U.S. patent application number 10/450101 was filed with the patent office on 2004-03-18 for drug delivery system.
Invention is credited to O'hare, Dermot Michael.
Application Number | 20040052849 10/450101 |
Document ID | / |
Family ID | 9905052 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040052849 |
Kind Code |
A1 |
O'hare, Dermot Michael |
March 18, 2004 |
Drug delivery system
Abstract
A drug delivery system for the controlled release of a
pharmaceutically-active compound by oral route comprises an
intercalate of a layered double hydroxide having, before
intercalation, layers of metal hydroxides, and having intercalated
therein a pharmaceutically-active compound having at least one
anionic group. A preferred layered double hydroxide is one that has
layers which comprise [LiAl.sub.2(OH).sub.6].sup.+. The drug
delivery system has use in the delivery of drugs such as
4-biphenylacetic acid, Diclofenac, Gemfibrozil, Ibuprofen,
Naproxen, 2-Propylpentanoic acid and Tolfenamic acid.
Inventors: |
O'hare, Dermot Michael;
(Oxford, GB) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
200 MIDDLEFIELD RD
SUITE 200
MENLO PARK
CA
94025
US
|
Family ID: |
9905052 |
Appl. No.: |
10/450101 |
Filed: |
September 26, 2003 |
PCT Filed: |
December 12, 2001 |
PCT NO: |
PCT/GB01/05484 |
Current U.S.
Class: |
424/484 |
Current CPC
Class: |
A61K 9/14 20130101; A61K
31/192 20130101; A61K 31/196 20130101; A61K 31/19 20130101; A61K
33/08 20130101; A61K 47/6949 20170801; A61K 9/143 20130101; B82Y
5/00 20130101; A61K 33/10 20130101 |
Class at
Publication: |
424/484 |
International
Class: |
A61K 009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 14, 2000 |
GB |
0030460.0 |
Claims
1. A drug delivery system comprising an intercalate of a layered
double hydroxide having, before intercalation, layers of metal
hydroxides, and having intercalated therein a
pharmaceutically-active compound having at least one anionic
group.
2. The system according to claim 1 wherein the layered double
hydroxide, before intercalation, is represented by the general
formula[M.sub.(1-x).sup.IIM.sub.x.sup.III(OH).sub.2].sup.x+[A.sub.x/n.sup-
.n-]in which M.sup.II is a divalent metal cation; M.sup.III is a
trivalent metal cation; A is a displaceable anion; n is an integer;
and x is a number less than 1, which compound is optionally
hydrated with a stoichiometric amount or a non-stoichiometric
amount of water.
3. The system according to claim 2, wherein M.sup.II is Mg or Ca
and M.sup.III is Al.
4. The system according to claim 2 or claim 3, wherein A is
selected from OH, F, Cl, Br, I, SO.sub.4 and NO.sub.3.
5. The system according to claim 1, wherein the layered double
hydroxide, before intercalation, is represented by the general
formula[M.sup.IM.sub.2.sup.III(OH).sub.6].sup.+[A.sub.1/n.sup.n-]in
which M.sup.I is a monovalent metal cation; M.sup.III is a
trivalent metal cation; A is a displaceable anion; and n is an
integer, which compound is optionally hydrated with a
stoichiometric or non-stoichiometric amount of water.
6. The system according to claim 5, wherein M.sup.I is Li and
M.sup.III is Al.
7. The system according to claim 5 or claim 6, wherein A is
selected from OH, F, Cl, Br, I, SO.sub.4 and NO.sub.3.
8. The system according to claim 7, wherein the layered double
hydroxide is [LiAl.sub.2(OH).sub.6]Cl.H.sub.2O.
9. The system according to any one of claims 1 to 8, wherein the
pharmaceutically-active compound having at least one anionic group
is a pharmaceutically-active compound containing at least one
carboxylic acid group or a non-toxic salt thereof.
10. The system according to any one of claims 1 to 9, which
additionally comprises a non-toxic compound having an anion which
is capable of displacing the pharmaceutically-active compound from
the intercalate.
11. The system according to claim 10, wherein the non-toxic
compound is selected from magnesium carbonate, magnesium hydrogen
carbonate, calcium carbonate or calcium hydrogen carbonate.
12. The system according to any one of claims 1 to 11, wherein the
pharmaceutically-active compound is selected from 4-biphenylacetic
acid, Diclofenac, Gemfibrozil, Ibuprofen, Naproxen,
2-propylpentanoic acid and Tolfenamic acid.
13. A method of making an intercalate of a layered double hydroxide
having, intercalated therein, a pharmaceutically-active compound
having at least one anionic group which comprises treating an
aqueous solution of the pharmaceutically-active compound,
optionally in the form of a non-toxic salt thereof, with the
layered double hydroxide and separating the intercalate of the
layered double hydroxide.
14. The method according to claim 13, wherein the layered double
hydroxide, before intercalation, is represented by the general
formula[M.sub.(1-x).sup.IIM.sub.x.sup.III(OH).sub.2].sup.x+[A.sub.x/n.sup-
.n-]in which M.sup.II is a divalent metal cation; M.sup.III is a
trivalent metal cation; A is a displaceable anion; n is an integer;
and x is a number less than 1, which compound is optionally
hydrated with a stoichiometric amount or a non-stoichiometric
amount of water.
15. A method according to claim 14, wherein M.sup.II is Mg and
M.sup.III is Al.
16. The method according to either claim 14 or claim 15, wherein A
is selected from OH, F, Cl, Br, I, SO.sub.4 and NO.sub.3.
17. The method according to claim 13, wherein the layered double
hydroxide, before intercalation, is represented by the general
formula[M.sup.IM.sub.2.sup.III(OH).sub.6].sup.+[A.sub.1/n.sup.n-]in
which M.sup.I is a monovalent metal cation; M.sup.III is a
trivalent metal cation; A is a displaceable anion; and n is an
integer, which compound is optionally hydrated with a
stoichiometric amount or a non-stoichiometric amount of water.
18. The method according to claim 17, wherein M.sup.I is Li and
M.sup.III is Al.
19. The method according to either claim 17 or claim 18, wherein A
is selected from OH, F, Cl, Br, I, SO.sub.4 and NO.sub.3.
20. The method according to claim 19, wherein the layered double
hydroxide is [LiAl.sub.2(OH).sub.6]Cl.H.sub.2O.
21. The method according to any one of claims 13 to 20, wherein the
pharmaceutically-active compound having at least one anionic group
is a pharmaceutically-active compound containing at least one
carboxylic acid group or a non-toxic salt thereof.
22. The method according to claim 21 wherein the
pharmaceutically-active compound is selected from 4-biphenylacetic
acid, Diclofenac, Gemfibrozil, Ibuprofen, Naproxen,
2-propylpentanoic acid and Tolfenamic acid.
Description
[0001] The present invention relates to a drug delivery system.
More particularly, it relates to a system in which a drug is
intercalated into a layered double hydroxide.
[0002] Layered double hydroxides (LDHS) are a class of compounds
which comprise two metal cations and have a layered structure. A
brief review of LDHs is provided in Chemistry in Britain, September
1997, pages 59 to 62. The hydrotalcites, perhaps the most
well-known examples of LDHs, have been studied for many years.
[0003] LDHs can be represented by the general formula
[M.sup.II.sub.(1-x)M.sup.III.sub.x(OH).sub.2].sup.x+A.sup.z-.sub.x/z.yH.s-
ub.2O or
[M.sup.I.sub.(1-x)M.sup.III.sub.x(OH).sub.2].sup.n+A.sup.z-.sub.n-
/z.yH.sub.2O, where M.sup.I, M.sup.II and M.sup.III are mono, di-
and trivalent metal cations respectively, that occupy octahedral
positions in hydroxide layers, A.sup.Z- is an interlayer
charge-compensating anion where z is an integer, such as
CO.sub.3.sup.2-, NO.sub.3.sup.- or Cl.sup.-, n=2x-1, x is a number
less than 1 and y is 0 or a number greater than 0. A large number
of LDHs with a wide variety of M.sup.II-M.sup.III cation pairs
(e.g., Ca--Al) as well as the M.sup.I-M.sup.III cation pair
(Li--Al) with different anions in the interlayer space have been
reported and studied.
[0004] It is known that certain organic species may be intercalated
into the layers in some LDHs and into clays. For example, Ogawa et
al., in Chemistry Letters, 1992, no. 3, p.365-368, describe the
intercalation of maleic and methylmaleic acids into the clay
montmorillonite in a solid state reaction. The geometrical isomers
of the acids, fumaric and methylfumaric acids, were not
intercalated in the solid state reaction. However, when an
ethanolic solution of the two isomers was used, the montmorillonite
showed no selectivity and both isomers were intercalated.
[0005] The structure of the layered materials
[LiAl.sub.2(OH).sub.6]X, where X is Cl, Br or NO.sub.3, and their
hydrates has been described by Besserguenev et al., in Chem. Mater,
1997, no. 9, p.241-247. The materials can be produced by the
reaction of gibbsite [.gamma.-Al(OH).sub.3] or other forms of
Al(OH).sub.3, such as bayerite, nordstrandite or doyleite, with
lithium salts of formula LiX. The materials can also be formed in
other ways, such as by direct precipitation (see, for example,
Serna et al., Clays & Clay Minerals, (1997), 25,384). The
structure of the LiAl.sub.2(OH).sub.6.sup.+ layers in the compounds
is unusual amongst LDHs since it is based on an ordered arrangement
of metal cations within the layers.
[0006] The synthesis of LiAl.sub.2(OH).sub.6.sup.+ compounds is
described in U.S. Pat. No. 4,348,295 and U.S. Pat. No. 4,348,297.
The use of the materials for separating hydrocarbons and for gas
chromatograph columns is taught in U.S. Pat. No. 4,430,097 and U.S.
Pat. No. 4,321,065, respectively. In both of these latter two
documents, the technology described does not involve intercalation
chemistry but surface interactions with the stationary phase i.e.,
liquid-solid or gas-solid interactions.
[0007] Intercalates of compounds of formula LiOH.2Al(OH).sub.3 are
described in U.S. Pat. No. 4,727,167 and U.S. Pat. No. 4,812,245.
Both documents relate to uses of the intercalates as additives to
organic materials such as mineral oils.
[0008] A few other LDHs having cation ordering are known. The
layered double hydroxide
[Ca.sub.2Al(OH).sub.6].sub.2.sup.+SO.sub.4.sup.2- is an
example.
[0009] LDHs exhibit a wide range of anion-exchange reactions with
guests such as organic carboxylates, sulfonates and a range of
anionic metal complexes. These materials are of significant
technological importance in diverse areas such as catalysis,
optics, medical science and separation science.
[0010] The application of LDHs in separation science has until
recently been largely restricted to their role as fast, efficient,
high capacity ion-exchange materials. The major application being
the removal of organic and inorganic anions from aqueous streams.
According to WO 99/24139 a compound comprising at least two
negatively charged groups connected by a linker group can be
separated from a mixture containing it by selectively intercalating
it into an LDH. For example, it was disclosed therein that when
[LiAl.sub.2(OH).sub.6]Cl.H.sub.2O is treated with an equimolar
mixture of the disodium salts of either the 1,2-, 1,3- or
1,4-dibenzoic acids then the only crystalline phase observed is
formed by preferential and exclusive intercalation of the
1,4-dibenzoate anions.
[0011] Choy et al., J.Am.Chem.Soc. 1999, 121, 1399-1400, have
reported that the nucleoside monophosphates such as
adenosine-5'-monophosphate (AMP), guanosine-5'-monophosphate (GMP)
and cytidine-5'-monophosphate (CMP) can be ion-exchange
intercalated in the layered double hydroxide
[Mg.sub.0.68Al.sub.0.32(OH).sub.2](NO.sub.3).sub.0.32.1.2H.sub.2O.
[0012] The present invention provides a drug delivery system
comprising an intercalate of a layered double hydroxide having,
before intercalation, layers of metal hydroxides and having
intercalated therein a pharmaceutically-active compound having at
least one anionic group.
[0013] The present invention is based on the discovery that a
pharmaceutically-active compound having at least one anionic group
can be intercalated into an LDH compound and that the intercalate
releases the pharmaceutically-active compound in a controlled
manner when subjected to pH conditions that may prevail inside the
stomach of a patient. It is known that certain
pharmaceutically-active compounds, when administered orally, may
cause irritation of the stomach. Some patients are, of course, more
vulnerable to irritation of this kind than others. By controlling
the release of such compounds in the stomach such a side-effect can
be avoided or, at least, reduced.
[0014] The layered double hydroxide that can be used in the drug
delivery system of the invention comprises two metal cations and
hydroxide ions and has a layered structure. Between the layers, the
LDH contains an intercalated anionic group which is one that can be
displaced by the pharmaceutically-active compound.
[0015] A first, preferred, class of LDH compounds that can be used
in the manufacture of the drug delivery system of the invention has
the general formula I
[M.sup.IM.sub.2.sup.III(OH).sub.6].sup.+[A.sub.1/n.sup.n-] (I)
[0016] in which M.sup.I is a monovalent metal cation, M.sup.III is
a trivalent metal cation, A is a displaceable anion and n is an
integer. These compounds are optionally, but preferably, hydrated.
The amount of water of hydration may be a stoichiometric amount or
a non-stoichiometric amount. Of this class of LDH compounds, those
wherein M.sup.I is a lithium ion and M.sup.III is an aluminium ion
are particularly preferred such that the layers in the compound
comprise [LiAl.sub.2(OH).sub.6].sup.- +. The cations in such a
layer have an ordered arrangement, i.e., the LDH has cation
ordering. The ordered (i.e., non-random) arrangement of cations is
believed to be beneficial and to enhance the intercalation of the
pharmaceutically-active compound in the system of the
invention.
[0017] In the above formula I the anion A is one that can be
displaced from its location between the metal cation-containing
layers in the LDH by the pharmaceutically-active compound. For
example, it may be an anion selected from hydroxide, halide (i.e.,
fluoride, chloride, bromide or iodide), sulfate or nitrate ions.
Preferably, the anion A is chloride or nitrate.
[0018] A second, preferred, class of LDH compound that can be used
in the manufacture of the drug delivery system of the invention has
the general formula II
[M.sub.(1-x).sup.IIM.sub.x.sup.III(OH).sub.2].sup.x+[A.sub.x/n.sup.n-]
(II)
[0019] in which M.sup.II is a divalent metal cation, for example,
Ca.sup.2+, Mg.sup.2+, Zn.sup.2+ and Ni.sup.2+ ions, M.sup.III is a
trivalent metal cation, for example Al.sup.3+ and Fe.sup.3+ ions, A
is a displaceable anionic group such as one disclosed above in
connection with the described first class of LDH compounds, n is an
integer and x is a number less than 1. Such compounds are
optionally, but preferably, hydrated. The water of hydration, if
present, may be present in a stoichiometric amount or a
non-stoichiometric amount.
[0020] A preferred LDH compound for use in preparing the drug
delivery system of the invention is
[LiAl.sub.2(OH).sub.6]Cl.H.sub.2O.
[0021] The drug delivery system of the invention comprises an LDH
in which is intercalated a pharmaceutically-active compound having
at least one anionic group. The pharmaceutically-active compound
may be any compound which may have use in the treatment of any
disease, disorder or condition in the body of an animal, including
human, provided that the compound has activity when administered by
an oral route and provided that it has at least one anionic group
which will enable it to intercalate into the LDH to displace the
anion A from the initial LDH compound. Thus, provided that the
above requirements are met the pharmaceutically-active compound may
be a drug, a pro-drug or drug precursor or a substance for treating
a treatable disorder or condition of the animal body, including the
human body. Such active compounds have at least one anionic group,
for example a carboxylic acid group or a non-toxic metal or
ammonium salt thereof. Examples of pharmaceutically-active
compounds that may be intercalated into an LDH to form an
intercalation compound having use as a drug delivery system
according to the invention include, but are not limited to,
4-biphenylacetic acid, sodium (2-(2,6-dichloroanilino)phenyl)
acetate (Diclofenac Sodium), 2,2-dimethyl-5-(2,5-xylyloxy)valeric
acid (Gemfibrozil), 2-(4-isobutylphenyl) propionic acid
(Ibuprofen), (+)-2-(6-methoxy-2-naphthyl)propionic acid (Naproxen),
2-propylpentanoic acid and N-(3-chloro-o-tolyl)anthranilic acid
(Tolfenamic acid).
[0022] In order to effect intercalation, an aqueous solution of the
pharmaceutically-active compound, optionally in the form of a
non-toxic salt thereof, is treated with the layered double
hydroxide and then the intercalate compound, so formed, is
separated from the reaction mixture. Typically, the treatment will
be performed by, firstly, preparing an aqueous suspension of the
LDH compound and then mixing this with an aqueous solution of the
pharmaceutically-active compound (or a non-toxic salt thereof).
Preferably, an aqueous suspension of the LDH is treated by
ultrasonication for a period of time of from 1 to 60 minutes, .more
preferably from 30 to 45 minutes, prior to mixing this with the
solution containing, the pharmaceutically-active compound, since
this prior sonication treatment enhances the extent of the
intercalation reaction. Typically, the intercalation reaction is
carried out by stirring the aqueous mixture of the reactants for a
period of time within the range of from 2 to 72 hours. The
pharmaceutically-active compound in the solution treated with the
LDH will preferably be in a molar excess with respect to the LDH.
Typically, the molar ratio of pharmaceutically-active compound to
LDH will be at least 2:1 since such guest:host ratios promote a
greater extent of intercalation. The temperature of the reaction
mixture will typically be held at at least 30.degree. C. for at
least part of the reaction period. Whereas Naproxen is intercalated
into the LDH after a reaction time of 1 to 2 days at 30.degree. C.,
the reaction of Tolfenamic acid with the LDH requires a longer
period of time and a higher reaction temperature, typically about 3
days at a temperature of about 80.degree. C.
[0023] After the intercalation reaction, the particles of the LDH
containing intercalated pharmaceutically-active compound are
separated from the aqueous medium, for instance by filtration.
[0024] The separated LDH particles containing the intercalated
pharmaceutically-active compound will then be dried prior to
formulation into the required oral dosage units.
[0025] The intercalate compounds have been found to release the
pharmaceutically-active compound in a controlled manner when
subjected to an acid environment similar to that which exists in
the stomach of an animal (including a human). This is because the
LDH is broken down by treatment with a dilute acid, such as
hydrochloric acid. LDH compounds, themselves, are known to have an
antacid effect. Thus, an intercalate of the invention when
administered orally to a patient has the effect of altering the pH
of the environment inside the stomach of the patient which, in
turn, affects the breakdown of the intercalate and, therefore, the
rate of release of the pharmaceutically-active compound from the
intercalate. Since the rate of breakdown of the intercalate in the
stomach and the degree of antacid effect depends on the chemical
nature of the lattice of the LDH used it is possible to control or
modify the rate of release of the pharmaceutically-active compound
from the intercalate by an appropriate selection of the host
lattice used in the manufacture of the intercalate. The pH of the
contents of the stomach can also be controlled by the addition of a
buffer, for instance, a phosphate buffer. Thus, the incorporation
of a buffer into a formulation, which includes the intercalate
containing the pharmaceutically-active compound, to be administered
to a patient allows the pH to be fine tuned to optimise the rate of
breakdown of the LDH lattice and, thus, the rate of release of the
pharmaceutically-active compound from the intercalate. According to
a different embodiment, it may be advantageous to include, with the
intercalate compound in the formulation to be administered to a
patient, a non-toxic compound which contains an anion that
intercalates between the layers in the LDH in preference to the
pharmaceutically-active compound. By providing such a compound, the
release of the pharmaceutically-active compound in the patient's
stomach is promoted by the action of the anion to displace the
pharmaceutically-active compound from the layers in the LDH.
Suitable anions for this purpose include carbonate and hydrogen
carbonate anions although anions, which intercalate more or less
strongly than carbonate can be used. A carbonate compound is,
however, preferred on account of the strong capacity of carbonate
anion to bind with the LDH and displace the guest
pharmaceutically-active compound from the LDH. Examples of suitable
non-toxic carbonate and hydrogen carbonate compounds that can be
used in this embodiment of the invention include CaCO.sub.3,
Ca(HCO.sub.3).sub.2, MgCO.sub.3 and Mg(HCO.sub.3).sub.2.
EXAMPLES
Example 1
[0026] Intercalation of Pharmaceutically-active Compounds in
[LiAl.sub.2(OH).sub.6]Cl.H.sub.2O
[0027] Table 1 lists pharmaceutically-active compounds which we
have intercalated into a layered double hydroxide (LDH) host of
formula [LiAl.sub.2(OH).sub.6]Cl.H.sub.2O. The intercalation of the
drug was achieved by adding 1.4 mmol of the sodium salt of the drug
in 10 ml of deionised H.sub.2O to a suspension of 0.7 mmol of the
host in 10 ml of deionised H.sub.2O. The suspension of the host was
sonicated for 30 minutes prior to the addition of the sodium salt
of the drug. The mixture was then stirred in a sealed glass ampoule
for 1-2 days at a temperature of 30.degree. C.
[0028] 4-Biphenylacetic acid and Tolfenamic acid are
anti-inflammatory and analgesic agents. Diclofenac is used for the
treatment of arthritis, ibuprofen and naproxen are both
non-steroidal anti-inflammatory agents. Gemfibrozil is a lipid
regulating agent and 2-propylpentanoic acid inhibits GABA
transaminase.
1TABLE 1 Summary of the guest molecule used and the analytical and
structural data of the LDH-drug intercalation compounds. Interlayer
Spacing/ Elemental Analysis Guest Molecular Structure of
Guest.sup.a .ANG..sup.b Found (calc).sup.c 4-Biphenylacetic acid
C.sub.14H.sub.12O.sub.2 1 20.4 C 30.77(30.77) H 5.16(5.20) x =
0.58, y = 2 Diclofenac C.sub.14H.sub.10Cl.sub.2NaNO.sub.2 2 22.3 C
30.91(30.92) H 4.12(3.91) N 2.60(2.58) x = 0.72. y = 1. Gemfibrozil
C.sub.15H.sub.22O.sub.3 3 23.2 C 35.35(35.36) H 6.56(6.65) x =
0.69, y = 1 Ibuprofen C.sub.13H.sub.18O.sub.2 4 22.7 C 31.92(31.98)
H 6.15(5.99) x = 0.75. y = 3 Naproxen C.sub.14H.sub.14O.sub.3 5
21.5 C 27.91(28.08) H 4.98(4.99) x = 0.48. y = 1 2-Propylpentanoic
acid C.sub.8H.sub.18O.sub.2 6 18.7 C 14.78(14.82) H 5.77(6.04) x =
0.35, y = 1 Tolfenamic acid C.sub.14H.sub.12ClNO.sub.2 7 21.9 C
23.24(23.18) H 5.25(5.29) N 1.90(1.93) x = 0.46. y = 3
.sup.aNeutral guest molecules were converted to the sodium salt
prior to intercalation. .sup.bBased on hexagonal cell .alpha. =
.beta. = 90.degree., .gamma. = 120.degree., a = b = 5.1 .ANG., and
c =2 x d.sub.(002) .sup.cBased on the general formula formula
Li.sub.xAl.sub.2(OH).sub.6[dru- g].sub.x.yH2O
[0029] Methods of r Covery/release of the Drugs From the Solid
Host
[0030] All of the above drugs have been quantitatively exchanged
back out of the host LDH, for example, by using one of the
following procedures:
[0031] 1. Addition of carbonate; adding 0.113 g of Na.sub.2CO.sub.3
to approx. 0.100 g of the intercalation compound in 8 ml of
D.sub.2O and stirring overnight in a sealed glass ampoule.
[0032] 2. Addition of acid; All the intercalation compounds react
with 0.2M HCl to produce the neutral drug molecule.
[0033] 3. Addition of phosphate buffer (ca. pH7).
[0034] NMR spectra and XRD patterns were measured to confirm the
release of the drugs.
Example 2
[0035] Intercalation compounds were obtained by intercalating the
pharmaceutically-active compounds described in Example 1 into
[LiAl.sub.2(OH).sub.6]Cl.H.sub.2O according to the procedure of
Example 1.
[0036] Release of the drugs from their intercalation compounds was
performed in each case by the addition of 0.0250 g-0.100 g of the
intercalation compound to 250 mL phosphate buffer solution at
37.degree. C. (body temperature) in a round bottom flask and the
mixture stirred at 100 rpm. The release in phosphate buffer at pH 7
and at pH 4 was investigated. Aliquots were removed from the flask
at regular time intervals, the solution was filtered and the UV
spectrum of the filtrate recorded in a 1 cm.sup.2 quartz cuvette. A
baseline scan using the neat solution was recorded prior to the
collection of the first spectrum of the filtrate.
[0037] The release profiles for diclofenac at pH 4 and pH 7 are
shown in FIG. 1. The release profiles for Naproxen at pH 4 and pH 7
are shown in FIG. 2. The release profiles for Gemfibrozil at pH 4
and pH 7 are shown in FIG. 3. The release profiles for Tolfenamic
acid at pH 4 and pH 7 are shown in FIG. 4. The release profiles for
4-biphenylacetic acid at pH 4 and pH 7 are shown in FIG. 5.
[0038] The release of Diclofenac (FIG. 1), Naproxen (FIG. 2) and
4-biphenylacetic acid (FIG. 5) was rapid at pH 4 but was slower and
more controlled at pH 7.
Example 3
[0039] Intercalation of Pharmaceutically-active Compounds in
[Ca.sub.2Al(OH).sub.6]NO.sub.3.xH.sub.2O
[0040] Intercalation of the pharmaceutically-active compounds was
achieved by the addition of 1.4 mmol of the sodium salt of the drug
in 10 ml deionised H.sub.2O to 0.7 mmol of the LDH host of formula
[Ca.sub.2Al(OH).sub.6]NO.sub.3.xH.sub.2O. The mixture was then
stirred in a sealed glass ampoule for 18 hours at a temperature of
80.degree. C. The solid products were isolated by filtration and
washed with an excess of deionised water and acetone and allowed to
dry in air. The formulae and d-spacings of the intercalation
compounds synthesised are listed in the following Table 2.
2TABLE 2 d-spacing Drug Molecule Intercalation Compound A
4-Biphenyl-
[Ca.sub.1.875Al(OH).sub.6][C.sub.14H.sub.11O.sub.2].sub.0.75.2H.sub.2O
19.5 acetic acid C.sub.14H.sub.12O.sub.2 Diclofenac
[Ca.sub.1.9Al(OH).sub.6][C.sub.14H.sub.10Cl.sub.2NO.sub.2].sub.0.8.2H.sub-
.2O 22.4 C.sub.14H.sub.10Cl.sub.2NaNO.sub.2 Gemfibrozil
[Ca.sub.1.825Al(OH).sub.6][C.sub.15H.sub.21O.sub.3].sub.0.65.H.sub.2O
22.5 C.sub.15H.sub.22O.sub.3 Ibuprofen
[Ca.sub.1.9Al(OH).sub.6][C.sub.13H.sub.17O.sub.2].sub.0.8.H.sub.2O
19.8 C.sub.13H.sub.18O.sub.2 Naproxen [Ca.sub.2Al(OH).sub.6][C.sub-
.14H.sub.13O.sub.3].sub.0.63.3H.sub.2O 19.7 C.sub.14H.sub.14O.sub.3
Tolfenamic [Ca.sub.1.75Al(OH).sub.6][C.sub.14H.sub.11ClNO.sub.2].s-
ub.0.5.2H.sub.2O* 19.8 acid C.sub.14H.sub.12ClNO.sub.2 *In order to
achieve the intercalation of tolfenamic acid the mixture was heated
at a temperature of 80 C. for approx. 3 days.
[0041] Release of Naproxen was performed and investigated as
described in Example 2. The release profile of Naproxen from its
intercalation compound at pH 7 is shown in FIG. 6.
Example 4
[0042] Intercalation of Pharmaceutically-active Compounds in
[Mg.sub.2Al(OH).sub.6]NO.sub.3.H.sub.2O
[0043] Intercalation of the drug molecules listed in Table 2 was
achieved by the addition of 1.4 mmol of the sodium salt of the drug
in 10 ml deionised H.sub.2O to 0.7 mmol of the LDH host of formula
[Mg.sub.2Al(OH).sub.6]NO.sub.3.H.sub.2O. The mixture was then
stirred in a sealed glass ampoule for 12 hours at a temperature of
60.degree. C. The solid products were isolated by filtration and
washed with an excess of deionised water and acetone and allowed to
dry in air.
* * * * *