Link:  Pharm/Biotech Resources

Title:  Intravaginal drug delivery devices for the administration of an antimicrobial agent

United States Patent:  6,951,654

Issued:  October 4, 2005

Inventors:  Malcolm; Karl (Belfast, IE); Woolfson; David (Belfast, IE); Elliott; Grant (Islandmagee, IE); Shephard; Martin (Belfast, IE)

Assignee:  Galen (Chemicals) Limited (Dublin, IE)

Appl. No.:  107997

Filed:  March 27, 2002

An intravaginal antimicrobial drug delivery device is disclosed having an antimicrobial agent dispersed throughout a biocompatible elastomeric system. Also disclosed is a method of making the antimicrobial drug delivery device.

SUMMARY OF THE INVENTION

Accordingly, the invention provides, in a first aspect, an intravaginal drug delivery device comprising an antimicrobial agent or a mixture thereof dispersed in an elastomer or a mixture thereof, the device being of matrix design.

This invention is directed to an intravaginal drug delivery device comprising a therapeutically effective amount of at least one antimicrobial agent dispersed throughout a biocompatible elastomeric system that forms the delivery device, i.e., the device is a matrix device. It is preferable for the elastomeric system to be hydrophobic. Preferably, the device of this invention takes the shape of a ring and most preferably the antimicrobial agent is a water soluble antimicrobial agent such as Metronidazole. Advantageously, the at least one antimicrobial agent is homogeneously dispersed in the elastomeric system.

Another embodiment of this invention is directed to a method of preparing the device of this invention. Significantly, the intravaginal antimicrobial drug delivery device of this invention provides a substantially first order release of the antimicrobial agent for about the first twenty four hours after insertion in a vaginal space followed by at least three days of substantially zero order release. Accordingly, the device of this invention provides a means of treating vaginitis in a convenient and high compliance manner with a preferred dosing strategy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention primarily concerns itself with intravaginal delivery of antimicrobial agents, including microstatic agents and/or microcidal agents, for the treatment or prevention of vaginitis, although by no means is limited thereto.

Other microbial infections to affect the female genital tract include fungal infections such as vaginal candidiasis, viral herpes genitalis and human papilloma virus—the present invention also concerns itself therewith.

The term "microstatic agent" is intended to embrace any antimicrobial agent which, in use, prevents an increase in the number of susceptible pathogenic organisms. The term "microcidal agent" is intended to embrace any antimicrobial agent which, in use, results in a clinically significant reduction in the number of susceptible pathogenic organisms. The terms "microstatically effective" and "microcidally effective" are analogously intended to embrace effective to prevent an increase in the number of susceptible pathogenic organisms or effective to result in a clinically identifiable reduction in the number of susceptible pathogenic organisms, respectively. A therapeutically effective amount of antimicrobial agent is that which is microstatically effective and/or microcidally effective.

The term "antimicrobial agent" is intended to embrace antibacterial agents, antifungal agents, antiprotozoal agents, antiviral agents and mixtures thereof.

Suitable antibacterial agents include Acrosoxacin, Amifloxacin, Amoxycillin, Ampicillin, Aspoxicillin, Azidocillin, Azithromycin, Aztreonam, Balofloxacin, Benzylpenicillin, Biapenem, Brodimoprim, Cefaclor, Cefadroxil, Cefatrizine, Cefcapene, Cefdinir, Cefetamet, Cefmetazole, Cefprozil, Cefroxadine, Ceftibuten, Cefuroxime, Cephalexin, Cephalonium, Cephaloridine, Cephamandole, Cephazolin,Cephradine, Chlorquinaldol, Chlortetracycline, Ciclacillin, Cinoxacin, Ciprofloxacin, Clarithromycin, Clavulanic Acid, Clindamycin, Clofazimine, Cloxacillin, Danofloxacin, Dapsone, Demeclocycline, Dicloxacillin, Difloxacin, Doxycycline, Enoxacin, Enrofloxacin, Erythromycin, Fleroxacin, Flomoxef, Flucloxacillin, Flumequine, Fosfomycin, Isoniazid, Levofloxacin, Mandelic Acid, Mecillinam, Metronidazole, Minocycline, Mupirocin, Nadifloxacin, Nalidixic Acid, Nifuirtoinol, Nitrofurantoin, Nitroxoline, Norfloxacin, Ofloxacin, Oxytetracycline, Panipenem, Pefloxacin, Phenoxymethylpenicillin, Pipemidic Acid, Piromidic Acid, Pivampicillin, Pivmecillinam, Prulifloxacin, Rufloxacin, Sparfloxacin, Sulbactam, Sulfabenzamide, Sulfacytine, Sulfametopyrazine, Sulphacetamide, Sulphadiazine, Sulphadimidine, Sulphamethizole, Sulphamethoxazole, Sulphanilamide, Sulphasomidine, Sulphathiazole, Temafloxacin, Tetracycline, Tetroxoprim, Tinidazole, Tosufloxacin, Trimethoprim and salts or esters thereof.

Preferred antibacterial agents include tetracyclines such as Doxycycline, Tetracycline or Minocycline; macrolides such as Azithromycin, Clarithromycin and Erythromycin; nitroimidazoles such as Metronidazole or Tinidazole; quinolones such as Ofloxacin, Norfloxacin, Cinoxacin, Ciprofloxacin and Levofloxacin; Clindamycin and Dapsone.

Suitable antifungal agents include Bifonazole, Butoconazole, Chlordantoin, Chlorphenesin, Ciclopirox Olamine, Clotrimazole, Eberconazole, Econazole, Fluconazole, Flutrimazole, Isoconazole, Itraconazole, Ketoconazole, Miconazole, Nifuroxime, Tioconazole, Terconazole, Undecenoic Acid and salts or esters thereof.

Preferred antifungal agents include Clotrimazole, Econazole, Fluconazole, Itraconazole, Ketoconazole, Miconazole, Terconazole and Tioconazole.

Suitable antiprotozoal agents include Acetarsol, Azanidazole, Chloroquine, Metronidazole, Nifuratel, Nimorazole, Omidazole, Propenidazole, Secnidazole, Sineflngin, Tenonitrozole, Temidazole, Tinidazole and salts or esters thereof.

Metronidazole, Tinidazole and Chloroquine are most preferred antiprotozoal agents.

Suitable antiviral agents include Acyclovir, Brivudine, Cidofovir, Curcumin, Desciclovir, 1-Docosanol, Edoxudine, Fameyclovir, Fiacitabine, Ibacitabine, Imiquimod, Lamivudine, Penciclovir, Valacyclovir, Valganciclovir and salts or esters thereof.

Curcumin, Acyclovir, Famcyclovir and Valacyclovir are preferred antiviral agents.

The most preferred antimicrobial agents of this invention include, without limitation, Metronidazole, Acyclovir, Clotrimazole, Fluconazole, Terconazole, Azithromycin, Erythromycin, Doxycycline, Tetracycline, Minocycline, Clindamycin, Famcyclovir, Valacyclovir, Clarithromycin, a prodrug or salt thereof and combinations thereof.

Mixtures of antibacterial agents, mixtures of antifungal agents; mixtures of antiviral agents; mixtures of antiprotozoal agents and mixtures of agents from two or more of these categories are also envisaged by the present invention. In addition, it is also envisaged that the present invention embraces at least one antimicrobial agent (microstatic and/or microcidal agent) with one or more other pharmaceutically active agent.

The antimicrobial agent is generally present in the device of this invention in an amount from about 0.5 to about 80 w/w % and preferably from about 10 to about 70 w/w % of the device. However, the amount of antimicrobial agent may clearly be varied depending on, for example, the desired dosing level, the particular antimicrobial agent, the release rate effect of excipients used in the device, and the particular elastomeric system employed.

The term "elastomer" is intended to mean an amorphous high polymer (or mixture thereof) above its/their glass transition temperature. Elastomers can be stretched and retracted rapidly; exhibit high strength and modulus when stretched; and recover fully when the stress is removed. The term "elastomer" includes covalently-linked elastomers, in which the polymer(s) is/are permanently crosslinked to restrain gross mobility, and thermoplastic elastomers, in which the polymer(s) is/are reversibly crosslinked to restrain gross mobility.

The term "hydrophobic" is intended to describe a polymer that is more soluble in organic solvent than water in a hydrophilic solvent such as water.

Examples of suitable biocompatible elastomers include, but are not limited to, silicones (organo polysiloxanes including dimethylpolysiloxanes), polyethylene-co-poly (vinyl acetate), styrene-butadiene-styrene block copolymers, polyphosphazenes, poly(isoprene), poly (isobutylene), polybutadienes, polyurethanes, nitrile rubbers, neoprene rubbers or mixtures thereof. Silicones are particularly preferred.

More preferred elastomers include hydroxyl-terminated organopolysiloxanes (such as polydimethylsiloxanes) of the RTV (room temperature vulcanising) type, which harden to elastomers at room temperature or higher, following the addition of cross-linking agents (such as alkylorthosilicates, preferably n-propyl or ethyl orthosilicate) in the presence of curing catalysts. Suitable cross-linking agents and curing catalysts are well known in the art. A typical curing catalyst would be stannous octoate. Curing temperatures and times will vary, depending on the particular elastomer(s) used. For example, the curing temperature may vary between room temperature (15-25° C.) and 150° C. but is preferably within the range 60-100° C. The curing time may vary between a few seconds and several hours, depending on the elastomer(s) used.

Other preferred and suitable elastomers include two-component dimethylpolysiloxane compositions using platinum as the curing catalyst and at a curing temperature of from room temperature to an elevated temperature.

Said intravaginal elastomer drug delivery device may have any shape and be of any dimensions compatible with intravaginal administration to the human female or other animal. With the requirements imposed by drug delivery kinetics, a particularly preferred intravaginal drug delivery device according to the present invention is a ring. Such a ring can be self-inserted high into the vagina, where it is held in place due to its shape and inherent elasticity. More preferred is a drug delivery device in the form of a ring, in which the elastomer is silicone.

Such an intravaginal elastomer drug delivery device permits single intravaginal dosing of an antimicrobial agent(s), with an initially high "loading" and a subsequent, lower "maintenance" release profile. In addition, such a device provides high patient compliance, ease of application and exhibits no leakage or messiness on insertion and subsequent placement within the vaginal space.

Preferred antimicrobial agents include quinolones, macrolides, clindamycin, tetracyclines, antibacterial and antifungal agents such as nitroimidazoles and antiviral agents such as acyclovir, a pro-form thereof or a salt thereof. More preferably, the antimicrobial agent is a nitroimidazole such as metronidazole, a pro-form thereof or a salt thereof. A pro-form (or pro-drug) means a precursor which, in vivo, is broken down to release the active agent. Most preferably, the intravaginal drug delivery device is capable of releasing metronidazole, a pro-form thereof or a salt thereof. The intravaginal drug delivery device is capable of releasing an antimicrobial agent into, in use, the vaginal space, at an initial release rate of 1-600 mg, preferably 1-500 mg, most preferably 1-250 mg, of at least one antimicrobial agent, most preferably 1-250 mg of metronidazole, as determined in vitro, over a first day followed by a "maintenance" release rate of 0.25-400 mg, preferably 0.25-300 mg, most preferably 0.25-100 mg, of at least one antimicrobial agent, most preferably 0.5-100 mg of metronidazole as determined in vitro, on a daily basis for at least the following three day period, so that, in use, there is at least no clinically significant increase in the number of viable colony forming units of susceptible pathogenic micro-organisms within the vaginal space.

In a preferred embodiment, the antimicrobial agent should have a solubility in distilled water of not less than 1 μg per 100 ml, more preferably not less than 100 μg per 100 ml, still more preferably not less than 1 mg per 100 ml, most preferably not less than 10 mg per 100 ml, at 20° C. Such hydrophilicity is desired to ensure an adequate level of the antimicrobial agent in the space between the device and the vaginal epithelium, hereinafter referred to as the "vaginal space". While not necessary, one, or each, antimicrobial agent generally will have a lipid solubility in liquid silicone at 37° C. of not less than 0.01 mg per 100 ml, optionally not less than 0.1 mg per 100 ml. Such lipophilicity may be desirable to ensure adequate diffusion of the one, or each, antimicrobial agent throughout the matrix of the device.

While the description hereunder mainly concerns metronidazole, which is a preferred antibacterial and/or antiprotozoal agent, it is not intended that the description be limited thereto. Metronidazole, a synthetic 5-nitroimidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), has antimicrobial action against anaerobic bacteria (e.g., Gardnerella vaginalis, Bacteroides fragilis, Clostridia species, Fusobacteria species, Peptococci and Peptostreptococci species), and protozoals (e.g., Giardia lamblia, Entameba hystolytica, Trichomonas vaginalis) and is of clinical value in the treatment of trichomoniasis and bacterial vaginosis.

Prejudice against the incorporation of antimicrobial agents such as metronidazole, a pro-drug or a salt thereof, in particular, in an intravaginal elastomer drug delivery device, for the treatment of vaginitis of susceptible bacterial or protozoal origins in the human female is due to:

Despite its unpromising water and oil solubilities, it has now been found possible to deliver microstatically and/or microcidally effective quantities of metronidazole, a pro-drug or a salt thereof, from an elastomeric intravaginal drug delivery device of matrix design.

Preferably, said device is capable of releasing between 5 and 250 mg, more preferably between 9 and 150 mg, of at least one antimicrobial agent, most preferably between 9 and 150 mg of metronidazole, a pro-drug or a salt thereof over the first day, as determined in vitro.

More preferably, said device is capable of releasing at least one antimicrobial agent, at a mean daily rate, following the initial 24 hour period, of between 3 and 175 mg, preferably between 3 and 75 mg of at least one antimicrobial agent, most preferably between 3 and 75 mg of metronidazole, a prodrug or a salt thereof, per day over at least the following three day period, as determined in vitro.

Advantageously, the intravaginal drug delivery device may contain other pharmaceutically compatible agents. Such agents include pharmacologically active agents, as well as, pharmacologically inactive agents known in the art as pharmaceutical excipients. Examples of pharmacologically active agents that may be advantageous include, but are not limited to, a local anaesthetic such as lidocaine or a local analgesic or a mixture thereof. Examples of pharmacologically inactive agents that may be advantageous include, but are not limited to, a buffer (or buffers), or hydrophilic compounds that enhance the rate of release of the agent from the device, such as for example, polyvinylpyrrolidone (PVP or povidone), modified cellulose ethers (e.g., hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose) microcrystalline cellulose, polyacrylic acid, carbomer, alginic acid, carrageenan, cyclodextrins, dextrin, guar gum, gelatin, xanthan gum and sugars (e.g., monosaccharides such as glucose, fructose and galactose, and dissaccharides such as lactose, maltose and fructose). When employed, the release rate enhancing excipient is generally present in an amount of about 0.5 to about 40 w/w % and preferably about 2.5 to about 15 w/w % of the device.

According to a second aspect of the invention, there is provided a method of manufacturing an intravaginal drug delivery device according to the first aspect of the present invention, said method comprising the steps of combining and curing an antimicrobial agent or the mixture thereof, and an elastomer, or the mixture thereof, whereby the amount of the agent(s), included in the device is/are selected to provide the desired agent(s) release characteristics.

The amount of antimicrobial agent to be included should be such as to achieve, in use, at least a microstatic effect, i.e., no change in the number of susceptible pathogenic organisms in the vaginal space, but preferably a microcidal effect, i.e., a dclinically significant reduction in the number of susceptible pathogenic organisms in the vaginal space. Similarly, the terms "bacteriostatic" and "bacteriocidal" mean no change, and a clinically significant reduction, respectively, in the number of susceptible pathogenic bacteria in the vaginal space following insertion of the device into the vaginal space.

A drug loading of at least 0.64% (w/w) metronidazole produces a microstatic effect, whereas a drug loading of at least 1.6% (w/w), preferably at least 6.4% (w/w), metronidazole is needed to produce a microcidal effect, in the absence of a release enhancing excipient, as will be evident from Examples 1-6 hereunder. When a release enhancing excipient is present, and this is preferred, lower drug loadings can achieve the same microstatic or microcidal effects, as will be evident from Examples 7 and 8 hereunder.

Although a matrix device shows first order release decay, the "maintenance" rate of drug release, following the initial 24 hour period, can be adapted to "appear" substantially constant if the diffusional distance that the drug must travel from the receding drug boundary to the outer surface of the device is as small as possible. This, in effect, means that the drug loading can be employed to reduce the diffusional distance and, thereby, "simulate" a zero order release over the present required time span, whilst maintaining an initial loading dose over the first 24 hours. The geometry of the ring (where the device is a ring) also plays a role in achieving the desired drug release characteristics—in the present context, the term "igeometry" encompasses the overall diameter of the ring and its cross-sectional diameter.

An initial release rate of at least 1 mg/day of metronidazole, as determined in vitro, produces a microstatic effect in susceptible organisms, whereas an initial release rate of at least 2.5 mg/day, more preferably at least 9 mg/day metronidazole, as determined in vitro is needed to produce a microcidal effect.

A "maintenance" release rate of at least 0.5 mg of metronidazole, per day, over at least the following three days produces a microstatic effect, whereas a "maintenance" release rate of at least 1 mg, preferably at least 3 mg, more preferably at least 4 mg, per day over at least the following three day period, is needed to produce a microcidal effect.

The particle size of the antimicrobial agent may be varied to alter the release rate characteristics of the device of this invention. Generally, the antimicrobial agent used in the present invention will have a particle size distribution wherein 90% have a particle size of less than 200 μm and 50% have a particle size of less than 50 μm, preferably 90% have a particle size less than 150 μm, and 50% have a particle size less than 30 μm and most preferably 90% have a particle size less than 90 μm and 50% have a particle size less than 20 μm.
 

Claim 1 of 42 Claims

1. An intravaginal antimicrobial drug delivery device comprising:

a therapeutically effective amount of at least one antimicrobial agent dispersed throughout a biocompatible elastomeric system that forms said delivery device,

wherein between 5 mg and 600 mg of said at least one antimicrobial agent is released during an initial 24 hour period of use, and

wherein said delivery device consists essentially of a ring.

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