AU2008361734A1 - Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral delivery system for Econazole moxifloxacin and refampicin - Google Patents
Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral delivery system for Econazole moxifloxacin and refampicin Download PDFInfo
- Publication number
- AU2008361734A1 AU2008361734A1 AU2008361734A AU2008361734A AU2008361734A1 AU 2008361734 A1 AU2008361734 A1 AU 2008361734A1 AU 2008361734 A AU2008361734 A AU 2008361734A AU 2008361734 A AU2008361734 A AU 2008361734A AU 2008361734 A1 AU2008361734 A1 AU 2008361734A1
- Authority
- AU
- Australia
- Prior art keywords
- moxifloxacin
- plg
- econazole
- nanoparticles
- drugs
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229960003702 moxifloxacin Drugs 0.000 title claims description 50
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 title claims description 49
- 239000002105 nanoparticle Substances 0.000 title claims description 33
- 229960003913 econazole Drugs 0.000 title description 36
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 title description 32
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 title description 20
- 229960001225 rifampicin Drugs 0.000 title description 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 20
- 238000012377 drug delivery Methods 0.000 claims description 13
- 229940126701 oral medication Drugs 0.000 claims description 13
- 201000008827 tuberculosis Diseases 0.000 claims description 12
- 229940079593 drug Drugs 0.000 description 47
- 239000003814 drug Substances 0.000 description 47
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 238000005538 encapsulation Methods 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 210000000952 spleen Anatomy 0.000 description 6
- 230000003442 weekly effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 244000052616 bacterial pathogen Species 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000003851 azoles Chemical class 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 239000000814 tuberculostatic agent Substances 0.000 description 3
- 241001529936 Murinae Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- 239000001971 Middlebrook 7H10 Agar Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 238000007401 Ziehl–Neelsen staining Methods 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940124976 antitubercular drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
IN-PA210 Title - Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral drug delivery system for Econazole moxifloxacin and refampicin FIELD OF INVENTION This invention relates to an oral drug delivery system of poly DL-lactide-co glycolide nanoparticles (PLG-NP) having active drug separately encapsulated for treatment of tuberculosis. In particular, this invention relates to PLG-NP having azoles and moxifloxacin and RIF separately encapsulated therein. BACKGROUND OF INVENTION It is known that azoles possess antifungal properties and was hitherto used only in the form of a cream or ointment for skin infections. Azole has a poor oral bioavailability, and hence could not be effectively employed for the treatment of any Systemic infections. The use of moxifloxacin as an antituberculosis drug is known in the art. However, moxifloxacin is cleared from the host within 24 hours and, therefore, such a drug is required multiple drug administration on a daily basis resulting in patient non-compliance. -1- IN-PA210 OBJECTS OF THE INVENTION An object of this invention is to propose an oral drug delivery system of PLG-NP having an azole and moxifloxacin separately encapsulated therein. Another object of this invention is to propose an oral drug delivery system of PLG-NP having an azole and moxifloxacin separately encapsulated therein which has an enhanced drug bio availability. Still another object of this invention is to propose an oral drug delivery system of PLG-NP having an azole and moxifloxacin separately encapsulated therein which remains in blood circulation of the host for a longer period. A further object of this invention is to propose an oral drug delivery system of PLG-NP having an azole and moxifloxacin separately encapsulated therein which is effective against TB. A still further object of this invention is to propose an oral drug delivery system of PLG-NP having an azole and moxifloxacin separately encapsulated therein which does not exhibit hep atotoicity. DESCRIPTION OF INVENIirON According to this invention there is provided an oral drug delivery system for treatment of tuberCulosis comprising: -2- IN-PA210 a) poly DL-lactide-co-glycolide nanoparticles having encapsulated an azole therein; b) poly DL-lactide-co-glycolide nanoparticles having moxifloxacin encapsulated therein; c) poly DL-lactide-co-glycolide nanoparticles having RIF encapsulated therein. It is generally known that INH, PZA and RIF are active substances or drugs employed for the treatment of tuberculosis. Thus, patent application no. 765/DEL12003 suggests a process for the simultaneous or co-encapsulation of two or more of the aforesaid drugs, but which are stable with respect to each other. Besides, the aforesaid three drugs or active substances, it is also known that EMB is a drug, which is also eniployed for the treatment of tuberculosis. However, EMB is unstable in the presence of the INH, PZA or RIF, and particularly in the presence of INH. Thus, it has been found that EMB could not be co-encapsulated simultaneously with INH, as any such co-encapsulation would result in a degradation of RMB. Thus, patent application no. 765/DEL/95 had a useful application for co-encapsulated of active substances or drugs which were compatible to each other with respect to stability. -3- IN-PA210 It has now been found that the normal anti-tubular drugs of INH, PZA and EMB can be replaced by nanoparticles containing separately azole, moxifloxacin and RIF. Thus, the oral drug delivery system consists of separate nanoparticles having moxifloxacin, azole and RIF encapsulated therein. The bioavailability and the retention period in the bloodstream is considerably increased. Drug loaded PLG nanoparticles were prepared by the multiple emulsion and solvent evaporation technique. Briefly, the active drug was dissolved in distilled water which was then added to dichloromethane (DCM) containing PLG. The mixture was sonicated to form. the primary emulsion which was poured into aqueous PVA and resonicated. The secondary emulsion so formed was stirred for the removal of DCM, centrifuged to harvest the nanoparticles which were washed with distilled water and vacuum dried. Secondly, it has now been found that the active drugs when encapsulated in nanoparticles, is not eliminated from the body within few hours, but has a slow release for days together. In accordance with this invention, the active drug is administered orally in an encapsulated form, but not in the same nanopartides as the other antitubular drugs. EXAMPLES Characterization of ATD-loaded PLG-nanoparticles The particles were characterized for their size and polydispersity index on a -4- IN-PA210 Zetasizer 1000 HS (Malvern Instruments, Malvern, UK). The formulation were lysed in 5% w/v SDS in 0.1N NaOH to release the drugs. The percentage drugs encapsulation efficiency was determined by the formula: (amount of drug (mg) released form the nanoparticles/amount of drug (mg) initially taken to prepare the nanoparticles) x 100. The drugs were analysed by an HPLC system comprising of a dual-piston reciprocating pump, an online de-gasser, a UV-visual dual wavelength detector (each of Series 200) and a 600 series Link interface for date acquisition/processing, all from Perkin Elimer Instruments LLC (Shelton CT, USAS). Moxifloxacin was analyzed by employing a USP gradient program (USP 2000) with Water (pH=2.0, set with orthophosphoric acid)' acetonitrile (60/40) as the mobile phase @ 1.5 (mi/min), 292 nm as the detection wave length and reversed phase C18 column (Cosmosil 5C18-MS-II from Waters; 250 x 4.6 mm; 5pm particle size). Econazole and ATDs were analyzed by employing USP gradient / isocratic programs as described earlier. The sensitivity of the methods was: moxifloxacin 0.1 mg/L, econazole 0.2 mg/L, rifampicin 0.4 mg/L. Preparation of drugs doses for in vivo studies The drug doses used throughout the example were moxifloxacin 8 mg/kg, econazole 3.3 mg/kg, rifampicin 12 mg/kg body weight according to the standard adult human doses. The dose being different for each drug, the initial amount of drug taken to prepare the formulations was calculated by the formula: -5- IN-PA210 (amount of drug required per animal / mean drug encapsulation efficiency) x 100, as previously described. Once the total amount of drugs required was known, an equivalent amount of PLG was used in the preparation process. PLG nanoparticle formulation encapsulating drugs was suspended in distilled water just before oral dosing in each experiment. Similarly, free drugs were also freshly dissolved in distilled water / methanol (5:1 v/v) immediately before closing. In vivo druq disposition studies Mice were grouped as follows with 12 mice per group: Group 1, free moxifloxacin; Group 2, free econazole; Group 3, free ATDs; Group 4 moxifloxacin loaded PLG nanoparticles; Group 5, econazole loaded PLG nanoparticles; Group 6, ATDs loaded PLG nanoparticles and Group 7, empty PLG nanoparticles (a positive control to explore the influence of PLG nanoparticles on drug estimations). The animals were bled at several time points. The plasma obtained from, each mouse was deproteinized and analyzed by HPLC for drugs to obtain the plasma drug concentration versus time profile. The HP.C method for moxifloxacin was same as described above fro encapsulation studies and of other drugs-as reported. The animals were sacrificed at different time points. Drug levels were determined in 20% w/v of tissue homogenates (lungs, liver and spleen) by following the same analytical procedure as described for plasma. -6- IN-PA210 Experimental infection and chemotherapy Mice were infected via the lateral tail vein with 1 x 107 bacilli of M. tuberculosis
H
3 7 Rv. Fifteen days later, the establishment of infection was confirmed by sacrificing 5 mice and Ziehl-Neelsen staining of lung/spleen homogenates. In addition, 100 p 1 of undiluted, 1 in 100 and 1 in 1000 diluted homogenates were placed on Middle brook 7H10 Agar supplemented with OADC for the enumeration of basal colony forming units (cfu). Subsequently, mice were grouped as follows (n = 6 per group) - Group 1, untreated control; Group - 2, Free econazole twice daily; Group 3, Free moxifloxacin once daily, Group 4, Free econazole + moxifloxacin ; and Group 5, free econazole + moxifloxacin + RIF; Group 7, PLG - econazole weekly; Group 8, PLG - econazole + moxifloxacin; Group 9, PLG econazole + moxifloxacin + RIF. On day 62 following the initiation of chemotherapy all the animals were sacrificed. The lungs and spleen were removed aseptically and homogenized in 3 ml sterile isotonic saline. 100 p1 of undiluted, 1 in 100 and 1 in 1000 diluted homogenates were plated on Middle brook media and cfu were counted after 28 days of plating. The cfu data was analyzed by one way analysis of variance (ANOVA) followed by unpaired't-test' to compare the untreated and treated groups. -7- IN-PA210 RESULTS Physicohemical characterization of PILG-nanoparticles The average size of PLG nanoparticles was 217 to 250 nm with a polydispersity index of 0.38 to 0.4. The drug encapsulation efficiency of PLG-nanoparticles for econazole and moxifloxacin was found to be 52.27 + 3.80% and 33.69 + 3.88% respectively. In vivo druq disposition Oral free econazole and moxifloxacin were detectable up to 3-4 and 12 h in plasma respectively. However, following a single oral administration of drug loaded PLG nanoparticles, therapeutic drug concentrations in the plasma were maintained for up to 5 and 4 days in case of econazole and moxifloxacin respectively (Figure 1), which in the organs (lungs, liver and spleen) both the drugs were detected in therapeutic concentrations for up to 6 days (Table 1). In comparison, free econazole and moxifloxacin were detected in organs up to 12 and 24 h respectively. Chemotherapy efficacy Based on tissue drug distribution free econazole and moxifloxacin were administered twice and once daily while the encapsulated drugs were -8- IN-PA210 administered weekly. Al the free ATDs (INH, RIF, PZA and EMB) were administered once daily and encapsulated were administered every 10*h day with the exception of ethambutol which was administered weekly. Eight weeks of chemotherapy with econazole or moxifloxacin either in free form (112/56 doses, administered twice or once/day) or in encapsulated form (8 doses, administered weekly) resulted in approximately 2 Logio cfu reduction from lungs and spleen of mice as compared to untreated controls (Table 2). Further, the combination of econazole and moxifloxacin proved significantly better than individual drugs as it resulted in the reduction of 3.5 Logio cfu in free or encapsulated form (Table 2). Supplementation of rifampicin to this combination resulted in the most potent regimen that yielded total bacterial clearance in mice with in eight weeks equivalent / comparable to 4ATD's conventional treatment (Table 2). PLG-nanopartides encapsulating econazole and moxifloxacin have exhibited immense potential against tuberculosis especially in multidrug resistant and latent or persistent forms of the disease. A single oral administration of drug (Mox, Eco) loaded PLG-nanoparticles to mice maintained- therapeutic drug levels in organs for up to 6 day, this formed the basis of the chemotherapeutic schedule as tuberculosis infection is localized in different tissues. Therefore, PLG-formulation was administered weekly in comparison to free drugs were administered once or twice daily. -9- IN-PA210 Mice were infected with 1.5 x 10 7 bacilli of M.tuberculosis
H
3 7 R,, because similar inoculum has been used in other reports and is known to provide bacillary loads similar to those in human TB cases. Eight weeks of chemotherapy with econazole or moxifloxacin reduced bacterial burden in organs by about 2 log cfu's. Further, PLG-nanoparticles showed their potential to reduce dosing frequency of azoles and moxifloxacin by 14 and 7 fold respectively without compromising therapeutic efficacy. The combination of econazole and moxifloxacin proved to be much better as it reduced bacterial burden by about 3.5 log cfu's compared to 2 log cfu by individual drugs. These results can be explained on the basis that the two drugs have different targets, therefore in combination might act synergistically. Recent studies have shown that econazole inhibits the biosynthesis of glycopeptidolipids (GPLs) which in turn are responsible for maintaining integrity of mycobaterial cell envelope. Thus, econazole might improve the penetration of other drugs like moxifloxacin and make improve the penetration of other drugs like moxifloxacin and make their target (DNA - gyrase in case of moxifloxacin) more accessible. The most interesting finding was the observation that combination of econazole, moxifloxacin and rifampicin resulted in the total bacterial clearance as compared to approximately 7 log cfu in untreated controls. This observation can be explained on the basis of the fact that all three drugs of this combination are active against actively multiplying as well as non dividing bacilli. This combination is more beneficial than conventional regimen on the basis that econazole and moxifloxacin are highly active drug and multidrug resistant bacilli. In addition, all of its three drugs are exhibiting sterilizing actively owing to their activity against non-replicating bacilli as against -10- IN-PA210 conventional regimen where only refampicin bears this activity. This regimen is also expected reduce the total duration of tuberculosis chemotherapy owing to sterilizing activity of all its drugs compared to conventional regimen. PLG nanoparticles have made this new regimen more acceptable as dosing frequency was reduced by 14, 10 and 7 fold for econazole, moxifloxacin and rifampicin respectively as has been demonstrated earlier for all antitubercular drugs. The efficacy of three drug combination (econazole, moxifloxacin and rifampicin) in free or in encapsulated form against murine tuberculosis is apparent. -11- IN-PA210 Table II: Chemotherapeutic efficacy of oral econazole and moxifloxacin-loaded PLG nanoparticles against murine tuberculosis Groups Log 10 cfu Log 10 cfu Lung Spleen Untreated controls 6.88 + 0.035 6.90 + 0.025 Free econazole twice daily 4.87 +0.040 4.89 + 0.020 (112 doses) Free moxifloxacin once daily 4.96 +0.013 4.96 +0.013 (56 doses) Free econazole + moxifloxacin 3.03 + 0.070 3.14 + 0.130 (112 doses + 56 doses) Free econazole + moxifloxacin + RIF N.D. N.D. (112 doses + 56 doses + 56 doses) Free - RIF + INH + PZA + EMB N.D. N.D. (56 doses) PLG - econazole weekly 4.85 +0.050 4.89 +0.040 (8 doses) PLG - moxifloxacin once daily 4.94 +0.013 4.96 +0.030 (8 doses) PLG econazole + moxifloxacin 3.04 + 0.120 3.13 + 0.140 (8 doses) PLG - econazole+ moxifloxacin + RIF N.D. N.D. (8 doses + 6 doses) PLG - RIF + INH + PZA + EMB N.D. N.D. (6 doses) Values are mean + S.D. of 5 animals -12-
Claims (4)
1. An oral drug delivery system for treatment of tuberculosis comprising: a) poly DL-lactide-co-glycolide nanoparticles having encapsulated an azole therein; b) poly DL-lactide-co-glycolide nanoparticles having moxifloxacin encapsulated therein; c) poly DL-lactide-co-glycolide nanoparticles having RIF encapsulated therein.
2. An oral drug delivery as claimed in claim 1, wherein the average size of PLG nanoparticles are 217 nm to 250 nm.
3. An oral drug delivery as claimed in claim 1, wherein PLG nanoparticles have a polydispersity index of 0.38 to 0.4.
4. An oral drug delivery system consisting of Mox, Eco & RIF for treatment of tuberculosis substantially as herein described. -13-
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2008361734A AU2008361734A1 (en) | 2008-10-15 | 2008-10-15 | Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral delivery system for Econazole moxifloxacin and refampicin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2008361734A AU2008361734A1 (en) | 2008-10-15 | 2008-10-15 | Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral delivery system for Econazole moxifloxacin and refampicin |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2008361734A1 true AU2008361734A1 (en) | 2010-04-29 |
Family
ID=42139157
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2008361734A Abandoned AU2008361734A1 (en) | 2008-10-15 | 2008-10-15 | Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral delivery system for Econazole moxifloxacin and refampicin |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2008361734A1 (en) |
-
2008
- 2008-10-15 AU AU2008361734A patent/AU2008361734A1/en not_active Abandoned
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Booysen et al. | In vivo/in vitro pharmacokinetic and pharmacodynamic study of spray-dried poly-(dl-lactic-co-glycolic) acid nanoparticles encapsulating rifampicin and isoniazid | |
EP0317120B1 (en) | Improved amphotericin b liposome preparation | |
EP2648709B1 (en) | Disulfiram formulation and uses thereof | |
Zarif et al. | Cochleates: new lipid-based drug delivery system | |
CN105579028A (en) | Antifungal topical composition and methods of treatment | |
JPH11503459A (en) | Pharmaceutical composition containing benzimidazole for inhibiting cancer growth | |
Sharma et al. | Reclaiming hijacked phagosomes: hybrid nano-in-micro encapsulated MIAP peptide ensures host directed therapy by specifically augmenting phagosome-maturation and apoptosis in TB infected macrophage cells | |
US11672806B2 (en) | Methods and compositions for treating mesothelioma and small lung cancer that express midkine | |
JP5449388B2 (en) | Polymeric micelle composition for resistant cancer treatment and method for producing the same | |
US20240173412A1 (en) | Sensitizing cells to proton radiation | |
Tabari et al. | Antitrichomonal activity of metronidazole-loaded lactoferrin nanoparticles in pigeon trichomoniasis | |
Ling et al. | Preparation, characterization, and pharmacokinetics of tilmicosin‐and florfenicol‐loaded hydrogenated castor oil‐solid lipid nanoparticles | |
Li et al. | RETRACTED ARTICLE: Preparation of novel pirfenidone microspheres for lung-targeted delivery: in vitro and in vivo study | |
CN1927203A (en) | Nano micelle preparation of Catharanthus roseus alkaloids antineoplastic drugs with coating of phospholipid derived from polyethylene glycol | |
Mathpal et al. | Development and characterization of spray dried microparticles for pulmonary delivery of antifungal drug | |
Pandey et al. | Oral poly (lactide-co-glycolide) nanoparticle based antituberculosis drug delivery: Toxicological and chemotherapeutic implications | |
US8409619B2 (en) | Oral drug delivery system for azole, moxifloxacin and rifampicin | |
AU2008361734A1 (en) | Poly DL-lactide-co-glycolide (PLG) nanoparticle based oral delivery system for Econazole moxifloxacin and refampicin | |
US9919027B2 (en) | Lipid nanoparticle of polymyxin | |
CN105796495B (en) | Irinotecan hydrochloride liposome pharmaceutical composition and preparation method thereof | |
TWI737974B (en) | Dosing regimens for treatment of proliferative disorders | |
CN110123762A (en) | A kind of medicament-carried nano compound and its preparation method and application | |
RU2418585C1 (en) | Rifampicin-based medication with prolonged action for treatment of resistent forms of tuberculosis | |
US20240065983A1 (en) | Composition and method for treating covid-19 | |
EA016410B1 (en) | Pharmaceutical composition based on cyclodextrin nanoparticles comprising rifabutin, method for preparing thereof, method for treating mikobacteriosis and helicobacterial infection (variants) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE NAME OF THE INVENTOR TO READ KHULLER, GOPAL KRISHAN AND VERMA, JITENDRA NATH |
|
MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application |