acetyl -poly (L-lactic acid) with n = 10, NM = 715, MW = 865 (by SFC).

Example 12 L-lactide (300 grams, 2.08 moles) and water (300 ml, Millipore) were placed in a 3-liter neck flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to a temperature of 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 4 hours the reaction was cooled to 80 ° C and acetic anhydride (300 ml) was added. The solution was stirred at 80 ° C overnight under a slow nitrogen purge. After 12 or more hours the acetic anhydride and remaining acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 180 ml of tetrahydrofuran / water was added (85/15; volume / volume) with stirring and allow the flask temperature to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Ethyl acetate (11) is added and the resulting solution is extracted twice with Millipore water. (200 ml) in a separatory funnel and then dried with MgS0. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 6.4. The product was then distilled at 0.4 mm of mercury and a temperature of 110 ° C (lx), 156 ° C (3x) in a still or falling film molecular distiller to separate certain low molecular weight polymers to result in acetyl- poly (L-lactic acid) with n = 6.64, NM = 524, MW = 576 (by SFC).

EXAMPLE 13 Six batches of acetyl-poly (L-lactic acid) with average n-values ranging from 5 to 9 were combined and the final solvent traces were separated under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus to a temperature of 90 ° C. Then the product was distilled at 0.4 mm mercury and 156 ° C (2x) in a still with falling film molecular distiller to separate the polymers to give acetyl-poly (L-lactic acid) with n = 8.54, NM = 162, MW = 1032 (by GPC).

Example 14 DL-lactic acid (150 grams of a nominal 85% solution in water, 1.42 moles) and glycolic acid (46.1 grams, 0.61 moles) were combined and heated (120-140 ° C) under vacuum of vacuum with stirring during 23 hours. Acetic anhydride (310 grams) is added and the resulting mixture is heated with stirring for about 150 minutes to remove the acetic acid. Water (146 ml) is added. The volatile components are separated by distillation under vacuum vacuum followed by rotary evaporation. The crude product was dried under high vacuum during the weekend. Then the crude product was extracted with chloroform. The chloroform extract was washed 4 times with dilute hydrochloric acid and then evaporated. The residue was dried under high vacuum overnight to provide 130 grams of acetyl-poly (DL-lactic-co-glycolic acid). Based on proton nuclear magnetic resonance spectroscopy, the product had a total chain length of n = 12 with an average of 8.7 units of lactic acid and 3.4 units of glycolic acid randomly distributed in it and where NM = 578 and MW = 867 (by GPC).

Example 15 L-lactic acid (200 grams of a nominal 85% solution in water, 1.89 moles) and toluene (1200 ml) were combined and heated for 24 hours to azeotropically remove in water. Acetic anhydride (289 grams, 2.84 moles) is added and the reaction is heated for an additional 2 hours. Water (50 ml) is added and the reaction mixture is heated for an additional hour, during which time 300 ml of solvent are removed. The volatile components are separated by distillation under vacuum vacuum followed by rotary evaporation. The crude product was dissolved in chloroform (80 ml). The chloroform solution was washed with dilute hydrochloric acid and then evaporated to give acetyl-poly (L-lactic acid). A portion of this material was chlorinated as follows: Oxalyl chloride (32.7 ml, 0.375 mole) was added dropwise to a cooled solution (0 ° C) containing acetyl-poly (L-lactic acid) (40 grams) in 1,2-dichloroethane (400 ml). The reaction mixture is stirred at a temperature of 0 ° C for one hour after the addition is consumed. The reaction mixture was heated slowly to a temperature of 45 ° C and stirred at that temperature overnight during which time most of the 1,2-dichloroethane evaporated. Oxalyl chloride added (10.9 ml) and 1,2-dichloroethane (250 ml) and the reaction mixture was heated to a temperature of 50 ° C for 1 hour. The reaction mixture was heated under vacuum vacuum to remove volatile components. The residue was dried from a rotary evaporator and then under high vacuum to provide 33.7 g of acetyl-poly (L-lactoyl) chloride where n = 4.7. Acetyl-poly (L-lactoyl) chloride (33.7 grams, 0.081 moles) was dissolved in chloroform (200 ml). Glycine (15.8 grams, 0.211 moles) is dissolved in sodium hydroxide (8.42 grams, 0.211 moles) in water (45 ml). The two solutions were combined and stirred at room temperature for 4 hours. Hydrochloric acid (25 ml) is added to adjust the pH to 2; then the reaction mixture was diluted with chloroform (80 ml). The phases were separated and the organic phase was evaporated to provide a crude product. The crude product was partitioned between chloroform and water. The chloroform layer was evaporated to provide material that by means of proton nuclear magnetic resonance spectroscopy consisted of a 70:30 mixture of acetyl-poly (L-lactoyl) N-glycine and acetyl-poly (L-lactic acid) with n = 4.0, NM = 491 and MW = 565 (by GPC).

EXAMPLE 16 DL-2-hydroxycaproic acid (1.00 grams, 0.0076 moles) was placed in a reaction minimaq (5 ml) equipped with a distillation head and magnetic spinning fin. The flask was heated at a temperature of 110 ° C for 24 hours under vacuum (vacuum). Acetic anhydride (1 gram) is added; 0.0098 moles) to the polymer, followed by heating at a temperature of 110 ° C for 18 hours. The acetic anhydride and excess acetic acid are distilled under vacuum. Tetrahydrofuran / water (1 ml of 85/15 volume / volume) is added with stirring and heating at 60 ° C for 0.5 hour. Most of the solvent is removed by vacuum distillation on a rotary evaporator. The resulting crude product was dissolved in chloroform (10 ml). The chloroform solution was washed twice with Millipore water (5 ml) and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvent were separated under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 120 ° C to provide acetyl-poly (DL-hydroxycaproic acid) with n = 7.4, NM = 830 and MW = 1214 (through GPC).

Example 17 DL-2-hydroxycaproic acid (1.00 grams, 0.0076 mole) and L-lactic acid (4.5 grams of a nominal 85% solution in water, 0.043 mole) were placed in a reaction flask equipped with a distillation head and mechanical agitator. The flask was heated at a temperature of 110 ° C for 6 hours under vacuum (vacuum) while the water was separated. Then the temperature was raised to 140 ° C for 6 hours. Acetic anhydride (5.16 grams, 0.0506 moles) is added to the polymer, followed by heating at a temperature of 80 ° C for 14 hours. The acetic anhydride and excess acetic acid were distilled under vacuum. Tetrahydrofuran / water (15 ml of 85/15; volume / volume) is added with stirring and heating at 60 ° C for 0.5 hour. Most of the solvent is removed by vacuum distillation on a rotary evaporator. The resulting crude product was dissolved in chloroform (20 ml). The chloroform solution was washed twice with Millipore water (5 ml) and then dried with MgSO. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvent were separated under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 120 ° C to provide acetyl-poly (DL-2-hydroxycaproic-co-L-lactic acid) with n = 7.5 for lactic acid and 1.4 for hydroxycaproic acid, NM = 763 and MW = 1044 (by GPC).

Example 18 L-lactide (8.72 grams, 0.061 moles), p-dioxanone (1.34 grams, 0.013 moles) and water (10 ml, Millipore) were placed in a 3-neck 50 ml flask equipped with mechanical stirrer, distillation head and thermometer. The reaction mixture was heated to 80 ° C and stirred under nitrogen atmosphere overnight. Then the flask was placed under vacuum (vacuum, 7 mm of mercury) and the temperature was raised to 110 ° C to distill the water. After 1 hour, 200 μl of tin octanoate (0.33 M in toluene) was added and the reaction proceeded for 16 hours. The flask was cooled to 80 ° C and 10 ml of acetic anhydride were added. The solution was stirred at 80 ° C overnight under a slow nitrogen purge. After 8 hours the remaining acetic anhydride and acetic acid were removed under vacuum. After the distillation of acetic acid and acetic anhydride was complete, 25 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes, the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum on a rotary evaporator. Chloroform (50 ml) was added and the resulting solution was extracted twice with 20 ml of Millipore water in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of the solvent and monomer were separated under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to produce acetyl-poly (dioxanone-co-L-lactic acid) with dioxanone n = 0.6, lactic acid n = 7.5.

Example 19 Various batches of acetyl-poly (L-lactic acid) were distilled at 0.4 mm of mercury at a temperature of 110 ° C (lx), 156 ° C (3x) and 212 ° C (3x) in a still or distiller Molecular descending film to obtain a low molecular weight polymer distillate, mainly with a range of n = 2-6 and an average n = 4.14. Then this distillate was distilled at a pressure of 0.4 mm of mercury and a temperature of 110 ° C (3x) in a still or falling film molecular distiller to result in acetyl-poly (L-lactic acid) with n = 4.96, mainly with a range of n = 3-6, NM = 383, MW = 406 (by SFC).

Example 20 L-lactide (300 grams, 2.08 moles) and water (300 ml; Millipore) were placed in a 3-liter necked flask equipped with a mechanical stirrer, distillation head and thermometer. The reaction was heated to 80 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was placed under vacuum (7 mm of mercury) and the temperature was raised to 140 ° C to distill the water. After 6 hours the reaction was cooled to 80 ° C and acetic anhydride was added (300 ml). The solution was stirred at 80 ° C overnight under a slow nitrogen purge. After 12 or more hours the remaining acetic anhydride and acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, 230 ml of tetrahydrofuran / water (85/15 v / v) was added with stirring and the flask temperature was allowed to drop to 60 ° C. After 15 minutes the reaction mixture was transferred to a round bottom flask and the tetrahydrofuran was removed under vacuum in a rotary evaporator. Chloroform (700 ml) is added and the resulting solution is extracted twice with Millipore water (200 ml) in a separatory funnel and then dried with MgSO4. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were removed under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactic acid) with n = 5.8. The product was then distilled at 0.4 mm of mercury and a temperature of 110 ° C (2x), 156 ° C (3x) in a still or falling film molecular distiller to separate certain low molecular weight polymers to result in acetyl- poly (L-lactic acid) with n = 6.5, NM = 708, MW = 803 (by GPC).

Example 21 L-lactide (200 grams, 1398 moles) and ethyl lactate (0.82 grams, 0.79 ml) were placed in a 250 ml single neck flask equipped with a stir bar and reflux head. The reaction was heated to a temperature of 150 ° C and stirred under a nitrogen atmosphere overnight. Then the flask was transferred to a Kugelrohr distillation unit and placed under vacuum (7 mm of mercury) at a temperature of 140 ° C with oscillation. After 6 hours the reaction was cooled to 80 ° C and acetic anhydride (15 ml) was added. The solution was stirred at 80 ° C overnight under a slow nitrogen purge. After 12 or more hours the remaining acetic anhydride and acetic acid were removed under vacuum. After the distillation of acetic acid / acetic anhydride was complete, the polymer was dissolved in 100 ml of acetonitrile and extracted with hexane (2 x 30 ml). The acetonitrile layer was transferred to a round bottom flask and the acetonitrile was removed under vacuum on a rotary evaporator. Chloroform (700 ml) was added and the resulting solution was extracted twice with Millipore water (200 ml) in a separatory funnel and then dried with MgSO. The mixture was filtered through a fritted glass funnel "d" and the solvent distilled from the polymer by rotary evaporation. The final traces of solvents were separated under high vacuum (0.4 mm of mercury) in a Kugelrohr apparatus at a temperature of 90 ° C to provide acetyl-poly (L-lactoyl) -O-hydroxyethane with n = 21.8, NM = 1530, PM = 2400 (by GPC).

Examples 22-23: Fractionation of polymers by supercritical fluid Fractionation of the polymer was carried out using a commercially available dense gas handling system (DGM) from Marc Sims SFE Inc. Berkeley, CA. by using supercritical fluid (SCF) techniques known to those skilled in the art. In a typical fractionation according to the present invention, PLA (8 grams) and 2 mm glass beads (20 g) were transferred to a 100 ml sample cartridge, then inserted into an extraction container of the handling system of dense gas of 300 ml. The sample cartridge was equipped with 30-micron metal alkaline fluxes at both ends. The C02 flow of supercritical fluid (99.99% anhydrous instrument grade from Oxygen Services Co., St. Paul, NM) was initiated at the temperature and pressure described in Tables 1 and 2 to separate each fraction in a glass tube in U-shape. As each fraction was collected, the U-tube was changed and the pressure was increased (optionally, the temperature could also be changed) and the flow of the supercritical fluid C02 was continued. After completion of the fractionation, the supercritical fluid C02 was vented at atmospheric pressure and the residual fraction was collected from the sample cartridge by dissolution in methylene chloride or ethyl acetate. These examples demonstrate the general ability of supercritical fluids to fractionate both derived (e.g., esterified) and non-derived polymers, as well as both amorphous and semi-crystalline polymers.

Example 22: Fractionation by Supercritical Fluid of the Polymer of Example 4 The ability of supercritical fluids to fractionate polyhydroxycarboxylic acids (eg acetylated) (PHA) and eliminate the selective distributions of the PHAs is shown in Table 1. In this example, the supercritical fluid fractionation of the semicrystalline L isomer derived from Example 4 results in 7 cuts, each with unique MLs and polydispersity distributions (P) narrower than the starting material.

Table 1 Fractionation by supercritical fluid of the polymer of example 4 Example 23: Supercritical Fluid Fractionation of the Polymer of Example 5 The ability of supercritical fluids to fractionate undifferentiated polyhydroxycarboxylic acids (e.g., containing a hydroxyl end group) (PHA) and eliminate selective PHA distributions is demonstrated in Table 2. In this example, the fractionation by supercritical fluid of the isomeric polymer DL without amorphous derivative of Example 5 resulted in 10 cuts, each with unique MLs and narrower distributions than the starting material.

Table 2 Fractionation by supercritical fluid of the polymer of Example 5 Examples 24-29. Properties of biocompatible polymers Example 24: Solubility properties Attempts to solubilize a variety of polylactic acids and polylactic / glycol copolymer in HFCl34a and HFC227 demonstrated that polyhydroxycarboxylic acids of the type previously used in the administration of pulmonary drugs, such as those described by E. Poyner, J. Cont. Reí. , 35, 41-48 (1995) (PLA2000) and L. Masinde, Int. J. Pharmaceutics, 100, 123-131 (1993) (PLA100, 000), were insoluble in HFCs. The poly-L-lactic acids obtained from Polysciences Inc., Warrington, PA, [L-PLA 100,000, 50,000 and 2,000 (Catalog Nos. 18402, 06529 and 18580)] were insoluble in ambient HFC134a and HFC227 at 0.1% in weight / weight after 10 minutes of sonication at ambient conditions. Likewise, the polylactic / glycolic acid copolymers [DL / PLAGA 5,000: 9/1 and 50,000: 8/2 (Nos. Catalog 19076 and 19077)] were insoluble at 0.1%. After one day, DL / PAGE 5,000: 9/1 exhibited partial solubility. Poly-DL-lactic acid [DL / PLA 20,000 (Catalog No. 16585)] was soluble at 0.1% but not fully soluble at 1%. The polymers, as exemplified by the compounds of Examples 1-21 were commonly completely soluble in HFC 227 at 1% by weight with levels that are commonly approaching 3%. The solubility levels of the polymeric hydroxycarboxylic acids were a portion of the molecular weight of the polymers and the polydispersity, as well as the chemical nature of the repeating units and end groups. In general, the solubilities of the polyhydroxycarboxylic acids were increased if their tendency towards crystallization was reduced. For example, DL-lactic acid was substantially more soluble than L-lactic acid which was more soluble than polyglycolic acid for a given molecular weight and polydispersity. Also, the lower molecular weight polymers were more soluble than their higher molecular weight counterparts. And for a specific molecular weight, the polymer with a lower polydispersity commonly exhibited a greater degree of solubility.

Example 25: Degradation of PA Comparative studies were carried out between polylactic acids of relatively low molecular weight (<1800, some with low polydispersity distributions of PM) and polylactic acid, with a nominal molecular weight of 2000 by subcutaneous implant of cylinders (10 x 1 mm) of PLA retained separately in woven polypropylene mesh envelopes (2 x 1 cm) in New Zealand rabbits. Polypropylene mesh envelopes were used to facilitate handling of the PLA compound of Example 6 and PLA2000 [Polysciences Inc., PA, (Catalog No. 18580)] and to facilitate the separation of the implants at the desired times. The explants were analyzed by NMR and quantified by supercritical fluid C02 chromatography (SFC). The compounds used are described in Table 3. The compound of Example 6 and PLA2000 are composed of undisturbed distributions of their molecular weights resulting from synthesis (ie, the distributions are substantially unchanged from those obtained by their synthesis). PLA2000 appears to be the lowest molecular weight polylactic acid that is commercially available in the present. The compounds of Examples 7 and 8 are examples of low polydispersity distributions of PLA with properties and unique value. The compound of Example 7 was obtained by separating molecular distillation of the very low molecular weight polymers (n = 1 to 7) from a "normal" distribution. The compound of Example 8 was obtained by fractionating supercritical fluid to separate the low and high molecular weight fractions from the original distribution.

Table 3 CFS analysis of polymers used in biodegradation studies Table 4 compares the degradation of narrow distribution polymers (polymers of examples 7 and 8) during the first 4 days of implantation with the polymers of normal distribution of example 6 and PLA2000. The polymers of Examples 6, 7 and 8 degrade rapidly with more than 85% of the absorbed polymer within 24 hours of the implant. The PLA 2000 had not begun to degrade after 4 days. Certainly, the degradation of PLA2000 was not observed even after 10 days. This observation is in agreement with the literature that indicates a half-life that fluctuates from 63 to 191 days for the PLA2000.

Table 4 Percent by weight remaining after implantation of most PLA Low molecular weight polymeric lactic acids are clearly rapidly absorbed in vivo which makes them highly desirable for applications requiring rapid separation. The degradation of polylactic acids is likely to be faster in preferred inhalation applications than those observed in the previous study. Degradation times are commonly correlated with the dimensions of the implant and the study of implants was carried out with relatively large cylindrical matrices which would be expected to degrade more slowly than the microparticles used in certain preferred inhalation applications of the invention. In addition, the lungs are a more robust environment, which is richer in esterases and other defense mechanisms, compared to a subcutaneous implant site. Additionally, in this implant study, significant amounts of unidentified compounds (which are not PLA) of biological origin were incorporated into the explant by the fourth day. The biological component interfered partially with the analysis of the implants and caused an overestimation of the amount of the remaining PLA. Hence, the observed degradation can be considered as the lowest probable degradation rate. Supporting this hypothesis, two metabolism studies (via intraperitoneal injection and aerosol inhalation in rats using PLA labeled with C14 radio of identical chemical composition and molecular weight distribution similar to the polymer of Example 6 in Table 3 exhibits an initial half-life of 2 hours with more than 80% that is eliminated within 24 hours In the first study, two Charles River CD male rats were dosed with 10 mg (0.24 μCi / mg) of radiolabeled PLA with 14 C of intraperitoneal injection of a DMSO solution (0.2 ml). Urine, fecal and complete C02 collections were made up to 4 days after the dose. The tissues were collected at the time of sacrifice. In the second study, the same compound was administered to 5 rats through an inhalation exposure in the nose for only 30 minutes. Doses were supplied from a HFC227 metered dose inhaler containing 0.9% PLA (51.5 μCi total) in a cylindrical chamber (34 cm height x 13.4 cm diameter) equipped with individual rat carrier tubes. All the contents of the bottle were administered to the rats. The rats were transferred to glass metabolism cages and urine, fecal and full C02 collections were made up to 3 days after the dose. The tissues were collected at the time of sacrifice. In both studies, the global waste of radiolabelled PLA with 14C resembles that of endogenous lactic acid as reported in the literature. These results clearly indicate that the low molecular weight hydroxycarboxylic acid polymers (PHA) have the highly desirable feature of rapid biodegradation that is necessary for the safe frequent inhalation of PHAs. These results also clearly indicate that hydroxycarboxylic acid polymers of narrow molecular weight distributions (compounds of Examples 7 and 8) have been obtained which retain the rapid absorption of conventional low molecular weight PLA. The following example demonstrates the improved physical properties of these relatively narrow molecular weight distributions.

Example 26: Vitreous transition temperatures (Tg) The glass transition temperatures Tg of the polymeric compounds of examples 6, 7, 8 and PLA2000 were determined by modulated DSC. The compound of Example 6 (NM = 592) had a Tg below room temperature (4.2 ° C). The compounds of example 7 (NM = 958,), example 8 (NM = 982) and PLA2000 (NM = 2150) had vitreous transition temperatures higher than room temperature (23 ° C, 25 ° C and 44 ° C respectively ). These data and those in Table 4 demonstrate that by modifying the naturally occurring distribution of the molecular weights (ie, polydispersity) of these polymeric compounds, relatively narrow molecular weight distributions can be obtained which retain the rapid bioabsorption. biodegradation of the compound of Example 6 while exhibiting vitreous transition temperatures Tg greater than room temperature. Thus, materials with Tg greater than room temperature were obtained by separating the low molecular weight polymers which results in an increase in NM. For polymers of the same chemical composition it is known that the vitreous transition temperatures Tg vary with the NM of the polymer as described by the Flory-Fox equation. The biodegradation times were shortened by controlling the weight percent of the high molecular weight polymers that slowly degrade, especially the polymers that have a tendency towards the formation of a crystalline phase. The polymers were fractionated into useful distributions by supercritical fluid techniques as shown in examples 22 and 23. Useful distributions were also obtained by separating low molecular weight polymers by the molecular distillation method discussed in U.S. Patent 5569450 (WO 94 / 21229) and exemplified by the compound of Example 7. The resulting combination of rapid biodegradation properties with good physical properties - is extremely useful for many drug delivery systems and is believed not to have been previously demonstrated by using PHA polymers or the like . For example, a preferred application of such formulations is in dry powder inhalers.

Example 27: Drugs in polymer matrices It is common for smaller molecules (eg plasticizer) to be added to the polymers to reduce and extend the Tg, thereby improving processing or polymer flexibility. Hence, there was the possibility that some drugs could behave as plasticizers when added to polymers, which would reduce the range of PHAs useful for solid preformed matrices, for example as used in dry powder inhalers. Accordingly, the effect of a variety of drugs on the compound of Example 7 was examined. Surprisingly, the data in Table 5 demonstrate that the drugs actually raise the Tg of the matrix, to allow a wider range of PHAs to be used due to the improved handling characteristics of the PHA-drug mixture. Thus, comparison of the Tg of the PHA matrix material (the compound of Example 7) with the Tg of the polymer composition with medicament present demonstrated an increase in the Tg of the polymer / drug mixture relative to the Tg of the material of original matrix. It is believed that this ability of the medicament to improve the material properties of the matrix material has not been previously reported. It will also be recognized that other biologically acceptable molecules (eg excipient) that are not the active agent can be added to improve the properties of the matrix material.

Table 5 Table 5 Effect of the drug on the Tg of P A (continued) Changes in the melting point of the drug (Tm) as determined in a modulated DSC provide evidence of salt formation between the medicament and the PLA of Example 7 as shown in Table 6. Salts were prepared by mixing appropriate solutions (e.g., acetone, chloroform, methanol) of the drug and PLA in the desired proportion, followed by evaporation and extensive drying under high vacuum to remove all traces of the solvent. As the examples below demonstrate, these new salt complexes alter the bioavailability of the drug and may provide a new way to control the release of the drug. Among PHAs, alpha-PHAs are preferred because they exhibit very low pKa (>3.5) and are rapidly biodegraded. Bioavailability is frequently correlated with the water solubility of the drug-complex. The solubility in water of PHAs is dependent on the molecular weight and the nature of the end groups. For example, the non-esterified polylactic acid is soluble in water up to a molecular weight of 522 (7 repetitive units) some authors report up to 882 (12 repetitive units) as soluble in water. Acetylated polylactic acids are not soluble in water beyond 276 (3 repetitive units). Thus, for example, if an acetylated polylactic acid of molecular weight greater than 564 is used it is unlikely to provide a water-soluble complex until the chain has been hydrolyzed into an ester linkage. The molecular weight of the acetylated polymer necessary to provide an insoluble salt is dependent on the nature of the medicament and the end group used. It will be recognized that the characteristics (PM, distribution, chemical nature, extreme groups, etc.) of the polymeric counterion will be important for the final pharmacokinetics of the drug. In addition, the ability to provide adapted kinetics (eg, zero-order, pulsed) must be possible by combining different polymers. Thus, the biodegradability of-Cx contraion provides a new method to alter the drug's pharmacokinetics. Additionally, the increased thermal stability of the salt complex with respect to the free base drug exemplifies the utility of such polymers as stabilizers. In the preferred application (MDI) the ability of PHAs to form stabilizing salts with amine-containing medicaments is especially valuable when the salts are soluble in the propellant formulation (such as HFC 134a and 227).

Table 6 Thermal properties Example 29: Polymers as solubilization aids The insolubility of many drugs together with the normally deficient shelf life (long-term chemical stability) of those drugs that can form solutions has presented a general problem to the formulators. The stabilizing effect of PHAs is presented in Table 6. The general utility of PHAs to aid in the preparation of formulations in propellant solution has been demonstrated for example by the ability of polylactic acids to increase the solubility of drugs in the HFC propellants 134a and 227. The solubilizing effect of the polymers is shown in Table 7. It also shows the effect of co-solvents and polymer structure on the ability of the polymer to function as a solubilizer for a given medicament. When cosolvents were present, sometimes synergistic increases in solubility were observed. The utility of PHAs to provide formulations in stable solution provides a significant advance in the technique of administration of medicaments by inhalation.

Table 7 Solubilization of drugs in propellant% by weight of PLA * data not collected Examples 30-34: sustained release formulations The PLA formulations shown in Table 8 were prepared and tested for sustained release in vivo. PLA was used to prepare aerosol formulations in solution and suspension using the following general method. Medications and PLA were weighed in a 120 ml glass aerosol bottle together with the necessary cosolvent. A continuous or dosed valve was clamped onto the vial and the flask was filled under pressure with propellant, either HFC 134a or HFC 227 to provide a concentrated solution containing the desired wt% PLA and medicament. Then the concentrated solutions were used as such or transferred by cold filling to 15 ml bottles equipped with metered dose valves using techniques known in the art. The following medicaments were used: 4-amino-a, a-2-trimethyl-1H-imidazo [4, 5-c] quinolin-1-ethanol ("IMQ") described in Comparative Example Cl in U.S. Patent No. 5, 266, 575; 2, 5-diethyl-10-oxo-l, 2,4-triazole [1, 5-c] pyrimido- [5, 4-b] [1,4] thiazine ("PD4") and described as example 148 in U.S. Patent No. 4,981,850; 1- (1-ethylpropyl) -l-hydroxy-3-phenylurea ("5L0") and described as compound 42 in International Publication No. WO 96/03983; butixocort propionate ("BTX") and beclomethasone dipropionate ("BDP").

Table 8 Example 30: Sustained Release of IM The formulation of Example 30 in Table 8 and its PLA-free analog were administered to mice by inhalation. Typical inhalation exposure systems consist but are not limited to an aerosol generator, for example an MDI, an aerosol expansion space and a box device that ensures that animals must inhale the aerosol, for example an inhalation chamber. through flow Normally, the animals were exposed to 20 drives per minute for 25 minutes of an average MAD aerosol of 2 microns generated by MDI. Lung lavage and bleeding of the exposed mice were carried out by standard methods known to those skilled in the art and tumor necrosis factor (TNF) analysis was performed by a specific ELISA method for TNF in the mouse (Genzyme Immunobiologicals, Cambridge, MA). TNF is a marker for the activity of this medication. The IMQ pulmonary therapy application prefers the activity of the medication located in the lung. Therefore, it was desirable to maintain high levels of medication in the lung and minimize systemic medication. However, this formulation and method could also be clearly used to provide long-term release of IMQ or analogous compounds for systemic applications. The results are presented in Table 9. Wash numbers are measurements of TNF levels in the lungs while serum levels measure systemic TNF levels.

Table 9 Matos not collected These results show that IMQ only produces the highest activity, as seen by the reduction of TNF in the serum instead of in the lung lavage. The addition of TLA reverses this result by causing the increased activity of TNF production in the lung along with the longer duration of activity in the lung. The IMQ was used in its free base form and thus formed a biodegradable salt complex with the compound of Example 9. The biodegradable polymer-IMQ salt was soluble in the HFC-based propellant system. This example also demonstrates the generation of microspheres for the sustained release and utility of biodegradable polymeric counterions in the administration of medicament.

Example 31: Sustained Release of BDP The formulation of Example 31 in Table 8 and its PLA-free analog were administered to adult dogs by inhalation. Sedated dogs were intubated with a low-pressure cuff endotracheal tube (Hi-Lo Jet®, Mallinkrodt, Glen Falls, NY). The side hole was fitted with a Delrin® actuator and in MDI it was fired through the side hole tube normally 20 times in the course of 10 minutes. Serum samples were collected with respect to time and analyzed for the metabolite of beclomethasone dipropionate, specifically free beclomethasone. The results are presented in table 10.

Table 10 These results show that BDP only produces serum metabolite levels rapidly, which follows a short residence time of BDP in the lung. BDP / PLA not only causes a delay in the appearance of the metabolite in the serum but also results in higher levels in a longer time, which shows that the BDP / PLA formulation results in a residence time in the lungs longer. Previous experiments indicate that the BDP had only commonly reached peak or peak concentrations at 350 minutes after exposure. BDP is a steroid and lacks the ability to form a salt complex with compound of Example 13. Hence, this example demonstrates the utility of biodegradable polymeric hydroxycarboxylic acids with hydrophobic drugs in the administration of the sustained release medicament. This biodegradable polymer and non-salt-forming steroid were soluble in the propellant system based on HFC and provide another example of the generation of microspheres for sustained release.

Example 32: Sustained Release of Butixocort Propionate The formulation of Example 32 in Table 8 and its PLA-free analog were administered to the respiratory system and lungs of adult dogs. Sedated dogs were intubated with a low pressure cuff endotrachial tube (Hi-Lo Jet®, Mallinkrodt, Glen Falls, NY). The side hole was fitted with a Delrin® actuator and the MDI was fired through the side hole tube. Blood samples were collected from the dogs and the primary BTX metabolite (JO-1605) was analyzed. The results are presented in table 11.

Table 11 * data not collected These results showed that after the exposure of BTX, the appearance of the metabolite (JO-1605) in the blood was rapid, had a peak soon and was administered quickly. The addition of the compound of Example 1 to BTX caused the presence of JO-1605 to be extensively extended as compared to the formulation without PLA. Thus, PLA formulations exhibit an increased residence time of the drug in the lungs. BTX is a steroid and lacks the ability to form a salt complex with polymers. Hence, this example demonstrates the utility of the biodegradable polymeric hydroxycarboxylic acids with the hydrophobic drugs in the administration of the sustained release medicament and provides another example of the generation of microsphere particles for sustained release.

Example 33: Sustained Release of PD4 The MDI formulation of Example 33 in Table 8 and its PLA-free analog were administered to mice by inhalation and the amount of PD4 was determined for the lavage fluid of the lung and serum. Typical inhalation exposure systems consisted, but were not limited to, an aerosol generator, for example an MDI, an aerosol expansion space and a box device ensures that the animals should inhale the aerosol, for example a chamber through flow inhalation. Normally, 15 mice were continuously exposed to a MMAD aerosol of 0.88 microns from a pressure vessel for 11 minutes. The results are presented in table 12.

Table 12 Time (minutes) PD4 with the compound of Ex. 1 (μg) PD4 (μg) after dosing Washing serum wash serum 10 0.342 2.81 0.032 3.19 60 0.146 2.02 0.008 7.38 These results demonstrate that PD4 only produces reduced levels of drug in the lung lavage fluid and large proportions in the serum. PD4 / PLA produces much higher levels of drug in the lavage fluid and smaller proportional amounts in serum, especially after 60 minutes after exposure, suggesting that PLA causes a residence time of the drug in the lung more long. This example demonstrates the utility of aerosol formulations of sustained release localized administration and salt formation.

Example 34: Sustained Release of 5LO The formulation of Example 34 in Table 8 and its PLA-free analog were administered to Indian Harley scale insects by inhalation and evaluated by the early-stage anaphylactic response test of cochineals of the Indies. Typical inhalation exposure systems consisted of an aerosol generator, for example, an MDI, a 150 ml aerosol expansion chamber and a tracheal cannula. Each cochineal received 5 drives containing 32 ultragrams of medicine / drive. The Indian mealybugs were treated by antigen (ovalbumin) at various times and dynamic pulmonary compliance was tested using a Buxco pulmonary mechanical analyzer (Buxco Electronics, Sharon CT) according to the method of Amdur and Mead (The American Journal of Physiology , Vol. 92, pp. 364-368 (1958)). The results are presented in table 13.

Table 13 * data not collected These results demonstrate that the activity of 5LO as measured by inhibition of bronchoconstriction was premature at the bottom at the 60 minute time point compared to the activity of 5LO / PLA exhibiting activity of at least 120 minutes Thus, the PLA causes the sustained activity of the 5LO.

Example 35-60: In vitro sustained release studies To minimize the use in animals associated with in vivo studies a variety of in vitro studies were carried out to further exemplify the invention. These studies were based on the release of the drug from a matrix impregnated with PLA-drug. The matrix was used to facilitate the management of the systems and did not affect the release of the medication. In a typical example, the medicament (exemplified by lidocaine (1.46 mg, 6.24 mM) and PLA (exemplified by the compound of example 10) were dissolved in 125 ml of acetone.To 50 ml of this solution, 72 paper discs are added filter (2.54 cm (one inch) in diameter) and allowed to soak for 15 hours After drying by air, discs impregnated with PLA were dried under reduced pressure (0.05 mm of mercury) for 2 hours. discs were then placed in separate 29.6 ml (1 oz) bottles containing 5 ml 0.02 M acetate pH buffer. At the desired test times, an aliquot is separated, acidified with 0.1 M HCl at a pH of 1 and filtered through a 0.2 μ PTFE filter (Millipore) and the absorbance is read at the desired wavelength (for example, 264 nanometers for lidocaine) to determine the amount of medication released. The method used above was used to prepare the specific compositions in Table 14. The data in Table 14 present the effect that the PHAs had on the release of the selected compounds. The discs impregnated with the medication only released the medication within 5 minutes.

PLAGA is Medisorb 85% DL-lactide-15% glycolide, IV 0.76, NM = 160,000 Matos not collected.

The PHA formulations shown in Table 15 were prepared for use in metered dose inhalers. PHA was used to prepare aerosol formulations in solution and suspension of the invention using the following general method. The active agent and the PHA were weighed in a 120 ml (4 inch) aerosol canister together with the cosolvent if necessary. A continuous valve was clamped on the flask and the flask was filled under pressure with propellant, either HFC 134a or HCF 227, to provide a concentrated solution containing the desired wt% PHA and medicament (optionally with a codisovente). The use of glass jars allowed the visual evaluation of the formulation. Using standard techniques known in the art, the formulations were cooled with dry ice to allow cold transfer to smaller bottles equipped with metered dose valves. Then the metered dose valve were actuated and the average mass aerodynamic diameters (MMAD) of the aerosol thus produced were determined by using a quartz crystal microvalve.

Table 15 Matos not collected These results show that a variety of PHAs are capable of being formulated with a variety of drug classes in solution and suspension formulations. These formulations were able to form microparticles composed of PHA and medicament with average mass aerodynamic diameters suitable for inhalation. The detailed description and previous examples have been provided for clarity of understanding only. No unnecessary limitations of the same will be understood. The invention is not limited to the exact details shown and described, obvious variations for those skilled in the art proposed to be included in the invention are defined by the claims.

Claims (34)

1. . Rei indications 1. A medicinal aerosol solution formulation characterized in that it comprises: (a) a biocompatible polymer dissolved substantially completely in the formulation; the biocompatilbe polymer comprises at least one chain of units of the formula - [X-R1-C (0)] - wherein: (i) each R1 is an independently selected organic group that links the -X- group to the carbonyl group; and (ii) each X is independently oxygen, sulfur or catenary nitrogen: (b) a propellant and (c) a medicament substantially completely dissolved in the formulation in a therapeutically effective amount.
2. 2. The formulation according to claim 1, characterized in that the medicament exhibits increased solubility in the propellant due to the biocompatible polymer.
3. 3. The formulation according to claim 1, characterized in that the medicament exhibits increased chemical stability due to the biocompatible polymer.
4. 4. A sustained release medicinal formulation characterized in that it comprises: (a) a propellant; (b) a therapeutically effective amount of a medicament and (c) a sufficient amount of a biocompatible polymer dissolved substantially completely in the formulation to provide sustained release of the medicament; wherein the sustained release formulation results in discrete particles that do not form a film during administration.
5. 5. The sustained release formulation according to claim 4, characterized in that the biocompatible polymer comprises at least one chain of units of formula - [X-R1-C (O)] - wherein: (a) each R1 is an independently selected organic group linking the group X to the carbonyl group; and (b) each X is independently oxygen, sulfur or catenary nitrogen.
6. 6. The formulation according to claim 1 or 4, characterized in that the biocompatible polymer is present in an amount greater than 1 part by weight based on 100 parts of the formulation.
7. 7. The formulation according to claims 1, 4 or 11 characterized in that the biocompatible polymer or biodegradable polymeric counterion is present in at least about a molar ratio of 1: 1 of the biocompatible polymer to the medicament.
8. The formulation according to claim 1 or 4, characterized in that the formulation comprises approximately 0.01-25 parts by weight of the biocompatible polymer based on 100 parts of the formulation.
9. 9. The formulation according to claim 1 or 4, characterized in that it comprises ethanol.
10. A biodegradable medicinal composition characterized in that it comprises: a therapeutically effective amount of a medicament and a biodegradable polymer comprising at least one chain of units of the formula - [0-R1-C (O)] - wherein: (a) each R1 is an independently selected organic group that links the -O- atom to the carbonyl group and (b) the polymer has a number average molecular weight of no greater than about 1800 and a polydispersity of less than about 1.2.
11. 11. A medicinal salt composition characterized in that it comprises: (a) an ionic drug comprising at least one ammonium, sulfonate or carboxylate group per molecule and (b) a biodegradable polymeric counterion comprising at least one ammonium, sulfonate or carboxylate group and at least one chain of at least three units of formula - [0-Rx-C (O)] - wherein each R1 is an independently selected organic group that links the oxygen atom to the carbonyl group.
12. The medicinal salt composition according to claim 11, characterized in that it is dispersed within a matrix of a second biocompatible polymer that is substantially incapable of forming a salt with the medicament.
13. The medicinal salt composition according to claim 11, characterized in that the second biocompatible polymer has a number average molecular weight greater than about 1800.
14. 14. The medicinal salt composition according to claim 11, characterized in that the second biocompatible polymer includes at least one chain of at least three units of formula - [X-R1-C (O)] - wherein: (a) each R1 is an independently selected organic group that binds the group X to the carbonyl group and (b) each X is independently oxygen, sulfur or catenary nitrogen.
15. 15. The medicinal salt composition according to claim 14, characterized in that the chain of the second biocompatible polymer comprises units derived from one or more hydroxy acid precursors.
16. 16. The composition according to claim 10 or 11, characterized in that it is in the form of microspheres.
17. 17. The composition according to claim 10 or 11, characterized in that it has a glass transition temperature greater than about 23 ° C.
18. 18. The formulation or composition according to claim 1 or 5, characterized in that each X is oxygen.
19. The formulation or composition according to claim 1, 4, 10 or 11, characterized in that the biocompatible polymer chain comprises units derived from one or more hydroxy acid precursors.
20. The formulation or composition according to claim 19, characterized in that the biocompatible polymer chain comprises units derived from one or more precursors selected from the group consisting of glycolic acid, trimethylene carbonate, hydroxybutyric acids, p-dioxanone, L acid -lactic and D-lactic acid.
21. 21. The formulation or composition according to claim 20, characterized in that the biodegradable polymer comprises units derived from L-lactic acid.
22. 22. The formulation or composition according to claim 1 or 4, characterized in that the biocompatible polymer is biodegradable.
23. 23. The formulation or composition according to claim 10, 11 or 12, characterized in that the biodegradable polymer has a number average molecular weight of not more than about 1500.
24. The formulation or composition according to claim 1, 5, 10 or 11, characterized in that the biocompatible polymer has an average chain length of about 3-25 of the units.
25. 25. The formulation or composition according to claim 24, characterized in that the biocompatible polymer chain comprises units derived from lactic acid and has an average chain length of about 3-25 of the units.
26. 26. The formulation or composition according to claim 1, 4 or 11 characterized in that the bicompatible polymer has a polydispersity of less than about 1.4.
27. 27. The formulation or composition according to claim 1, 5, 10 or 11, characterized in that the biocompatible polymer is crowned on at least one end by an acetyl group.
28. 28. The formulation or composition according to claim 1, 4, 10 or 11, characterized in that the medicament is selected from the group consisting of adrenaline, albuterol, atropine, beclomethasone dipropionate, budesonide, butyxocort propionate, clomastine, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, fluticasone, formoterol, ipratropium bromide, isoproterenol, lidocaine, morphine, nedocromil, pentamidine isoethionate,? irbuterol, predisolone, salmeterol, terbutaline, tetracycline, 4-amino-a, a-2-trimethyl -III-i idazo [4, 5-c] quinolin-1-ethanol, 2,5-diethyl-10-oxo-l, 2,4-triazole [1, 5-b] pyrimido [5, 4-b] [1,4] thiazine, 1- (1-ethylpropyl) -l-hydroxy-3-phenylurea and pharmaceutically acceptable salts and solvates thereof and mixtures thereof.
29. 29. A metered dose inhaler for delivering a formulation or composition, characterized in that it comprises: an aerosol container equipped with a metered dose valve and containing a formulation according to claim 1 or 4 or a propellant and a compliant composition with claims 10 or 11, suitable for nasal and / or oral inhalation.
30. 30. The metered dose inhaler according to claim 29, characterized in that the propellant comprises a hydrofluorocarbon.
31. The metered dose inhaler according to claim 30, characterized in that the propellant comprises 1,1,1,2-tetrafluoroethane, 1, 1, 1, 2, 3, 3, 3-hepta-fluoropropane or a mixture of the same.
32. 32. A method for improving the physical and degradation characteristics of a biodegradable condensation-type polymer comprising fractionating the polymer with a supercritical fluid to obtain a polydispersity of less than about 1.3 and a number average molecular weight of not greater than about 1800.
33. 33. The method according to claim 32, characterized in that the polymer comprises at least one chain of units of formula - [X-R1-C (O)] - wherein: (a) each R1 is a selected organic group independently linking the group X to the carbonyl group and (b) each X is independently oxygen, sulfur or catenary nitrogen.
34. 34. The method according to claim 32, characterized in that the supercritical fluid is selected from the group consisting of carbon dioxide, 1,1,1-tetrafluoroethane, 1,1,1,3,3,3 -heptafluoropropane and nitrogen dioxide.