Title:  Biocompatible compounds for pharmaceutical drug delivery systems

United States Patent:  6,126,919

Inventors:  Stefely; James S. (Woodbury, MN); Schultz; David W. (Pine Springs, MN); Schallinger; Luke E. (Maplewood, MN); Perman; Craig A. (Woodbury, MN); Leach; Chester L. (Lake Elmo, MN); Duan; Daniel C. (St. Paul, MN)

Appl. No.:  797803

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.

SUMMARY OF THE INVENTION

The methods, compounds, and medicinal formulations of the present invention provide broadly applicable means for delivery of a drug. They are particularly useful for drug solubilization and chemical stabilization, as well as for providing sustained release of drug from a drug delivery system, such as topical, implantable, and inhalation systems. Additionally, means are provided for improving the physical and degradation characteristics of 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 drug delivery, such as by inhalation from a metered dose inhaler.

Biocompatible Polymers

All of the formulations of the present invention utilize one or more biocompatible, and preferably biodegradable, polymeric compounds. As used herein, "polymer" and "polymeric" are, unless otherwise indicated, intended to broadly include homopolymers and block/random copolymers (and oligomers) including a chain of at least three or more monomer structural units formed by polymerization reactions (e.g., condensation or ring-opening polymerization). Preferred biocompatible polymers are biodegradable and are preferably formed by a condensation type polymerization. For some preferred embodiments, the biocompatible polymers are homopolymers, while for others they are copolymers. Preferably, the repeating structural units contain amide units, ester units, or mixtures thereof.

Preferred such biocompatible polymers include at least one chain of units 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. Such compounds can include chains having different R¹ groups, although for certain embodiments each R¹ moiety is the same. The preferred X group is oxygen. Particularly preferred biocompatible polymers are relatively low molecular weight polylactic acids (PLAs). One reason they are preferred is because lactic acid is well known to be endogenous in humans, highly biocompatible and, therefore, desirable from a regulatory approval standpoint. Other biocompatible polymers are also useful in methods and formulations according to the present invention. For example, homopolymers and copolymers of lactic acid, glycolic acid, trimethylene carbonate, hydroxybutyric acid, and p-dioxanone have all been found to be particularly useful in various embodiments of the present invention. In particular, polydioxanone and polylactic-co-glycolic acids are well established as being biocompatible and, accordingly, are also good candidates from a regulatory approval standpoint.

It is also sometimes preferred that one or more chains of the biocompatible polymer can be capped at one end or both ends by either a monovalent, divalent, or polyvalent organic moiety (each valence of the capping group being independently bonded to a chain) that does not contain hydrogen atoms capable of hydrogen bonding, or by a monovalent, divalent, or polyvalent ionic group, or a group that does contain hydrogen atoms capable of hydrogen bonding. 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 intended application of the invention. One preferred polymer end cap is an acetyl group.

Also, it should be pointed out that the various preferred amounts, molecular weights, and ranges set forth below are given for general guidance and are based primarily on poly-L-lactic acids, so this should be taken into account when considering other polymers for use in the present invention. For example, polyglycolic acids typically hydrolyze more quickly, exhibit higher degrees of crystallinity, and have higher melting points than polylactic acids. This should be taken into account when considering such things as what polymer to use to achieve the particular sustained release or formulation characteristics desired. Moreover, in the case of polylactic acids, the naturally occurring form is frequently preferred over 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 the DL compounds (i.e., 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 below, relates to improving the physical and degradation characteristics of biodegradable polymers. As noted above, conventional polymer compositions with the highly desirable property of relatively rapid biodegradation typically also exhibit poor physical characteristics. They tend to be sticky, waxy, and generally unable to maintain the physical integrity of articles formed therewith (e.g., microspheres anneal together, rods conform to their container shape, etc.). However, it has been found that, contrary to conventional understanding, it is in fact possible to achieve the highly desirable combination of relatively rapid biodegradation and good physical characteristics with a relatively low molecular weight biodegradable polymer. This surprising effect is accomplished by limiting the polydispersity (i.e., the ratio of weight-average to number-average molecular weight) of the polymer to a relatively narrow range as compared to the normally occurring distribution (i.e., the molecular weight distribution that occurs normally from the conventional polymerization methods). It is hypothesized that this unexpected improvement is the result of several factors: reducing the amount of the slowly degrading high molecular weight component of the polymer reduces the polymer's overall biological half-life; while reducing the amount of the plasticizing low molecular weight component of the polymer raises the Tg of the material. Also, removal of the low molecular weight component seems to "sharpen" the transition between the flowing and non-flowing phases, i.e., it raises the Tg onset temperature (the point where tackiness and flow begins to occur) closer to the mid-point Tg. 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, and relatively rapidly degrading material can be produced. With this aspect of the present invention it is thus possible to make relatively low molecular weight drug-containing medicinal compositions that have both more rapid biodegradation and improved handling characteristics. This has potential application in virtually any context where a relatively rapidly biodegrading polymer is desired. For example, it can be used to make preformed drug-containing microparticles and implants. As discussed below, narrow polymer polydispersity can also provide benefits when dissolved in an MDI formulation to provide controlled release, solubilization and/or chemical stabilization of a drug.

In order to provide rapid biodegradation and good physical characteristics, the biodegradable polymer preferably has a number-average molecular weight of no greater than about 1800, and more preferably no greater than 1500 (and generally no less than about 700), and a polydispersity of less than about 1.3, more preferably less than about 1.2, and most preferably less than about 1.15. The biodegradable polymer preferably comprises at least one chain of units of the formula --[O--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 most preferably, it is poly-L-lactic acid. Some examples of uses for such biodegradable polymers having a relatively narrow molecular weight distribution include preformed drug-containing powders and particles (e.g., microspheres), such as used in dry powder inhalation systems, nebulizers, injection formulations, topical sprays, and suspension type MDI aerosol formulations, as well as subcutaneous implants, drug-delivery dental packs, and other drug-delivery systems. Polymers having such a relatively narrow molecular weight distribution can be prepared by any suitable means for limiting polydispersity. One 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.

Drug Solubilizing and/or Stabilizing

In another important aspect of the invention, biocompatible polymers are dissolved in medicinal formulations in order to help solubilize and/or chemically stabilize a drug. One preferred embodiment of this aspect of the invention is a medicinal formulation suitable for nasal and/or oral inhalation, such as from an MDI, that includes a propellant, a biocompatible condensation-type polymer, preferably comprising at least one chain of units 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, 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 solubilizing aid and/or as a chemical stabilizing aid for many drugs. This is important because, as noted above, many drugs are not sufficiently soluble in aerosol formulations or, if soluble, are chemically unstable in their dissolved form. Optionally, a cosolvent may also be present, which may help solubilize either the drug, 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, i.e., polydispersity of less than about 1.8, preferably less than about 1.4, and more preferably less than about 1.2. This helps to prevent the inclusion of the larger polymers which could accumulate in the lung over time due to repeated dosing. It also can allow a greater amount of the polymer to be completely dissolved in an aerosol formulation, which may be particularly important when a polymer is being used as a drug solubilizing aid because such use can require substantial amounts of polymer to be dissolved (e.g., 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 drug to the body. Such formulations include a drug and a sufficient amount of biocompatible (preferably, biodegradable) polymer which when delivered is associated with the drug (i.e., drug entrapped/encapsulated in a polymer matrix or, described below, as a drug-polymer salt,) so as to provide for such sustained release of the drug as the polymer degrades and the drug is released. This is useful in many drug delivery contexts, such as solid and semi-solid implants and microspheres, as well as for liquid injection formulations and topical sprays. However, it is particularly useful and surprising in the context of medicinal aerosol formulations, such as for oral and/or nasal inhalation from a metered dose inhaler (MDI).

Such sustained release aerosol formulations include drug and a sufficient amount of biocompatible polymer dissolved in a propellant to provide sustained release of the drug when inhaled, and may also include a cosolvent and other excipients. The drug 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 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.

It is particularly surprising to discover that when such biocompatible (preferably biodegradable) polymers are substantially completely dissolved in sufficient quantities relative to the drug in, for example, medicinal aerosol formulations, and administered to the body the drug is released in a highly desirable sustained manner over a period ranging, for example, from about 30 minutes to a day or more. The time period for release of the drug depends upon 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 may be determined on a case-by-case basis with little difficulty. In many situations, the polymer will comprise at least about 1% of the formulation to provide suitable sustained release, although this will depend on the polymer used and the amount, type and physical and chemical form of the drug. 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, where the drug is present as micronized particles, the amount of biocompatible polymer necessary to provide sustained release is generally substantially more than that which would normally be used as a dispersing aid in, for example, the context of U.S. Pat. No. 5,569,450.

Moreover, although it may be preferred 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 most preferably less than about 1.2), it is not required according to all aspects of the invention, particularly in the sustained release formulations. For example, when poly-L-lactic acids of normal polydispersity are used in a formulation for pulmonary delivery, it is preferred that the number-average molecular weight of the polymer be no greater than about 800, and more preferably no greater than about 600. Otherwise, depending upon the frequency of administration, the higher molecular weight component present can accumulate in the lung. Additionally, normal polydispersity poly-L-lactic acids with molecular weights greater than about 800 may exhibit partial insolubility (depending on the weight percentage, propellant used, and the presence of co-solvents 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 encountered. When narrow molecular weight range poly-L-lactic acids (i.e., those having a polydispersity of less than about 1.8 and preferably less than about 1.4, and most preferably less than about 1.2) are used, however, the number-average molecular weight is preferably no greater than about 1300, and more preferably, for most applications, no greater than about 1000. For poly-DL-lactic acid, although solubility is generally not a problem, it is nonetheless desirable to use the lower polydispersity polymer due to the more rapid degradation. The molecular weight and polydispersity can be relatively higher in cases where frequent dosing or rapid bioabsorption are less important (e.g., vaccine or nasal delivery). One skilled in the art will recognize that these parameters will vary with each monomer type used. The choice of polymer used will also be based on the ability of the polymer, when delivered, to incorporate the drug into a matrix or as a salt (discussed below) and release it in a controlled manner. This depends on such factors as the polymer molecular weight, polydispersity, tendency toward crystallization, and specific functionality, as well as the nature of the drug and the form it is in (e.g. dissolved or suspended).

Thus, one can adjust the system according to the particular requirements of the delivery system. For example, where it is desired to provide a therapeutic drug inhalation system requiring only a single dose per day, the biocompatible polymer amount, average molecular weight, polydispersity, and other factors will preferably be selected so that the drug is controllably released, and substantially all of the polymer biodegraded (such that the polymer matrix material is substantially undetectable at the delivery site), over about a 24 hour period, and in some cases preferably over about a 12 hour period. This can typically be accomplished 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 other various factors, such as the amount of polymer used, and selection of co-monomers (e.g., 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 tract. Rather, they form discrete particles spontaneously upon the formulation exiting the aerosol canister valve (for example, from a metered dose inhaler). This aspect of the invention is important both in the context of providing sustained release microparticles, and for providing inhalable microparticles which are not for sustained release. Thus, there is also provided a simple method of forming discrete particles of a medicinal aerosol formulation, which is broadly applicable, cost effective, and, when a suitable propellant is used, environmentally friendly. 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 drug (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 canister equipped with a valve, and more preferably, a metered dose valve); and actuating the device to form an aerosol of discrete particles that are sufficiently stable to avoid aggregation and film formation under conditions of use (e.g., upon inhalation, upon 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.-hydroxycarboxylic acids (PHAs), can form salts with many drugs. Such low molecular weight biodegradable polymers, in their salt form with a drug, can provide sustained release of the drug, aid solubilization of the drug, and chemically stabilize the drug, without requiring the presence of additional release controlling matrix materials. Thus, another embodiment of the invention is a medicinal salt of a drug and a low molecular weight biodegradable polymer. The salt comprises: an ionic drug comprising at least one ammonium, sulfonate, or carboxylate group per molecule (preferably, ammonium group); and a biodegradable polymeric counterion comprising at least one ammonium, sulfonate, or carboxylate group (preferably, carboxylate group) and at least one chain of at least three units of the formula --[O--R¹ --C(O)]-- wherein each R¹ is an independently selected organic moiety that links the oxygen atom to the carbonyl group. Preferably, the hydroxyl end of the non-branched chain is esterified. The salt can be used to advantage in various medicinal formulations, whether they be solid, semi-solid, or liquid formulations. Preferred formulations include medicinal aerosol formulations suitable for oral and/or nasal inhalation, such as MDIs.

Such use of a biocompatible low molecular weight polymeric counterion in a medicinal salt of a drug can in many cases provide advantages over the use of a polymeric matrix in a nonionic form. For example, the presence of a biocompatible polymer and the formation of such salts can provide significant improvement in chemical stability over the same formulation without a salt-forming biocompatible polymer.

It can thus be seen from the above that the present invention provides methods, compounds, and medicinal formulations that represent a dramatic advance in providing for enhanced solubilization and chemical stabilization of a drug, as well as providing sustained release of drugs. This is particularly important in the field of aerosol drug delivery, such as for inhalation. The biocompatible polymers described above, particularly the biodegradable polyesters and polyhydroxycarboxylic acids, can be used either as a drug containing matrix or counterion in solid, semi-solid, or liquid formulations.

Claim 1 of 31 Claims

What is claimed is:

1. A metered dose inhaler for delivering a sustained release medicinal formulation comprising:

an aerosol canister equipped with a metered dose valve and containing a sustained release medicinal aerosol formulation suitable for nasal and/or oral inhalation including a hydrofluorocarbon propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and mixtures thereof, a drug in a therapeutically effective amount, and a biodegradable polymer dissolved in the formulation in an amount such that the period of therapeutic activity of the drug when delivered is extended relative to the same formulation without the biodegradable polymer, said biodegradable polymer comprising at least one chain of units of the formula --[X--R¹ --C(O)]-- 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.

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