FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention – RIFAXIMIN COMPLEXES
2. Applicant(s)
(a) NAME: CIPLA LIMITED
(b) NATIONALITY: An Indian Company
(c) ADDRESS: Cipla House, Peninsula Business Park, Ganpatrao
Kadam Marg, Lower Parel Mumbai 400013,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed:
2
Divided out of
Patent Application No. 1383/MUMNP/2011 dated 5 December 09, 2009
(Nationalisation date: July 04, 2011)
10 Technical Field of the Invention
The present invention relates to complexes of rifaximin and processes for
preparing such complexes.
15 Background
Rifaximin is a semi-synthetic, rifamycin antimicrobial drug with in vitro activity
against Gram-positive, Gram-negative and anaerobic bacteria. It acts by
inhibiting bacterial ribonucleic acid (RNA) synthesis. Rifaximin is chemically
20 termed as (2S, 16Z, 18E, 20S, 21S, 22R, 23R, 24R, 25S, 26S, 27S, 28E)-
5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-
(epoxypentadeca-[1,11,13]-trienimino)benzofuro-[4,5-e]-pyrido-[1,2-a]-
benzimidazole-1,15-(2H)-dione, 25-acetate (I).
C H3
C H3
H3C
C H3
O
N
N
C H3
O
OH OH
N H
O
C H3
O
C H3
HO
O H
C H3
O
MeO
C H3
O
25 (I)
3
Rifaximin is used for treatment of travelers’ diarrhea caused by noninvasive
strains of Escherichia coli.
WO2009137672 discloses a method of treating bowel disease 5 (BD), comprising
administering a gastointetinal cleanser to a subject in need thereof; and
administering a therapeutically effective amount of an antibiotic.
Rifaximin was first disclosed in US 4,341,785 which also discloses a process for
10 its preparation and a method for crystallization of rifaximin by using suitable
solvents or a mixture of solvents. This patent does not mention polymorphism of
rifaximin.
US 4,557,866, and its equivalent CA1215976, disclose processes for the
15 preparation of rifaximin.
WO2007047253 discloses a pharmaceutical composition of hydroxybutenyl
cyclodextrins with antifungal azole compounds. However, this application does
not provide any enabling methods nor proof of advantages of such a complex.
20
WO2008035109 discloses the amorphous form of rifaximin.
US 7,045,620, discloses various crystalline polymorphic forms of rifaximin which
are termed as rifaximin α, rifaximin β and rifaximin γ. These polymorphic forms
25 are characterized using X-ray powder diffraction. According to US 7,045,620,
the presence of water within the crystallization solvent plays an important role in
crystal formation. Thus, rifaximin polymorphs undergo changes with a change in
the moisture content, and interconversion of one form to another occurs with an
increase or decrease in the water content.
30
4
US 7,045,620 further discloses rifaximin α which has a water content between
2.0% and 3.0%, rifaximin β which has a water content between 5.0% and 6.0%,
and rifaximin γ which is poorly crystalline and has a water content between
1.0% and 2.0%.
5
EP1698630 discloses further polymorphic forms of rifaximin termed as δ and ε.
The stability of these forms also depends upon the water content.
However, all these forms are hygroscopic and they have a tendency to
10 interconvert from one to another. Thus, these forms are difficult to handle as
well as store and they require controlled conditions, specifically, humidity and
temperature during handling and storage.
Thus, transformations of polymorphic forms of drug substances are of great
15 disadvantage, because they cause difficulties in fulfilling pharmaceutical
requirements and specifications. The physicochemical properties of products
that exhibit such polymorphic change vary according to the actual ratio of
polymorphic forms. This causes further difficulties while formulating the
polymorphic forms into suitable dosage forms.
20
Also, as rifaximin is sparingly soluble in water, the formulation chemist finds it
difficult to prepare a consistent formulation using the known polymorphic forms.
Hence, there is a need to prepare rifaximin in a form which is suitable for
formulation and has increased solubility and stability.
25
Summary of the Invention
According to a first aspect of the present invention, there is provided a form of
rifaximin with enhanced solubility and stability. This form of rifaximin is a
30 complex comprising rifaximin and a complexing agent.
5
According to another aspect of the present invention, there is provided a
complex comprising rifaximin and a complexing agent. Throughout this
specification, this complex may be referred to as “the rifaximin complex”. In an
embodiment, the complex comprises solely rifaximin and the complexing agent,
i.e. no other components are present 5 in the complex.
Advantageously, the complex of the present invention exhibits enhanced
solubility and stability, particularly compared to a physical mixture of rifaximin
and a complexing agent.
10
The complexing agent used in the present invention comprises a polyvinyl
pyrrolidone (PVP) or a cyclodextrin (CD).
In an embodiment, the complexing agent is a PVP. In an alternative
15 embodiment, the complexing agent is a CD.
In an embodiment, the complexing agent is not hydroxybutenyl cyclodextrin or
sulfonyl hydroxybutenyl cyclodextrin.
20 In an embodiment, the complexing agent is a PVP having a K-value ranging
from K-15 to K-90. Suitably, the complexing agent is a PVP selected from the
group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80, K-90 and K-
120, preferably, K-25, K-30 or K-90. Typically, the complexing agent is PVP K-
30.
25
In an embodiment, the complexing agent is an unmodified cyclodextrin. In other
words, the CD is a cyclic glucose oligosaccharide in which none of the hydroxyl
groups has been modified. In an embodiment, the complexing agent is a
cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin
30 or γ-cyclodextrin, preferably β-cyclodextrin.
6
In an embodiment, the weight ratio of rifaximin to complexing agent ranges from
20:1 w/w to 1:20 w/w. It is to be understood that “w/w” means by weight.
Advantageously, the ratio of rifaximin to complexing agent ranges from 10:1
w/w to 1:2 w/w. Typically, the ratio of rifaximin to complexing agent ranges from
4:1 w/w to 1:2 w/w. The ratio 5 may be 1:1 w/w.
According to another aspect of the present invention, there is provided the
rifaximin complex characterized by having an intrinsic dissolution profile as
shown in any one of Figures 1 to 8.
10
According to another aspect of the present invention, there is provided a
process for preparing a complex comprising rifaximin and a complexing agent,
the process comprising:
15 a) dissolving rifaximin in a solvent;
b) adding the complexing agent to the rifaximin solution to form a mixture;
c) isolating the complex from the reaction mass obtained in step b).
In an embodiment, the complex comprises solely rifaximin and the complexing
20 agent, i.e. no other components are present in the complex.
The complexing agent used in the process comprises a polyvinyl pyrrolidone
(PVP) or a cyclodextrin (CD).
25 In an embodiment, the complexing agent is a PVP. In an alternative
embodiment, the complexing agent is a CD.
In an embodiment, the complexing agent is a PVP having a K-value ranging
from K-15 to K-90. Suitably, the complexing agent is a PVP selected from the
30 group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80, K-90 and K7
120, preferably, K-25, K-30 or K-90. Typically, the complexing agent is PVP K-
30.
In an embodiment, the complexing agent is a cyclodextrin selected from the
group consisting of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin, 5 preferably β-
cyclodextrin.
In an embodiment, the weight ratio of rifaximin to complexing ranges from 20:1
w/w to 1:20 w/w. It is to be understood that “w/w” means by weight.
10 Advantageously, the ratio of rifaximin to complexing agent ranges from 10:1
w/w to 1:2 w/w. Typically, the ratio of rifaximin to complexing agent ranges from
4:1 w/w to 1:2 w/w. The ratio may be 1:1 w/w. Thus, according to another
aspect of the present invention, there is provided a complex comprising
rifaximin and a complexing agent, wherein the weight ratio of rifaximin to
15 complexing ranges from 20:1 w/w to 1:20 w/w, preferably from 10:1 w/w to 1:2
and more preferably from 4:1 w/w to 1:2 w/w.
The rifaximin used in the process of the present invention may be in any
polymorphic form or in a mixture of any polymorphic forms.
20
The complexing agent may be added to the rifaximin solution as such or in the
form of a solution with a solvent.
The solvent for the rifaximin may be selected from the group consisting of an
25 ether, an alcohol, an ester, an aldehyde, a halogenated solvent, a hydrocarbon
and mixtures thereof. Preferably, the solvent is an alcohol, for example
methanol or ethanol. Typically, the solvent is ethanol.
The complexing agent may be added to the rifaximin in the form of a solution.
30 In which case, the solvent for the complexing agent may be selected from the
group consisting of an ether, an alcohol, an ester, an aldehyde, a halogenated
8
solvent, a hydrocarbon and mixtures thereof. Preferably, the solvent is an
alcohol, for example methanol or ethanol. Typically, the solvent is ethanol.
Alternatively, the complexing agent may be added to the rifaximin solution as
such, i.e. not in the form 5 of a solution.
Suitably, the isolation comprises concentrating the reaction mass obtained in
step b), and drying to obtain the isolated complex.
10 According to another aspect of the present invention, there is provided a
complex prepared according to the process described above.
According to another aspect of the present invention, there is provided a
complex comprising rifaximin and a complexing agent, which complex
15 enhances at least one of the following:-
a) stabilization of rifaximin against degradation (e.g. hydrolysis, oxidation, etc)
b) water solubility
c) dissolution
20 d) free flowability and non-hygroscopicity
e) solubility, delivery and/or performance
f) safe handling
According to yet another aspect of the present invention, there is provided a
25 rifaximin complex as described above for use in medicine.
According to yet another aspect of the present invention, there is provided a
rifaximin complex as described above for use in the treatment of travelers’
diarrhea caused by noninvasive strains of Escherichia coli. The present
30 invention further provides a rifaximin complex as described above for use in
treating bowel disease.
9
According to yet another aspect of the present invention, there is provided the
use of a rifaximin complex as described above for use in the manufacture of a
medicament for treating travelers’ diarrhea caused by noninvasive strains of
Escherichia coli as well as for treating 5 bowel disease.
According to yet another aspect of the present invention, there is provided a
method of treating hypertension or benign prostatic hyperplasia or for treating
bowel disease, comprising administering to a patient in need thereof a
10 therapeutically effective amount of rifaximin complex as described above.
Brief Description of Accompanying Drawings
Figure 1 – intrinsic dissolution profile of (1:2 w/w rifaximin:PVP) PVP complex of
15 rifaximin of the present invention compared with that of a physical mixture of β-
rifaximin and PVP (1:2 w/w rifaximin:PVP) by an HPLC-UV method.
Figure 2 – intrinsic dissolution profile of (1:1 w/w rifaximin:PVP) PVP complex of
rifaximin of the present invention compared with that of a physical mixture of β-
20 rifaximin and PVP (1:1 w/w rifaximin:PVP) by an HPLC-UV method
Figure 3 – intrinsic dissolution profile of (4:1 w/w rifaximin:PVP) PVP complex of
rifaximin of the present invention compared with that of a physical mixture of β-
rifaximin and PVP (4:1 w/w rifaximin:PVP) by an HPLC-UV method.
25
Figure 4 – intrinsic dissolution profile of (10:1 w/w rifaximin:PVP) PVP complex
of rifaximin of the present invention compared with that of a physical mixture of
β-rifaximin and PVP (10:1 w/w rifaximin:PVP) by an HPLC-UV method.
10
Figure 5 – intrinsic dissolution profile of (1:2 w/w rifaximin:β-CD) β-cyclodextrin
complex of rifaximin of the present invention compared with that of a physical
mixture of β-rifaximin and CD (1:2 w/w rifaximin:β-CD) by an HPLC-UV method.
Figure 6 indicates intrinsic dissolution profile of (1:1 w/5 w rifaximin:β-CD) β-
cyclodextrin complex of rifaximin of the present invention compared with that of
a physical mixture of β-rifaximin and CD (1:1 w/w rifaximin:β-CD) by an HPLCUV
method
10 Figure 7 indicates intrinsic dissolution profile of (4:1 w/w rifaximin:β-CD) β-
cyclodextrin complex of rifaximin of the present invention compared with that of
a physical mixture of β-rifaximin and CD (4:1 w/w rifaximin:β-CD) by an HPLCUV
method.
15 Figure 8 indicates intrinsic dissolution profile of (10:1 w/w rifaximin:β-CD) β-
cyclodextrin complex of rifaximin of the present invention compared with that of
a physical mixture of β-rifaximin and CD (10:1 w/w rifaximin:β-CD) by an HPLCUV
method.
20 Figure 9 indicates an X-ray powder diffractogram (XRD) of a β-cyclodextrin
complex of rifaximin at 1:1 w/w concentration.
Figure 10 indicates an X-ray powder diffractogram (XRD) of (10:1 w/w
rifaximin:PVP) a PVP complex of rifaximin.
25
Detailed Description of the Invention
The invention will now be described in detail in connection with certain preferred
and optional embodiments, so that various aspects thereof may be more fully
30 understood and appreciated.
11
The present invention provides a form of rifaximin with enhanced solubility and
stability. This form of rifaximin comprises a complex of rifaximin with a
complexing agent. The complexing agents used in the present invention include
more particularly a polyvinyl pyrrolidone or a cyclodextrin.
5
There is also provided by the present invention a process for preparing the
rifaximin-complexing agent complex of the present invention, the process
comprising:
10 a) dissolving the rifaximin in a suitable solvent;
b) adding the complexing agent to the rifaximin solution either as such or in the
form of solution to form a mixture;
c) isolating the complex, for example by concentrating the reaction mass
obtained in step b) and further drying to obtain the complex.
15
The rifaximin used in the process of the present invention may be obtained by
any one of the methods disclosed in the prior art. For example, the rifaximin
used in the process of the present invention may be in the polymorphic form α,
β, γ, δ or ε. In a preferred embodiment of the present invention, the rifaximin
20 used is in the β-form. The β-form of rifaximin is the least soluble known form of
rifaximin.
The solvent used may be selected from ethers, alcohols, esters, aldehydes,
halogenated solvents, hydrocarbons and combinations thereof.
25
In the process of the present invention, the complexing agent used may be
selected from polyvinyl pyrrolidone (PVP) or cyclodextrin (CD).
Polyvinyl pyrrolidone (PVP, also known as “povidone”) is commercially available
30 as a white powder of a given molecular weight. Generally, the molecular
weights of PVP polymers are given by their K-values, e.g., K-15 to K-90. The Kvalue
indicates the average molecular weight ranging from 20,000 to 1,000,000.
12
A preferred PVP is K-30, typically having a molecular weight of about 40,000.
An unusual property of PVP is its solubility in water as well as in various organic
solvents.
In the process of the present invention, the PVP may be 5 selected from the
group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-60, K-80, K-90 and K-
120. Preferably, K-25, K-30, K-90, and most preferably K-30.
In the process of the present invention, the cyclodextrin used to form the
10 complex may be in any form of cyclodextrin, including α-cyclodextrin having 6
glucose units, β-cyclodextrin having 7 glucose units, or γ-cyclodextrin having 8
glucose units. The cyclodextrin may also be in anhydrous or hydrated form.
The preferred cyclodextrin is β-cyclodextrin.
15 The complexing agent may be added as such or as a solution in a suitable
solvent. The amount of rifaximin that can be encapsulated is directly related to
the molecular weight of the rifaximin.
In some embodiments, one mole of complexing agent encapsulates one mole of
20 rifaximin. Preferably, the amounts of rifaximin and complexing agent used in the
formulation are typically sufficient to provide the desired therapeutic effect. On a
weight basis, the ratio between rifaximin and complexing agent in the given
composition (termed “w/w”), ranges from 20:1 to 1:20, preferably from 10:1 to
1:2. Typically, the ratio of rifaximin to complexing agent ranges from 4:1 to 1:2.
25 The ratio may be 1:1.
The solvent may be removed rapidly and completely by vacuum drying or
vacuum evaporation. In an embodiment, the solvent may be removed by spray
drying to yield the rifaximin complex. In another embodiment, the rifaximin
30 complex may be obtained freeze drying. In yet another embodiment, the
rifaximin complex may be isolated by microwave treatment techniques.
13
According to a third aspect of the present invention, there is provided a rifaximin
complex which enhances at least one of the following:-
a) stabilization of rifaximin against degradation (e.g. hydrolysis, 5 oxidation, etc)
b) enhancement of water solubility of rifaximin
c) better dissolution
d) free flowing and non-hygroscopic rifaximin
e) modified solubility, delivery or performance
10 f) safe handling of rifaximin
The rifaximin complex of the present invention is not a simple physical mixture
of the ingredients. This rifaximin complex is superior to the conventional free
base of rifaximin, for example in terms of storage stability.
15
Further, it was observed that the use of a complexing agent as an excipient in
the formulation enhances solubility to some extent but the formation of a
complex with rifaximin enhances solubility much more than mixing it physically
as an excipient. Further, the aqueous solubility of the rifaximin complex with
20 cyclodextrin or PVP is found to be greater than the aqueous solubility of
rifaximin. The enhanced solubility of the complex can further increase
dissolution rate as shown in Figures 1 to 8 and thus makes these complexes
more bio-available in the body. This increase in bioavailability and stability of
the complex further allows for smaller doses to achieve the desired therapeutic
25 effect compared to a larger dose of rifaximin alone. Further, these complexes
avoid interconversion of crystalline forms of rifaximin. In addition, these
complexes can be used to reduce or prevent gastrointestinal and ocular
irritation, to reduce or eliminate unpleasant smells or tastes, as well as to
prevent drug–drug or drug–additive interactions.
30
14
According to another aspect of the present invention, there is provided a
rifaximin complex characterized by having an intrinsic dissolution profile as
shown in any one of Figures 1 to 8.
To measure the intrinsic dissolution of a rifaximin complex, 5 for example a
rifaximin-PVP complex or a rifaximin-CD complex, rifaximin samples were
measured to compare the influence of the different parameter settings. At
appropriate time intervals, an automated sample collector removes aliquots
from the dissolution medium for analysis. The time interval for sampling can
10 vary, for example, from 2 to 30 minutes, depending on the properties of the drug
and dissolution medium used. Suitable dissolution equipment for these
operations includes LAB INDIA DISSO 2000.
The complexes may be used in a variety of applications. In an embodiment, the
15 composition of the present invention is in the form of a tablet, a capsule or a
liquid oral. The composition may further optionally include additional
components to enhance or achieve the desired therapeutic effect of rifaximin.
Examples of such components include, but are not limited to surfactants,
excipients, disintegrating agents, binders, lubricants, dispersing agents,
20 thickening agents.
The present invention will now be further illustrated by the following examples,
which do not limit the scope of the invention in any way.
25 Example 1 – Preparation of rifaximin-PVP complex (1:2 w/w ratio)
Preparation 1
2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30°C. 4 g of PVP K-30
was dissolved in 40 ml ethanol. The solution of PVP K-30 was added to the
30 rifaximin solution and stirred. The reaction mass was concentrated under
15
vacuum at 35°C till dryness and then dried completely at 30-35°C for 24 hours
to get 5.4 g rifaximin-PVP complex.
Preparation 2
5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30°C. 5 The reaction mass
was heated to 35°C and 10 g of PVP K-30 was added to the rifaximin solution
and stirred. The reaction mass was concentrated under vacuum at 35°C till
dryness and then dried completely at 30-35°C for 24 hours to get 13 g rifaximin-
PVP complex.
10
Example 2 – Preparation of rifaximin-PVP complex (1:1 w/w ratio)
Preparation 1
2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30°C. 2 g of PVP K-30
15 was dissolved in 20 ml of ethanol. The solution of PVP K-30 was added to the
rifaximin solution and stirred. The reaction mass was concentrated under
vacuum at 35°C till dryness and then dried completely at 30-35°C for 24 hours
to get 3.1 g rifaximin-PVP complex.
20 Preparation 2
5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30°C. The reaction mass
was heated to 35°C and 5 g of PVP K-30 was added to the rifaximin solution
and stirred. The reaction mass was concentrated under vacuum at 35°C till
dryness and then dried completely at 30-35°C for 24 hours to get 8.8 g
25 rifaximin-PVP complex.
Example 3 – Preparation of rifaximin-PVP complex (4:1 w/w ratio)
Preparation 1
30 10 g of rifaximin was dissolved in 150 ml of ethanol at 30-35°C. A solution of
PVP K-30 was prepared by dissolving 2.5 g of PVP K-30 in 25 ml of ethanol.
16
This solution was added to the rifaximin solution at 30-35°C. The reaction mass
was stirred, concentrated to dryness under vacuum at 30-35°C and then dried
completely at 70°C for 24-30 hours to get 12.5 g rifaximin-PVP complex.
5 Preparation 2
5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30°C. The reaction mass
was heated to 35°C and 1.25 g of PVP K-30 was added to the rifaximin solution
and stirred. The reaction mass was concentrated under vacuum at 35°C till
dryness and then dried completely at 30-35°C for 24 hours to get 5.5 g
10 rifaximin-PVP complex.
Example 4 – Preparation of rifaximin-PVP complex (10:1 w/w ratio)
Preparation 1
15 10 g of rifaximin was dissolved in 150 ml of ethanol at 30-35°C. A solution of
PVP K-30 was prepared by dissolving 1 g of PVP K-30 in 15 ml of ethanol. The
solution was added to the rifaximin solution. The reaction mass was stirred at
30-35°C, concentrated to dryness under vacuum at 30-35°C and then dried
completely at 30-35°C for 24-30 hours to get 10.3 g rifaximin-PVP complex.
20
Preparation 2
5 g of rifaximin was dissolved in 75 ml of ethanol at 25-30°C. The reaction mass
was heated to 35°C and 0.5 g of PVP K-30 was added to the rifaximin solution
and stirred. The reaction mass was concentrated under vacuum at 35°C till
25 dryness and then dried completely at 30-35°C for 24 hours to get 5.0 g
rifaximin-PVP complex.
Example 5 – Preparation of the rifaximin-β-cyclodextrin complex (1:2 w/w
ratio)
30
Preparation 1
17
2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30°C. To this solution 4
g of β-cyclodextrin was added and stirred. The reaction mass was concentrated
under vacuum at 35°C, stripped with 20 ml of ethanol. This residue was
concentrated to dryness and dried under vacuum at 30-35°C for 20-24 hours to
get 5.1 g rifaximin-β cyclodextrin 5 complex.
Preparation 2
4 g of rifaximin was dissolved in 60 ml of ethanol at 25-30°C. The reaction mass
was heated to 35°C and 8 g of β-cyclodextrin was added to the rifaximin
10 solution and stirred. The reaction mass was concentrated under vacuum at
35°C till dryness and then dried completely at 30-35°C for 24 hours to get 10.7
g rifaximin-β cyclodextrin complex.
Example 6 – Preparation of rifaximin β-cyclodextrin complex (1:1 w/w
15 ratio)
2 g of rifaximin was dissolved in 30 ml of ethanol at 25-30°C. To this solution 2
g of β-cyclodextrin was added and stirred. The reaction mass was concentrated
under vacuum at 35°C and then dried completely at 30-35°C for 20-24 hours to
20 get 2.8 g rifaximin-β cyclodextrin complex.
Example 7 – Preparation of the rifaximin-β-cyclodextrin complex (4:1 w/w
ratio)
25 7g of rifaximin was dissolved in 100 ml of ethanol at 30-35°C. To this solution
1.75 g of β-cyclodextrin was added and stirred. The reaction mass was stirred,
concentrated to dryness under vacuum at 30-35°C and then dried completely at
30-35°C for 24-30 hours to get 8.1 g rifaximin-β cyclodextrin complex.
30 Example 8 – Preparation of the rifaximin-β-cyclodextrin complex (10:1 w/w
ratio)
18
7g of rifaximin was dissolved in 100 ml of ethanol at 30-35°C. To this solution
0.7 g of β-cyclodextrin was added and stirred. The reaction mass was stirred,
concentrated to dryness under vacuum at 30-35°C and then dried completely at
30-35°C for 24-30 hours to get 6.75 g rifaximin-β cyclodextrin 5 complex.
Comparative Intrinsic Dissolution Study
Example 9 - Preparation of tablet:-
10
General process for preparing tableting mixture comprising rifaximin complex:-
A tableting mixture (100 mg) comprising solely rifaximin complex prepared
according to any of the examples 1 to 8 (i.e. with no excipients) was prepared
and compressed to a pellet using a manual hand press operating at a
15 compression pressure of 2.5 tones for 5 minutes.
General process for preparing tableting mixture comprising a physical mixture of
rifaximin and complexing agent:-
20 Similarly a tableting mixture (100 mg) comprising a solely physical mixture of
rifaximin and complexing agent in the proportionate ratio (i.e. with no excipients)
was prepared by mixing the rifaximin and complexing agent in the desired ratio
in a mortar and pestle for 5 minutes and compressing to a pellet using a manual
hand press operating at a compression pressure of 2.5 tones for 5 minutes.
25
Example 10 - Preparation of 1:2 Physical mixture comprising rifaximin and
PVPK (where PVPK is PVP K-30)
100 mg of input API of rifaximin and 200 mg of PVPK were mixed uniformly and
30 used for pellet preparation. (Inj volume: 30μl)
19
In-vitro dissolution studies were performed on the 100 mg pellet in a LAB INDIA
DISSO 2000.
The pellet was fixed in a PFTE holder, such that only the pellet surface came
into contact with the dissolution medium. The PFTE loaded 5 holder was placed
in the dissolution vessel containing 900 ml of 0.1M of sodium dihydrogen
phosphate having pH 7.4 at 37±0.5°C. Two pellets were measured for each run
of the design of the experiments. Stirring was performed with a paddle rotating
at 100 rpm. The dissolution was followed up to 1440 min and the concentration
10 of active ingredient, rifaximin, dissolved in the test medium was determined by
removing samples of 10 ml at the specified time.
The concentration of rifaximin complex was quantified by HPLC UV method at a
maximum wavelength of 300 nm under the conditions as specified below:
15
Mobile Phase Buffer:Acetonitrile: 45:55
Buffer 0.025M Sodium dihydrogen phosphate. The pH
adjusted
to 3.0 with orthophosphoric acid
20 Column Zorbax SB-phenyl, 4.6mm, 5μm
Column Temp 25°C
Flow 1.0 ml/min
Injection Volume 30 μL
Diluent Buffer:Acetonitrile: 1:1
25 Standard Preparation 25 mg standard dissolved to 25 ml with diluent.
5 ml of this solution diluted to 50 ml with dissolution
medium.
The percentage of rifaximin released from the PVPK complex (1:2 w/w) as well
30 as from the physical mixture (1:2 w/w) were plotted against time as shown in
20
Figure 1. The intrinsic dissolution rate was derived from the slope of this curve.
Table 1 shows the results in tabular form.
Table 1
5
TIME IN
MINS (1:2) PVP COMPLEX
(1:2) PVPK
PHYSICAL MIXTURE
15 0.65 0.12
30 0.97 0.11
45 1.92 0.14
60 2.62 0.19
120 6.42 0.42
180 9.78 1.34
240 11.51 3.10
360 15.98 10.09
480 20.08 15.48
600 26.79 18.02
720 30.40 21.20
840 31.25 21.10
960 32.40 22.78
1080 31.40 23.65
1200 30.86 22.66
Example 11 – Preparation of 1:1 Physical mixture comprising rifaximin and
PVPK
10
100 mg of input API of rifaximin and 100 mg PVPK respectively were mixed
uniformly and used for pellet preparation. (Inj volume: 20μl)
The percentage of rifaximin released from the PVP complex (1:1 w/w) as well
15 as from the physical mixture (1:1 w/w) were plotted against time as shown in
Figure 2. The intrinsic dissolution rate was derived from the slope of this curve.
Table 2 shows the results in tabular form.
Table 2
21
TIME IN
MINS
(1:1) PVP COMPLEX
(1:1) PVP
PHYSICAL MIXTURE
15 0.86 0.19
30 1.71 0.16
45 2.54 0.19
60 3.39 0.20
120 7.15 0.37
180 10.39 0.94
240 13.21 2.22
360 18.45 5.69
480 23.42 8.33
600 28.48 10.72
720 33.64 12.67
840 38.94 14.23
960 42.13 15.28
1080 42.46 16.17
1200 42.26 16.99
Example 12 - Preparation of 4:1 Physical mixture comprising rifaximin and
PVPK
5
100 mg of input API of rifaximin and 25mg PVPK were mixed uniformly and
used for pellet preparation. (Inj volume: 15μl)
The percentage of rifaximin released from the PVP complex (4:1 w/w) as well
10 as from the physical mixture (4:1 w/w) were plotted against time as shown in
Figure 3. The intrinsic dissolution rate was derived from the slope of this curve.
Table 3 shows the results in tabular form.
Table 3
15
TIME IN
MINS
(4:1) PVPK COMPLEX
(4:1) PVPK
PHYSICAL MIXTURE
15 1.37 0.17
30 2.68 0.27
22
45 5.65 0.48
60 7.09 0.77
120 13.22 1.29
180 18.01 2.06
240 20.34 3.09
360 29.76 7.99
480 37.20 15.86
600 41.53 22.53
720 49.81 27.01
840 54.99 29.87
960 60.41 32.22
1080 66.82 35.53
1200 71.08 33.83
Example 13 - Preparation of 10:1 Physical mixture comprising rifaximin and
PVPK
100 mg of input API of rifaximin and 10mg PVPK were mixed 5 uniformly and
used for pellet preparation. (Inj volume: 10μl)
The percentage of rifaximin released from the PVP complex (10:1 w/w) as well
as from the physical mixture (10:1 w/w) were plotted against time as shown in
10 Figure 4. The intrinsic dissolution rate was derived from the slope of this curve.
Table 4 shows the results in tabular form.
Table 4
TIME IN
MINS (10:1) PVPK COMPLEX
(10:1) PVPK
PHYSICAL MIXTURE
15 1.01 0.41
30 1.81 0.38
45 2.63 0.44
60 3.41 0.54
120 6.50 0.94
180 9.65 1.34
240 12.76 1.83
360 18.78 3.86
23
480 24.96 7.32
600 30.90 10.83
720 36.68 13.82
840 42.74 16.43
960 48.70 18.73
1080 53.95 21.13
1200 59.02 23.50
1320 63.10 25.54
1440 65.72 27.08
Example 14
Example 10 was repeated using Beta cyclodextrin instead of PVPK and the
percentage of rifaximin released from the CD complex (1:2 w/5 w) as well as from
the physical mixture (1:2 w/w) were plotted against time as shown in Figure 5.
The intrinsic dissolution rate was derived from the slope of this curve. Table 5
shows the results in tabular form.
10 Table 5
TIME IN
MINS
(1:2) BETA
CYCLODEXTRIN
COMPLEX
(1:2) BETA
CYCLODEXTRIN
PHYSICAL MIXTURE
15 0.48 0.17
30 0.82 0.25
45 1.35 0.35
60 2.05 0.48
120 4.83 0.80
180 7.67 1.33
240 9.87 1.81
360 15.23 2.82
480 20.21 4.14
600 23.58 4.84
720 25.33 6.43
840 24.97 6.97
960 25.67 7.19
1080 26.37 8.80
1200 26.37 8.50
24
Example 15
5
Example 11 was repeated using Beta cyclodextrin instead of PVPK and the
percentage of rifaximin released from the CD complex (1:1 w/w) as well as from
the physical mixture (1:1 w/w) were plotted against time as shown in Figure 6.
The intrinsic dissolution rate was derived from the slope of this curve. Table 6
10 shows the results in tabular form.
Table 6
TIME IN
MINS
(1:1) BETA
CYCLODEXTRIN
COMPLEX
(1:1) BETA
CYCLODEXTRIN
PHYSICAL MIXTURE
15 0.85 0.17
30 1.46 0.29
45 2.29 0.40
60 3.04 0.53
120 6.02 0.95
180 9.07 1.39
240 12.08 1.89
360 17.88 2.86
480 23.66 4.97
600 29.22 4.93
720 34.43 5.88
840 37.54 6.69
960 38.32 7.27
1080 38.49 7.82
1200 38.66 8.32
15
25
Example 16
Example 12 was repeated using Beta cyclodextrin instead of PVPK and the
percentage of rifaximin released from the CD complex (4:1 w/5 w) as well as from
the physical mixture (4:1 w/w) were plotted against time as shown in Figure 7.
The intrinsic dissolution rate was derived from the slope of this curve. Table 7
shows the results in tabular form.
10 Table 7
TIME IN
MINS
(4:1)BETA
CYCLODEXTRIN
(4:1) BETA
CYCLODEXTRIN
PHYSICAL MIXTURE
15 1.09 0.52
30 2.85 0.64
45 3.54 0.81
60 6.29 1.01
120 10.61 1.91
180 15.88 2.33
240 18.66 3.09
360 26.97 3.64
480 34.74 4.28
600 42.07 4.36
720 47.29 8.14
840 54.05 8.92
960 60.82 11.09
1080 66.13 10.90
1200 68.04 11.39
Example 17
15 Example 13 was repeated using Beta cyclodextrin instead of PVPK and the
percentage of rifaximin released from the CD complex (10:1 w/w) as well as
from the physical mixture (10:1 w/w) were plotted against time as shown in
26
Figure 8. The intrinsic dissolution rate was derived from the slope of this curve.
Table 8 shows the results in tabular form.
Table 8
5
TIME IN
MINS
(10:1) BETA
CYCLODEXTRIN
(10:1) BETA
CYCLODEXTRIN
PHYSICAL MIXTURE
15 0.96 0.28
30 1.78 0.38
45 2.58 0.49
60 3.36 0.56
120 6.65 1.00
180 9.84 1.37
240 12.87 1.78
360 19.00 2.58
480 25.52 3.41
600 31.48 4.22
720 37.35 4.92
840 43.19 5.65
960 46.88 6.34
1080 48.74 7.01
1200 49.97 7.67
1320 49.81 8.28
1440 50.01 8.86
The results were reported on an average of 2 results each.
When compared with a physical mixture of rifaximin with a complexing agent,
10 the rifaximin complex exhibited a superior rate of dissolution as shown in Tables
9 and 10 below.
The percentage of actual release of rifaximin is calculated from the
characteristics data obtained in the Figures 1 to 8. The formula for calculating
15 the percentage of actual release of rifaximin from the complex is given below:
27
% of actual release of rifaximin =
% relese of rifaximin from the complex
wt% of rifaximin in the complex
x 100
Table 9: The Actual release of Rifaximin from Rifaximin-PVP complex
compared with physical mixture:-
5
Content of complexing
agent (w/w)
% Rifaximin released from
PVP complex
% Rifaximin released from
Physical mixture
1:2 92.67 68.05
1:1 84.52 33.98
4:1 88.85 42.29
10:1 73.00 30.09
The above data shows that the PVP complex has more advantage over a
physical mixture. This advantage is maximum at lower concentration of PVP i.e.
when ratio is 10:1 (73:30), whereas at high concentration i.e. when ratio is 1:2
10 or 33.3% the advantage is about 1.36 times (92.67:68.05)
Table 10: The Actual release of Rifaximin from Rifaximin-CD complex
compared with physical mixture:-
Content of complexing
agent (w/w)
% Rifaximin released from
CD complex
% Rifaximin released from
Physical mixture
1:2 79.18 25.52
1:1 77.32 16.64
4:1 85.00 14.23
10:1 55.55 9.84
15
The above data shows that, the CD complex has more advantage over a
physical mixture. This advantage is maximum at a lower concentration of CD
28
i.e. when the ratio is 10:1 (55.55:9.84), whereas at high concentration i.e. when
ratio is 1:2 or 33.3% the advantage is about 3.1 times (79.18: 25.52)
These results further proved that rifaximin complex had been formed after this
5 technique.
It will be appreciated that the invention may be modified within the scope of the
appended claims.
10
15
29
WE CLAIM:
5
1. A complex comprising rifaximin and a complexing agent, wherein the
complexing agent is a polyvinyl pyrrolidone (PVP) or a cyclodextrin, with the
proviso that the complexing agent is not hydroxybutenylcyclodextrin or a
derivative thereof.
10
2. The complex as claimed in claim 1, wherein the complexing agent is a PVP
having a K-value ranging from K-15 to K-90.
3. The complex as claimed in claim 1, wherein the complexing agent is a PVP
15 selected from the group consisting of PVP K-12, K-15, K-17, K-25, K-30, K-
60, K-80, K-90 and K-120.
4. The complex according to any one of the preceding claims, wherein the
complexing agent is K-30.
20
5. The complex as claimed in claim 1, wherein the complexing agent is a
cyclodextrin selected from the group consisting of α-cyclodextrin, β-
cyclodextrin or γ-cyclodextrin.
25 6. The complex as claimed in claim 5, wherein the cyclodextrin is β-
cyclodextrin.
7. The complex as claimed in claim 1, characterized by having an intrinsic
dissolution profile as shown in any one of Figures 1 to 8.
30
8. The complex as claimed in claim 1, wherein the complex is in the
amorphous form.
30
9. The complex as claimed in any one of the preceding claim, wherein the
ratio of rifaximin to complexing agent ranges from 20:1 w/w to 1:20 w/w.
10. The complex as claimed in claim 9, wherein the ratio 5 of rifaximin to
complexing agent ranges from 10:1 w/w to 1:2 w/w.
Dated this the 30th day of November 2017
10
Mythili Venkatesh
Of S. Majumdar & CO
Applicant’s agent
15
31
ABSTRACT
RIFAXIMIN 5 COMPLEXES
There is provided a complex comprising rifaximin and a complexing agent,
wherein the complexing agent is a polyvinyl pyrrolidone (PVP) or a cyclodextrin.
10 There is also provided a process for preparing the complex, a pharmaceutical
composition including the complex and therapeutic uses of the complex.
FIG. 1