U.S. patent application number 10/524653 was filed with the patent office on 2006-07-27 for clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof.
Invention is credited to Min Bai, Wen-min Guo, Chao Liu, Wen-juan Liu, Zhan-qi Niu, Rong-duan Wang, Sui-chao Yan, Hong-zhong Yuan, Kai Zhao, Gui-rong Zhou.
Application Number | 20060166931 10/524653 |
Document ID | / |
Family ID | 31892708 |
Filed Date | 2006-07-27 |
United States Patent
Application |
20060166931 |
Kind Code |
A1 |
Niu; Zhan-qi ; et
al. |
July 27, 2006 |
Clathrates of butylphtualide with cyclodextrin or its derivatives,
a process for their preparation and the use thereof
Abstract
The present invention relates to the inclusion complexes of
butylphthalide, which is D,L-mixed or levorotatory, with
cyclodextrin or cyclodextrin derivatives, to a process for their
preparation and the use thereof. In the invention, the
butylphthalide is complexed with cyclodextrin or cyclodextrin
derivatives, preferably with hydroxypropyl-.beta.-cyclodextrin, in
order to increase the water-solubility of butylphthalide, develop
clinical solid or liquid formulations and improve the therapeutic
effect of butylphthalide. The inclusion complex, in which the molar
ratio of butylphthalide to cyclodextrin or cyclodextrin derivatives
is in the range of 1:1-10, can be used to prepare infusion,
injection, injectable powder, liquids for oral administration,
syrup, tablets, granules, dispersible tablets and others.
Inventors: |
Niu; Zhan-qi; (Hebei,
CN) ; Zhao; Kai; (Hebei, CN) ; Liu;
Wen-juan; (Hebei, CN) ; Zhou; Gui-rong;
(Hebei, CN) ; Liu; Chao; (Hebei, CN) ;
Wang; Rong-duan; (Hebei, CN) ; Yuan; Hong-zhong;
(Hebei, CN) ; Guo; Wen-min; (Hebei, CN) ;
Yan; Sui-chao; (Hebei, CN) ; Bai; Min; (Hebei,
CN) |
Correspondence
Address: |
IP GROUP OF DLA PIPER RUDNICK GRAY CARY US LLP
1650 MARKET ST
SUITE 4900
PHILADELPHIA
PA
19103
US
|
Family ID: |
31892708 |
Appl. No.: |
10/524653 |
Filed: |
August 21, 2002 |
PCT Filed: |
August 21, 2002 |
PCT NO: |
PCT/CN02/00579 |
371 Date: |
February 17, 2005 |
Current U.S.
Class: |
514/58 ;
536/41 |
Current CPC
Class: |
A61K 47/6951 20170801;
C08B 37/0015 20130101; A61P 7/02 20180101; B82Y 5/00 20130101; C07D
307/88 20130101; A61P 9/10 20180101; A61K 31/343 20130101 |
Class at
Publication: |
514/058 ;
536/041 |
International
Class: |
A61K 31/724 20060101
A61K031/724; C08B 5/10 20060101 C08B005/10 |
Claims
1. An inclusion complex of butylphthalide with cyclodextrin or
cyclodextrin derivatives, comprising butylphthalide and
cyclodextrin or cyclodextrin derivative, wherein the molar ratio of
butylphthalide to cyclodextrin or cyclodextrin derivatives is
1:1-10.
2. The inclusion complex according to claim 1, wherein said
butylphthalide is D,L-mixed or levorotatory butylphthalide.
3. The inclusion complex according to claim 1, wherein said
cyclodextrin is selected from the group consisting of
.alpha.-cyclodextrin, .beta.-cyclodextrin and
.gamma.-cyclodextrin.
4. The inclusion complex according to claim 1, wherein said
cyclodextrin derivatives are selected from the group consisting of
hydroxyethyl-.beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
dihydroxypropyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin,
glucose cyclodextrin, maltose cyclodextrin, meltotriose
cyclodextrin, carboxymethyl cyclodextrin and sulfonylalkyl
cyclodextrin.
5. The inclusion complex according to claim 1 or 4, wherein the
cyclodextrin derivative is hydroxypropyl-.beta.-cyclodextrin.
6. A process for preparing the inclusion complex of butylphthalide
with cyclodextrin or cyclodextrin derivatives, comprising the steps
of adding cyclodextrin or cyclodextrin derivatives into a suitable
solvent vehicle to obtain a solution with a concentration of 5-60%,
adding butylphthalide into the solution, stirring to obtain a
liquid inclusion complex of butylphthalide with cyclodextrin or
cyclodextrin derivatives.
7. The process according to claim 6, further comprising the step of
drying the liquid inclusion complex of butylphthalide with
cyclodextrin or cyclodextrin derivatives to obtain a solid
inclusion complex of butylphthalide with cyclodextrin or
cyclodextrin derivatives.
8. The process according to claim 6, further comprising the steps
of concentrating the liquid inclusion complex of butylphthalide
with cyclodextrin or cyclodextrin derivatives into a solution with
a concentration of 10-15% (W/V), cooling to obtain white
precipitate, filtering, and drying to obtain a solid inclusion
complex of butylphthalide with cyclodextrin or cyclodextrin
derivatives.
9. A process for preparing the inclusion complex of butylphthalide
with cyclodextrin or cyclodextrin derivatives, comprising the steps
of placing the cyclodextrin or cyclodextrin derivatives into a
colloid mill or mortar, adding a suitable solvent vehicle to obtain
a paste, adding butylphthalide into the paste, filtering, and
drying to obtain a solid inclusion complex of butylphthalide with
cyclodextrin or cyclodextrin derivatives.
10. A process for preparing the inclusion complex of butylphthalide
with cyclodextrin or cyclodextrin derivatives, comprising the steps
of adding cyclodextrin or cyclodextrin derivatives into a suitable
solvent vehicle to obtain a solution with a concentration of 5-60%,
dissolving butylphthalide into a selected amount of ethanol with
purity of 99%, mixing the two solutions, stirring, and drying to
obtain a solid inclusion complex of butylphthalide with
cyclodextrin or cyclodextrin derivatives.
11. The process according to claim 6, 9 or 10, wherein said
suitable solvent vehicle is selected from the group consisting of
water, ethanol, methanol, propanol, isopropanol, ethylene glycol,
propylene glycol, glycering, acetone, and a mixed solvent vehicle
of any two or more of the solvent vehicles.
12. A pharmaceutical composition comprising a therapeutically
effective amount of the inclusion complex according to claim 1 and
a suitable carrier.
13. The pharmaceutical composition according to claim 12 in a
liquid dosage form.
14. The pharmaceutical composition according to claim 12 in a solid
dosage form.
15. A method of treating ischemia-induced disease comprising
administering a therapeutically effective amount of the inclusion
complex according to claim 1 to a patient.
16. A method of treating thrombosis comprising administering a
therapeutically effective amount of the inclusion complex according
to claim 1 to a patient.
Description
TECHNICAL FIELD
[0001] The present invention relates to pharmaceutical
compositions. More particularly, it relates to the inclusion
complexes of butylphthalide, which is D,L-mixed or levorotary, with
cyclodextrin or its derivatives, to a process for their preparation
and the use thereof.
BACKGROUND ART
[0002] Butylphthalide is a water insoluble oily compound with the
following formula: ##STR1##
[0003] There are two optical isomers, levorotary and dextrorotary
butylphthalide, due to the presence of a chiral carbon therein.
Chinese patent application No. 98125618.X disclosed the use of
levorotary butylphthalide in the preparation of pharmaceutical
compositions for preventing thrombosis and platelet agglomeration.
It was found that butylphthalide could regulate the function of
NOS-NO-cGMP system and the metabolism of arachidonic acid in the
neurocytes after ischemia. Chinese patent application No.
93117148.2 disclosed the use of racemic butylphthalide mixture in
the preparation of pharmaceuticals for preventing and treating
ischemia-induced diseases in mammals or human.
[0004] Butylphtualide can be obtained by extraction from natural
celery seed oil or by chemical synthesis, as described in Chinese
patent application No. 99109673.8 and the prior reference: Junshan
Yang, Yalun Su, Chinese Pharmaceutical Bulletin, 1984, 31; 671,
which realized the availability of butylphthalide.
[0005] The pharmaceutical formulations are required to release
active agents quickly and exert therapeutic effects rapidly when
they are used to treat ischemia-induced diseases or thrombosis.
Usually, the formulations for treating acute disease are
administrated by intravenous instillation. However, the
butylphthalide can only be formulated into soft capsules for oral
administration because of its oily characteristics. Therefore,
solubility problem of the butylphthalide must be resolved firstly
in order to obtain injectable dosage forms.
[0006] For the purpose of investigation of the clinical value of
butylphthalide, the present applicant has filed a Chinese patent
application titled "A inclusion complex of butylphthalide with
cyclodextrin derivatives, a process for its preparation and the use
thereof" on Jun. 18, 2001, in which solubility problem of
butylphthalide was resolved. However, the levorotatory
butylphthalide was not mentioned in that application.
DISCLOSURE OF THE INVENTION
[0007] The present invention intends to provide inclusion complexes
of butylphthalide with cyclodextrin or its derivatives, a process
for their preparation and the use thereof. In order to improve
water-solubility of butylphthalide, it is complexed with
cyclodextrin or its derivatives, wherein the butylphthalide is
D,L-mixed or levorotary, and the inclusion complexes may be used to
prepare various clinically applicable solid and liquid
formulations.
[0008] The embodiments according to the present invention are as
follows:
[0009] An inclusion complex of butylphthalide with cyclodextrin or
its derivatives comprises butylphthalide and cyclodextrin or its
derivatives, wherein the molar ratio of butylphthalide to
cyclodextrin or its derivatives is in the range of 1:1-10.
[0010] The butylphthalide mentioned above comprises D,L-mixed or
levorotatory butylphthalide.
[0011] The cyclodextrin mentioned above is selected from the group
consisting of .alpha.-cyclodextrin, .beta.-cyclodextrin, and
.gamma.-cyclodextrin.
[0012] The derivatives of cyclodextrin mentioned above are selected
from the group consisting of hydroxyethyl-.beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
dihydroxypropyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin,
glucose cyclodextrin, maltose cyclodextrin, meltotriose
cyclodextrin, carboxymethyl cyclodextrin, and sulfonylalkyl
cyclodextrin.
[0013] Among the derivatives of cyclodextrin mentioned above,
hydroxypropyl-.beta.-cyclodextrin is preferred.
[0014] A process for preparing the inclusion complex of
butylphthalide with cyclodextrin or its derivatives is provided as
follows:
[0015] A solution with a concentration of 5-60% is prepared by
adding cyclodextrin or its derivatives into a suitable solvent
vehicle. A liquid inclusion complex of butylphthalide with
cyclodextrin or its derivatives is obtained by adding
butylphthalide into the above solution, stirring to provide a clear
and transparent solution without oil drops, wherein the molar ratio
of butylphthalide to cyclodextrin or its derivatives is in the
range of 1:1 to 1:10.
[0016] The process mentioned above may further comprise drying the
liquid inclusion complex of butylphthalide with cyclodextrin or its
derivatives at the temperature of 40-80.degree. C. to obtain a
solid inclusion complex of butylphthalide with cyclodextrin or its
derivatives.
[0017] The process mentioned above may also comprise concentrating
the liquid inclusion complex of butylphthalide with cyclodextrin or
its derivatives until the concentration of cyclodextrin or its
derivatives is 10-15% (W/V), cooling the solution for, e.g. about
12 hours to obtain white precipitate, filtering, and drying at
40-80.degree. C., to obtain a solid inclusion complex of
butylphthalide with cyclodextrin or its derivatives.
[0018] A process for preparing the inclusion complex of
butylphthalide with cyclodextrin or its derivatives according to
another aspect of the present invention comprises placing
cyclodextrin or its derivatives into a colloid mill or mortar,
adding an appropriate amount of suitable solvent vehicle, and
stirring the mixture to provide a paste; adding butylphthalide into
the paste described above, grinding for about 1-5 hours to provide
a homogenous and viscous paste, then filtering the paste, and
drying at 40-80.degree. C. to obtain a solid inclusion complex of
butylphthalide with cyclodextrin or its derivatives, wherein the
molar ratio butylphthalide to cyclodextrin or its derivatives is in
the range of 1:1-10.
[0019] A process for preparing the inclusion complex of
butylphthalide with cyclodextrin or its derivatives according to
yet another aspect of the present invention comprises adding
cyclodextrin or its derivatives into a suitable solvent vehicle to
obtain a solution with a concentration of 5-60%, dissolving the
butylphthalide into an appropriate amount of ethanol with purity of
99%, mixing the two solutions, stirring, and drying to obtain a
solid inclusion complex of butylphthalide with cyclodextrin or its
derivatives, wherein the molar ratio butylphthalide to cyclodextrin
or its derivatives is in the range of 1:1-10.
[0020] The drying method mentioned above may be any drying method,
such as direct drying, spray drying, or freeze-drying.
[0021] Examples of the above-mentioned solvent vehicles are water,
ethanol, methanol, propanol, isopropanol, ethylene glycol,
propylene glycol, glycerin, or acetone, or the mixture of any two
or more above-mentioned solvent vehicles, wherein water is
preferred.
[0022] Such liquid inclusion complex of butylphthalide with
cyclodextrin or its derivatives may be directly used to produce
liquid formulations, such as infusion, injection, injectable
powder, liquids for oral administration, syrup, and the like; The
solid inclusion complex of butylphthalide with cyclodextrin or its
derivatives may be used to produce solid formulations, such as
tablets, capsules, granules, dispersible tablets, and the like.
[0023] Not wish to be bound by any theory, the inventors believe
that cyclodextrin or its derivatives could trap the butylphthalide
into their tubular structure to generate an inclusion complex of
butylphthalide with cyclodextrin or its derivatives, thereby
improving the water-solubility of butylphthalide. Accordingly, the
active ingredient butylphthalide in the form of inclusion complexes
can be directly applied in solid or liquid dosage forms.
Limitations such as poor water-solubility, disability to be
directly applied in solid, especially injectable dosage forms can
be overcome.
[0024] Cyclodextrin or its derivatives are water-soluble
pharmaceutical excipients with little toxicity. The inclusion
complexes of butylphthalide with cyclodextrin or its derivatives
prepared thereby are suitable to be formulated into various liquid
and solid dosage forms. The inclusion complexes have the advantages
such as good water-solubility and little vascular irritation. The
solubility of inclusion complex of butylphthalide with
hydroxypropyl-o-cyclodextrin in water at 25.degree. C. is 924
mg/100 ml. The inclusion complex is particularly applicable for
preparing liquid dosage forms. The present invention overcomes the
limitation that butylphthalide cannot be used to prepare liquid
formulations. Due to the fact that the water-solubility is
improved, the resulting solid dosage forms have the advantages such
as rapid disintegration, good solubility and high bioavailability,
which is more applicable for clinical use.
[0025] The vascular irritation assay using inclusion complex of
butylphthalide with hydroxypropyl-.beta.-cyclodextrin is provided
as follows:
[0026] Eight rabbits were divided into two groups, namely, test
group and control group. For the test group, 2.45 g/kg of the
inclusion complex together with 40 ml of 5% glucose were instilled
via the marginal ear vein of a rabbit at the rate of 1.5 ml/min.
The administration was once per day and lasted for 3 days. For the
control group, 10% acetic acid was administrated into the ear vein
on one side and 5% glucose injection was instilled into the rabbit
ear on the opposite side serving as negative control. The
administration lasted for 3 days. Results showed that there was no
topical abnormity in the test group after 3 days, similar to the
negative control of 5% glucose injection. However, topical
hyperaemia, thickening, and exudation were observed after 10%
acetic acid injection.
[0027] The assay suggests that instillation of the inclusion
complex has little vascular irritation, and that the inclusion
complex can be used to produce injectable dosage forms.
BEST MODE FOR CARRYING OUT THE INVENTION
[0028] In the examples according to the present invention,
hydroxypropyl-.beta.-cyclodextrin is preferably used as trapping
agent.
[0029] In the examples according to the present invention, suitable
solvent vehicle for dissolving cyclodextrin or its derivatives is
water.
[0030] To illustrate the present invention, the following examples
are particularly described, but the present invention is not
intended to be limited thereto.
EXAMPLE 1
Preparation of the Solid Inclusion Complex of Butylphthalide with
hydroxypropyl-.beta.-cyclodextrin
[0031] The inclusion complex is prepared by
[0032] (1) weighing 32.38 g (0.0210 mol)
hydroxypropyl-.beta.-cyclodextrin, adding it into 400 ml distilled
water, and dissolving it with stirring;
[0033] (2) weighing 1 g (0.0052 mol) butylphthalide separately, and
adding it into the hydroxypropyl-.beta.-cyclodextrin solution
mentioned above;
[0034] (3) stirring the mixed solution for 20 minutes by magnetic
stirring method at a speed that the solution cannot be spattered,
until the solution is clear and transparent, to obtain the liquid
inclusion complex of butylphthalide with
hydroxypropyl-.beta.-cyclodextrin;
[0035] (4) filtering the liquid inclusion complex of butylphthalide
with hydroxypropyl-.beta.-cyclodextrin through a film, dividing it
into vials, and freeze-drying it.
[0036] IR (KBr): 3393.46, 2931.26, 1158.24, 1081.60, 1032.07,
946.55, 580.68..sup.13C-NMR: .delta. 131.47, 105.07, 84.03, 76.29,
75.04, 74.93, 62.89 ppm.
EXAMPLE 2
Preparation of the Solid Inclusion Complex of Levorotatory
Butylphthalide with Hydroxypropyl-.beta.-cyclodextrin
[0037] The solid inclusion complex is prepared by
[0038] (1) weighing 32.38 g (0.0210 mol)
hydroxypropyl-.beta.-cyclodextrin, adding it into a mixed solvent
of 400 ml distilled water and 20 ml absolute ethanol, and
dissolving it with stirring;
[0039] (2) weighing 1 g (0.0052 mol) levorotatory butylphthalide
separately, and adding it into the
hydroxypropyl-.beta.-cyclodextrin solution mentioned above;
[0040] (3) stirring the mixed solution for 20 minutes by magnetic
stirring method at a speed that the solution cannot be spattered,
until the solution is clear and transparent, to obtain the liquid
inclusion complex of levorotatory butylphthalide with
hydroxypropyl-.beta.-cyclodextrin;
[0041] (4) concentrating the liquid inclusion complex of
levorotatory butylphthalide with hydroxypropyl-.beta.-cyclodextrin,
and drying it under reduced pressure, to obtain the solid inclusion
complex of levorotatory butylphthalide with
hydroxypropyl-.beta.-cyclodextrin.
EXAMPLE 3
Preparation of the Solid Inclusion Complex of Butylphthalide with
hydroxypropyl-.beta.-cyclodextrin
[0042] The solid inclusion complex is prepared by
[0043] (1) weighing 8.2 g (0.0053 mol)
hydroxypropyl-.beta.-cyclodextrin, placing it into a mortar, adding
about 4 ml water and grinding the mixture into a paste; then
weighing 1 g (0.0052 mol) butylphthalide and adding it into the
mortar;
[0044] (2) grinding the mixture for 2 hours to obtain a homogenous
and viscous paste, filtering the paste, then drying at 60.degree.
C. for 4 hours and grinding, to obtain the target inclusion
complex.
EXAMPLE 4
Preparation of Lyophilized Injectable Powder using the Inclusion
Complex of Levorotatory Butylphthalide with
hydroxypropyl-.beta.-cyclodextrin
[0045] The lyophilized injectable powder is prepared by
[0046] (1) weighing 1 g (0.0052 mol) levorotatory
butylphthalide;
[0047] (2) weighing 82 g (0.053 mol)
hydroxypropyl-.beta.-cyclodextrin separately and dissolving it into
150 ml distilled water;
[0048] (3) adding the levorotatory butylphthalide into the
hydroxypropyl-.beta.-cyclodextrin solution mentioned above and
stirring the mixture;
[0049] (4) placing the mixture into a freeze drier, freeze-drying
and capping to obtain the lyophilized injectable powder.
EXAMPLE 5
Preparation of Saline Infusion of the Inclusion Complex of
Butylphthalide with hydroxypropyl-.beta.-cyclodextrin
[0050] The saline infusion of the inclusion complex is prepared
by
[0051] (1) weighing 32.38 g (0.0210 mol)
hydroxypropyl-.beta.-cyclodextrin, adding it into 400 ml distilled
water and dissolving with stirring, adding 0.5 g active carbon,
then stirring and heating to 80.degree. C. for 14 minutes, and
filtering to remove active carbon;
[0052] (2) weighing I g (0.0052 mol) butylphthalide separately and
dissolving it into 10 ml ethanol, adding the solution into the
hydroxypropyl-.beta.-cyclodextrin solution mentioned above, and
magnetically stirring for 20 minutes (the speed is controlled so
that the liquid cannot be spattered) to obtain a clear and
transparent solution of the inclusion complex of butylphthalide
with hydroxypropyl-.beta.-cyclodextrin without oil drops of
butylphthalide;
[0053] (3) supplementing water to reach a volume of 800 ml, adding
7-8 g injectable sodium chloride, measuring pH and adjusting the pH
to 3.5-7 with 0.05 N of HCl and 0.05 N of NaOH, supplementing water
to reach a volume of 1000 ml, adding 0.1 g active carbon, and
stirring for 20 minutes;
[0054] (4) separating carbon from the solution, filling the
solution into bottles (100 ml/bottle), and autoclaving at
115.degree. C. for 30 minutes.
EXAMPLE 6
Preparation of Glucose Infusion of the Inclusion Complex of
Butylphthalide with hydroxypropyl-.beta.-cyclodextrin
[0055] The glucose infusion of the inclusion complex is prepared
by
[0056] (1) preparing the solution of the inclusion complex of
butylphthalide with hydroxypropyl-.beta.-cyclodextrin as described
in step (1) and (2) of EXAMPLE 5;
[0057] (2) weighing 50 g injectable glucose, adding water to reach
a volume of 100 ml and dissolving with stirring, then adding 0.1 g
active carbon and heating the mixture until the mixture begin to
boil and maintaining that status for 15 minutes, then removing
carbon;
[0058] (3) adding the glucose solution into the solution of
inclusion complex, supplementing water to reach a volume of 800 ml,
and adjusting its pH to 4 with 0.05 N of HCl and 0.05 N of NaOH,
supplementing water to reach a volume of 1000 ml, then adding 0.1 g
active carbon into the solution, and stirring the solution for 20
minutes;
[0059] (4) filtering the solution coarsely and finely with filters
or filter stick (pore size of 1.0 .mu.m, 0.45 .mu.m, or 0.22
.mu.m), filling it into bottles and autoclaving at 115.degree. C.
for 30 minutes.
EXAMPLE 7
Preparation of Sterile Injectable Powder using the Inclusion
Complex of Levorotatory Butylphthalide with
hydroxypropyl-.beta.-cyclodextrin
[0060] The sterile injectable powder is prepared by
[0061] (1) weighing 32.38 g (0.0210 mol)
hydroxypropyl-.beta.-cyclodextrin in a sterile operation room,
dissolving it into water to reach a volume of 90 ml, adding 0.1 g
active carbon into the solution, then heating the mixture until the
mixture begin to boil and maintaining that status for 15 minutes,
and filtering to remove the carbon;
[0062] (2) weighing 1 g (0.0052 mol) levorotatory butylphthalide
and adding it into the solution of
hydroxypropyl-.beta.-cyclodextrin;
[0063] (3) magnetically stirring the mixed solution for 20 minutes
(the speed is controlled so that the liquid cannot be spattered) to
obtain a clear and transparent solution of the inclusion complex of
levorotatory butylphthalide with hydroxypropyl-.beta.-cyclodextrin
without oil drop of butylphthalide;
[0064] (4) supplementing water to reach a volume of 100 ml,
filtering through 0.22 .mu.m membrane, filling into 10 ml vials
(2-3 ml per vial), freeze drying and capping.
EXAMPLE 8
Complexation Levorotatory Butylphthalide with
.beta.-cyclodextrin
[0065] The complexation process is conducted by
[0066] Weighing 3.5 g .beta.-cyclodextrin, adding it into 100 ml
distilled water and heating the mixture at 40-60.degree. C. to
dissolve .beta.-cyclodextrin, then adding 1 g levorotatory
butylphthalide and mechanically stirring for 2-3 hours, cooling in
the refrigerator for 4 hours, filtering, washing with ethanol and
then drying to obtain the inclusion complex of levorotatory
butylphthalide with .beta.-cyclodextrin. The inclusion complex is
formulated into various solid dosage forms such as tablets and
capsules, etc.
* * * * *