The present invention relates to the field of pharmaceutical drugs and more
5 specifically it discloses a method for enhancing the solubility of the drug rifabutin
wherein solid dispersion method is incorporated.
BACKGROUND OF INVENTION
[002] Background description includes information that may be useful in understanding
the present invention. It is not an admission that any of the information provided
10 herein is prior art or relevant to the presently claimed invention, or that any
publication specifically or implicitly referenced is prior art.
[003] Oral absorption of a drug, enough bioavailability and all pharmacokinetic profile of
a drug molecule into the body is a crucial challenge in the oral dosages form
development of newly found drug molecule. Bioavailability of a drug, absorption
15 of a drug and the solubility of a drug ultimately affects the pharmacological
effectiveness of drug molecule. So in simple words we can say that the therapeutic
effectiveness of drug molecule depends upon its solubility. Thus solubility of a drug
molecule is considered as a most important factor to obtain the desired amount of
drug in the blood circulation so that the drug can give its pharmacological effect.
20 Around one-fourth of the newly discovered drugs listed in the united state
pharmacopoeia are comes into the category of poorly water-soluble drugs. At
3
present there are about more than 40 per cent of newly found drug molecules
discovered by the pharmaceutical industry are poorly soluble or highly lipophilic
compounds. Few years ago it was reported that more than 40% of the new drug
molecules are failed to reach into the systemic circulation. Therefore there are
5 failures in new drug development due to the poor water solubility of compounds. 4
[004] The oral delivery of the new drugs can be affected by the solubility issues and also
the delivery of many existing drugs. Poorly water soluble drugs cause many
difficulties in the formulation development, such as limited choices of delivery of
drug and a very complex dissolution testing with inadequate correlation to the in
10 vivo absorption. Due to the poor solubility drug cant reached into the systemic
circulation and cause problem in attaining expected in vivo/in vitro correlations.
There are various solubility enhancement techniques which are used to improve the
solubility of such drugs.
[005] Solubility is defined as the highest portion of a drug molecule that will be totally
15 dissolved in a given solvent at a fixed temperature and pressure. Miscibility is
describing the affinity between two liquids, when both solvent and solutes are
liquids. At the surface of the former when its molecules get removed until the
equilibrium is obtained between two molecules leaving the solid and those who are
returning to it, an extra amount of solid is brought into the contact with a liquid.
20 The prepared solution is called to be saturated at the particular temperature of the
experiment, and the extent to which the solute gets dissolved is referred as its
solubility. The solubility of different substances differs from almost imperceptible
4
amounts to relatively large quantities, but for a given solute the solubility has a
constant value at constant temperature. In some conditions it may be possible to
make a solution that has the more amount of solute than the amount of solute
required forming a saturated solution. This type of situation occurs when the
5 solution of solute is saturated solution at a particular temperature. From it, the extra
amount of solute gets removed out, and then the solution gets cooled. Solubility of
a substance is described in many ways. According to the USP/NF the solubility of
a substance is defined in the terms of the volume (amount) of solvent required to
dissolve the 1 gram of the drug at a given temperature.
[006] 10 Drugs who have poor water solubility can often present significant challenges
during early pre-clinical pharmacokinetic (PK) and toxicology investigations,
which may leads to high dose formulations being administered to obtain the
required therapeutic levels. Enhancement o solubility of poorly aqueous soluble
drug is an important aspect for formulation development. Although there is plethora
15 of reports to improve the solubility of drugs by using different techniques and a
comparative study between different solubilization approaches are few. Since it is
poorly aqueous soluble, various techniques could be used to increase its solubility.
During the process of enhancement of drug solubility, sufficient information was
gained about the physical & chemical properties of the drug substance, excipients
20 used for increasing the solubility and the solubility enhancement process.
Immediate release drug delivery system is to ensure safety as well as increase
absorption, hence bio availability also get enhanced. Identification and evaluation
5
of the parameters in various processes must be controlled in order to ensure batch
to batch reproducibility.
[007] When two or more liquids are mixed together in any portion and they formed a
homogenous mixture, then they are called as miscible liquids for example alcohol
5 and water. Those liquids in which only some amount produce homogenous
mixtures are called as miscible liquids in certain proportions (for example water
and chloroform). Those liquids are said to be immiscible who are not mixed with
each other (for eg. water and olive oil). The water solubility of all drugs is
interesting to us, because only in the aqueous form, a drug gets absorbed and shows
10 its pharmacological effects. Drug solutions are most common dosages forms.
Therefore a pharmacist should be aware about some methods of determining the
solubility of a drug in a liquid and should be known about the various precautions
that taken during solubility determinations.
[008] The water solubility of a drug is a complex interplay of several factors, such as the
15 H-bond donor and H-bond accepter properties of a molecule and water can
disrupting the crystal structure of the solid in order to bring it into solution. Water
solubility of a pharmaceutical active compound is a key property as it governs
dissolution and absorption and thus the in vivo efficacy. Pharmacological
effectiveness of a drug molecule depends upon the bioavailability and on the
20 solubility of the drug molecule. Thus, solubility of a drug is most important
parameter to achive a good bio availability in systemic circulation. In most of the
research it was found that around eight percent of new drug molecules have good
6
solubility and good permeability and most of the drugs are poorly soluble in water
and creating problems in drug development. Water solubility of a pharmaceutical
active compound is a key property because it governs the dissolution of a drug and
absorption of drug and thus the in vivo efficacy of drug. It means the
5 pharmacokinetic and pharmacologic profile of a drug is depends upon its solubility.
[009] Researches had been conducted in the past and the prior arts reveal as follows. A
researcher developed a spectrophotometric method for the estimation of poorly
water soluble drugs like olanzepine in pharmaceutical dosages forms. The method
was based on use of hydrotropic solutions to extract the drug from the dosages
10 forms thus predicting the use of costlier organic solvents.
[0010] Another researcher reviewed about the enhancement of solubility and was found
that among all newly discovered chemical entities about 40% drugs are lipophillic
and fail to reach market due to their poor water solubility. The solubility behavior
of drugs remains one of the most challenging aspects in formulation development.
15 Solid dispersions have tremendous potential for improving drug solubility.
[0011] Yet another researcher enhanced the solubility of poorly water soluble drug
norfloxacin by incorporating solubilizing additives such as ascorbic acid and citric
acid into the β-cyclodextrin complexes. It was observe that the solubilizing
additives like ascorbic acid and citric acid in β-cyclodextrin complexes reduces the
20 pH of the immediate microenvironment of the drug also the solubility of
norfloxacin increased with the increase in dissolution rate.
7
[0012] Yet another researcher studied about the various techniques employed to enhance
the aqueous solubility of poorly water-soluble drugs, mainly hydrotropic
solubilization. They prepared and evaluated hydrotropic solution of ornidazole by
using ibuprofen sodium (0.5M) as solubilizing agent. It was observed that the above
5 method is new, simple, safe, environmentally friendly, accurate and cost-effective
and can be successfully employed in routine to analyze ornidazole tablets.
[0013] Yet another researcher enhanced the solubility of valdecoxib by cosolvency and
cyclodextrins (CD) addition as a combined approach by using PEG-400,
poloxamer-188 and 2 CDs (b-CD and Hp-b-CD). It was observed that the solubility
10 of valdecoxib significantly improved by addition of PEG-400, CDs and poloxamer188 and both cosolvency and CD addition are promising approaches for enhancing
the solubility of valdecoxib. However there remains a need for further research in
the domain to improve the solubility of the drug and hence the present invention
discloses solid dispersion method in place.
[0014]15 Further limitations and disadvantages of conventional and traditional approaches
will become apparent to one of skill in the art through comparison of described
systems with some aspects of the present disclosure, as outlined in the remainder
of the present application and concerning the drawings.
[0015] In some embodiments, the numbers expressing quantities or dimensions of items,
20 and so forth, used to describe and claim certain embodiments of the invention are
to be understood as being modified in some instances by the term “about.”
Accordingly, in some embodiments, the numerical parameters outlined in the
8
written description and attached claims are approximations that can vary depending
upon the desired properties sought to be obtained by a particular embodiment. In
some embodiments, the numerical parameters should be construed in light of the
number of reported significant digits and by applying ordinary rounding techniques.
5 Notwithstanding that the numerical ranges and parameters setting forth the broad
scope of some embodiments of the invention are approximations, the numerical
values outlined in the specific examples are reported as precisely as practicable.
The numerical values presented in some embodiments of the invention may contain
certain errors necessarily resulting from the standard deviation found in their
10 respective testing measurements.
[0016] As used in the description herein and throughout the claims that follow, the meaning
of “a,” “an,” and “the” includes plural reference unless the context dictates
otherwise. Also, as used in the description herein, the meaning of “in” includes “in”
and “on” unless the context dictates otherwise.
[0017]15 Groupings of alternative elements or embodiments of the invention disclosed herein
are not to be construed as limitations. Each group member can be referred to and
claimed individually or in any or a combination with other members of the group
or other elements found herein. One or more members of a group can be included
in, or deleted from, a group for reasons of convenience and/or patentability. When
20 any such inclusion or deletion occurs, the specification is herein deemed to contain
the group as modified thus fulfilling the written description of all groups used in
the appended claims.
9
OBJECTS OF THE INVENTION:
[0018] The enhancement of oral absorption and bioavailability of poorly water soluble
drugs remains most challenging parameter in drug development process. There are
various techniques used to increase dissolution rate of drug like are particle size
5 reduction, salt formation and lyophilization, but all these methods have practical
limitations like improper enhancement of solubility and all the drugs are not
suitable for these techniques.
[0019] A general object of the present invention is to establish a novel approach towards
enhancement of solubility and bioavailability of Rifabutin.
[0020]10 Another object of the present invention is to overcome the above difficulties
through solid dispersion method to improve the solubility and dissolution rate of
rifabutin.
[0021] Yet another object of the present invention is to effectuate formulations, solubility
trials performed with different carriers in different ratios to enhance the solubility,
15 dissolution rate and consequently bioavailability of the drug.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The accompanying drawings are included to provide a further understanding of the
present disclosure and are incorporated in and constitute a part of this specification.
The drawings illustrate exemplary embodiments of the present disclosure and,
20 together with the description, serve to explain the principles of the present
disclosure.
10
FIG. 1 illustrates an exemplary representation of the structure of rifabutin.
FIG. 2 illustrates a graphical representation of the solubility profile of the drug solid
dispersions of various combinations
FIG. 3 illustrates a mathematical graph of the dissolution profile of PEG 4000 for
5 various combinations over a given time.
FIG. 4 illustrates a mathematical graph of the dissolution profile of PEG 6000 for
various combinations over a given time.
FIG. 5 illustrates a mathematical graph of the dissolution profile of solid dispersions
of HPβ-CD.
10 FIG. 6 illustrates a mathematical graph of the dissolution profile of solid dispersions
of poloxamer 407.

DETAILED DESCRIPTION

The following is a detailed description of embodiments of the disclosure depicted in the accompanying drawings. The embodiments are in such detail as to communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0024] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0025] Solid dispersion method is used for enhancement of the solubility of rifabutin. The solid dispersion was prepared by the solvent evaporation method by using different polymers in different ratios. The final % yield of the prepared solid dispersions shows above 92.0% which is calculated by measuring the weight of the final product compared with the theoretical weight. Solid dispersion of rifabutin with poloxamer 407 in 1:4 ratios showed highest % yield.
[0026] Drug content analysis was done for all solid dispersion formulations in triplicate. Solid dispersions of the rifabutin show uniformity in drug content in each batch so they can be used for further formulation development. All prepared dispersions have almost same drug content thus they can be considered very good for formulation development.
[0027] FIGURE 2 illustrates a graphical representation of the solubility profile of the drug solid dispersions of various combinations. Saturated solubility studies for drug and solid dispersions were carried out at room temperature. The prepared solid dispersions of rifabutin have very good solubility as compared to the pure rifabutin. Solvent evaporation method was used to prepare the solid dispersion and this method gives a synergistic effect for enhancing the solubility of rifabutin. All the prepared solid dispersions of rifabutin had very good solubility profile than the pure rifabutin. The solid dispersion contains poloxamer 407 in 1:4 ratios showed highest solubility as compared to other solid dispersions.
[0028] FIGURES 3, 4, 5 and 6 illustrates the mathematical graphs of the dissolution profile of PEG4000, PEG6000, HPß-CD and poloxamer 407 respectively for various combinations over a given time. Dissolution studies of prepared solid dispersions were performed in a dissolution test apparatus type II (Paddle) employing 900 ml 5 % w/v sodium lauryle sulfate buffer solution as a dissolution medium according to USP. In these results it is clearly noticed that the almost all the solid dispersions of rifabutin has good dissolution rate when the amount of polymers increased. Dissolution profile of pure rifabutin show very poor release of drug that is just 20% at 20 minutes. Dissolution rate of prepared solid dispersions was differentially higher as compared to the pure rifabutin. Highest rate of dissolution was obtained in solid dispersions of rifabutin with poloxamer 407 in 1:4 ratios.. In this dissolution profile it was found that the maximum % drug release was obtained in poloxamer 407 batches 1:4.
[0029] Fourier Transformed Infrared Spectroscopy (FTIR) analysis was employed for only those solid dispersions which shown highest dissolution rate from each formulation. The solid dispersion of both PEGs, especially at the lower proportions of PEG, showed IR spectra similar to the corresponding physical mixtures; they showed the superimposed spectra of rifabutin crystals and PEGs. The N – H stretching band of rifabutin at 3331 cm–1 disappeared in the spectra of the dispersion with PEGs at the 1:4 mixing ratio, and the broad O – H stretching band of PEGs slightly shifted to the lower frequency. It might be speculated that the intermolecular hydrogen bonding between rifabutin and PEG molecules existed.
[0030] The thermal behavior rifabutin and its dispersions with polymers were studied with the help of differential scanning calorimetry (DSC). It is most widely used method for thermal analysis of pharmaceutical powders because it provides detailed information about the physical properties and energetic properties of a pharmaceutical substance. An endothermic peak in DSC thermogram of pure rifabutin was obtained at 174°C, which is closed to the melting point of the rifabutin. This indicates crystalline nature of rifabutin. PEG 4000 shows its endothermic peak at 60.40°C. Thermogram of solid dispersion contains PEG 4000 shows two endothermic transactions. The first transition peak was observed near the melting point of PEG 4000 and the second peak was obtained at 162.36°C. DSC thermogram of solid dispersions showed some small peaks which indicate agood interaction between drug and polymers. Each sample had a sharp endothermic peak corresponding to their melting points.
[0031] While the foregoing describes various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions, or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person.

CLAIMS

We claim,

1. A method for enhancing the solubility of rifabutin using solid dispersion
comprising steps:
formulation of solid dispersions on solvent evaporation method
using a plurality of polymers on a plurality of ratios;
evaluation of the prepared solid dispersions for various tests on
percentage yield, drug content, saturated solubility and dissolution
parameters;
analysis of the solid dispersions with highest dissolution rate;
2. The method as claimed in claim 1 wherein, the solid dispersion of rifabutin
with poloxamer 407 in 1:4 ratios showed highest % yield.
3. The method as claimed in claim 1 wherein, the solid dispersions of the
rifabutin shows uniformity in drug content in each batch whereby the
rifabutin contents in the prepared solid dispersions shows a range of 95-
103%.
4. The method as claimed in claim 1 wherein, the solid dispersion containing
poloxamer 407 in 1:4 ratios showed highest solubility as compared to other
solid dispersions.

5. The method as claimed in claim 1 wherein, the highest rate of dissolution
was obtained in solid dispersions of rifabutin with poloxamer 407 in 1:4
ratios.