Field of Invention
This invention relates to solid lipid nanoparticles (SLN) having a drug or drugs encapsulated therein and to a process for the preparation thereof. In particular, this invention relates to SLN having a sustained controlled release property of the drug encapsulated therein. By way of example only, reference is made herein to the drugs as antitubercular drugs (AID). However, it is understood that other drugs besides ATD can be encapsulated in the SLN.
Background of Invention
The need to administer multiple ATD daily for 6-9 months is responsible for patient non-compliance as well as drug related hepatotoxicity, which result in therapeutic failure. Another consequence of incomplete/irregular treatment is the emergence of drug resistance.
Nanotechnology based drug delivery systems have been extensively studied over the past decade. Of the several procedures available to prepare nanoparticles such as double-emulsion-solvent-evaporation, solvent diffusion, micro emulsion, gas antisolvent precipitation etc., none is perfect in terms of particle size, drug encapsulation efficiency and drug release kinetics. Further, multidrug encapsulation in single formulation is not yet reported.
Qbiects of the Invention
An object of this invention is to propose solid lipid nanoparticles (SLNs) having a single or plurality of drugs, such as ATD, encapsulated therein and a process for the preparation thereof and which obviates the disadvantages associated with the known art. '
Another object of this invention is to propose solid lipid nanoparticles (SLNs) having a single or plurality of drugs, such as ATD, encapsulated therein and a process for the preparation thereof and which provides a prolonged and sustained release of drug(s).
Still another object of this invention is to propose solid lipid nanoparticles (SLNs) having a single or plurality of drugs, such as ATD, encapsulated therein and a process for the preparation thereof and capable of being modulated to entrap maximum drug.
A further object of this invention is to propose solid lipid nanoparticles (SLNs) having a single or plurality of drugs, such as ATD, encapsulated therein and a process for the preparation thereof and capable of distributing the drug(s) evenly to different organs where tubercle bacteria reside.
A still further object of this invention is to propose solid lipid nanoparticles (SLNs) having a single or plurality of drugs, such as ATD, encapsulated therein and a process for the preparation thereof and which is ready for oral and aerosol use without requiring any further treatment.
Yet a further object of this invention is to propose solid lipid nanoparticles (SLNs) having a single or plurality of drugs, such as AID, encapsulated therein and a process for the preparation thereof and which does not exhibit hepatotoxicity.
Description of the Invention
According to this invention there is provided a solid lipid nanoparticles having a drug or plurality of drugs encapsulated therein and having sustained controlled release of the drug.
Further according to this invention there is provided a process for the preparation of solid lipid nanoparticles having a single or a plurality of drugs encapsulated therein comprising in the step of pouring a primary organic emulsion of lipid and said drug or drugs into an aqueous solution of polyvinyl alcohol (PVA).
In accordance with this invention, the process for the preparation of SLNs having ATD encapsulated therein comprises:
1. mixing the lipid and the drugs in an organic solvent.
2. heating the mixture to above the melting point of the lipid.
3. pouring the emulsion into aqueous PVA, allowing the solvent to
diffuse by stirring.
4. recovering the nanoparticles by centrifugation, vacuum drying and
reconstituting the same by using distilled water (DW)/normal saline
(NS)/phosphate buffered saline (PBS).
In accordance with this invention, the drugs (hydrophilic and/or hydrophobic) and the lipid are put in a organic solvent preferably a mixture of acetone and ethanol (acetone: ethanol:: 1:1-2 v/v). The ratio of drug and lipid is kept at 1:1 w/w. The total solids (lipids + drugs) and the solvent should be in the ratio of 1-20:1 (w/v). The mixture is heated to 60°C-80°C in a closed water bath for 30-60 min. The emulsion is then poured into 0.5-2% w/v aqueous PVA at 4°C-10°C, keeping organic solvent: PVA:: 1:0.5-1.5 v/v. The emulsion is stirred for 5-20 min and centrifuged at 30,000-35,000 g for 20-30 min at 4°C-20°C obtained the pellet, washed 3-4 times with DW/NS/PBS, resuspended in same and vacuum dried for 18-30 h.
Example
A process for the preparation of SLNs having ATD encapsulated is explained by the following example:
20mg INH, 20mg PZA, 20mg RIF and 60 mg Stearic acid were put in a mixture of 12 mL each of acetone/ethanol. The mixture was heated to 75°C for 40 min and poured into 25 mL of 1% w/v PVA at 5°C. The emulsion was stirred for 10 min, centrifuged at 35000g at 10°C for 30 min, the pellet was washed thrice with DW and then resuspended in 3 mL of DW for vacuum drying for 24 h. The suspended SLNs were administered to guinea pigs by the aerosol route and the results are given in Table 1.
Table 1 - Colony forming units (CFUs) of M. tuberculosis in lungs of guinea pigs after drug treatment.
(Table Removed)
Determination of drug content in SLNs
The drug encapsulation efficiency was as under:
RIF - 54±4%
INH - 46±5%
PZA - 42±3%
The SLNs did not induce any hepatotoxicity as assessed by plasma bilirubin, alanine transaminase and alkaline phosphatase.

We Claim
1. Solid lipid nanoparticles having encapsulated drug comprising 50-
60% rifampicin, 40 to 50% isoniazid and 35 to 45% pyrazinamide
present as a combination having sustained controlled release of the
drug wherein the said lipid is stearic acid and the ratio of said drugs
in combination and lipid is 1:1.
2. A process for the preparation of solid lipid nanoparticles as clamied
in claim 1 wherein the process comprises.
a) preparing a primary organic emulsion by mixing said lipid and drugs in an organic solvent to form a mixture
b) heating the said mixture to above the melting point of the lipid
c) pouring the primary organic emulsion of lipid and said drug or drugs into an aqueous solution of polyvinyl alcohol allowing the solvent to diffuse by stirring
d) recovering the nanoparticles by centrifugation, vacuum drying and reconstituting the same

3. A process as claimed in claim 2 wherein the organic solvent is mixture of acetone and ethanol mixed in the ratio of 1:1-2 V/V.
4. A process as claimed in claim 2 wherein said solid (drugs + lipid): solvent ratio is 1-20:1 (W/V).
5. A process as claimed in claim 2 wherein said temperature is 60-80 °C
for 30-60 minutes.

6. A process as claimed in claim 2 wherein said emulsion is poured into aqueous PVA whose concentration is 0.5-2% W/V at 4°C -10°C.
7. A process as claimed in claim 2 wherein organic solvent: PVA ratio is
1:0.5 1.5 V/V the mixture is stirred for 5-20 minutes.
8. A process as claimed in claim 2 wherein the emulsion is centrifuged at 30000-35000 g at 4°C-20°C for 20-30 minutes.
9. A process as claimed in claim 2 wherein said particles are washed 3-4 times with distilled water/normal Saline/phosphate buffered saline pH 7.2-7.4 and vacuum dried for 18-30 hr.
10. Solid lipid nanoparticles having drug or drugs encapsulated therein
and a process for the preparation thereof substantially as herein
described and illustrated in the example.