Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-08-09
2002-07-09
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000
Reexamination Certificate
active
06416742
ABSTRACT:
The present invention relates to the use of relatively low molecular weight biocompatible polymeric compounds for pharmaceutical drug delivery formulations, and, in particular, to the use of such compounds as drug solubilizing and drug stabilizing aids and/or to provide sustained release of drug.
BACKGROUND OF THE INVENTION
Biodegradable polymers have long been examined for their use in providing sustained release of drugs and have also been used to make biodegradable medical products. For example, polymeric esters of selected hydroxycarboxylic acids or their derivatives (e.g., lactic acid, glycolic acid, p-dioxanone, etc.) are known to be highly biocompatible with, and biodegradable in, the human body. Such polymers are degraded into their constituent hydroxycarboxylic acids, which are metabolized and eliminated from the body, over periods typically ranging from several weeks to several years. Consequently, compounds of this type have been utilized 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 of 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 requiring frequent application and/or where a biological half-life of less than a week down to several hours is desired (e.g., topical application to a wound or for inhalation therapy). Certain relatively low molecular weight polymers having a number-average molecular weight under about 1800 may have sufficiently short biodegradation times for many such purposes, but have generally not been deemed suitable for most sustained release drug delivery systems. This is at least in part because the physical characteristics of these relatively low molecular weight polymers have been regarded 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 having a polydispersity (i.e., the ratio of the weight-average to number-average molecular weights) of greater than about 1.8, tend to have a glass transition temperature (Tg) below room temperature, which is about 23° C., and are generally soft, waxy, or tacky materials. Such materials are not generally suitable for making conventional preformed, solid, drug-containing structures, such as microspheres, for sustained drug release because the low Tg prevents the material from maintaining its physical integrity. Also, the release rate of drug from, and percent loading of drug into, conventional low molecular weight biodegradable systems have not generally been considered sufficient to be useful for most drug delivery systems. Accordingly, formulations and methods of utilizing biocompatible, and preferably biodegradable, polymers to provide relatively short term sustained release of drugs would be highly desirable.
One particular area where sustained release is extremely useful, and yet has been difficult to achieve satisfactorily, is in the context of drug inhalation therapy, such as with metered dose inhalers (MDIs). Drugs used for localized pulmonary administration, for example bronchodilators, are usually limited in their efficacy by the necessity for frequent administration. This is typically due to the rapid dissolution, absorption, and metabolism of the drugs in the lung. Many attempts have been made to provide sustained release of drugs to the lung, as well as other locations, by entrapping or encapsulating the drug in preformed, biodegradable microspheres.
However, there are serious drawbacks with 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, so that the Tg is high enough for the particles to remain discrete, or at least separable, prior to use. As noted above, polymers of too high molecular weight will typically degrade too slowly to be useful in inhalation therapy because of the tendency for higher molecular weight materials to collect and build up in the lung parenchyma upon continued use. Second, the production of preformed microspheres is often difficult, inefficient, costly, and may involve the use of materials which are physiologically and/or environmentally hazardous. Despite efforts to improve the processes, there are often problems with, for example, low and inefficient drug entrapment, aggregation of particles, wide distributions of particle sizes, and the presence of nonparticulate materials.
Hence, there is a substantial need for means of making microparticles that are suitable for pulmonary drug delivery and will not accumulate in the lung, and, even more preferably, for means of providing sustained release of drug without requiring the use of preformed microspheres at all.
Another important issue relating to medicinal aerosol formulations such as in MDIs relates to whether the drug 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 MDIs have the drug suspended in the propellant as a micronized dispersion. This is because in most cases the drug either is not sufficiently soluble in the formulation to form a stable solution or, if soluble, the drug is too chemically unstable in its dissolved form. Accordingly, there is also a substantial need for biocompatible compounds that act as solubilizing aids and/or chemical stabilizers for drug in medicinal aerosol formulations.
U.S. Pat. No. 5,569,450 (Duan et al.) discloses that biocompatible oligomers such as oligohydroxycarboxylic acids are useful as dispersing aids to help maintain particles as a suitable suspension. However, it does not disclose formulations of such compounds providing sustained drug release or as a drug solubilizing and/or stabilizing aid.
In other, non-inhalation contexts, biocompatible polymers have been used for various therapeutic systems, such as spray-on skin covering films which may have a drug included. Such systems, however, are generally not deemed to have both suitable physical and biological/degradation characteristics for most sustained release drug delivery applications.
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
Duan Daniel C.
Leach Chester L.
Perman Craig A.
Schallinger Luke E.
Schultz David W.
3M Innovative Properties Company
Bawa Raj
Howard MarySusan
Ringsred Ted K.
Sprague Robert W.
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