U.S. patent number 3,923,969 [Application Number 05/369,404] was granted by the patent office on 1975-12-02 for carrier system for a drug with sustained release.
This patent grant is currently assigned to Battelle-Institut e.V.. Invention is credited to Werner Baukal, Heinz-Joachim Kinkel, Erich Robens, Gerhard Walter.
United States Patent |
3,923,969 |
Baukal , et al. |
December 2, 1975 |
Carrier system for a drug with sustained release
Abstract
A carrier system for a drug which allows the sustained and
prolonged release of the drug which is comprised of (i) a porous
carrier material which is insoluble or only slightly soluble in the
body, which is in compacted form or powder form and which contains
cavities which are connected to the outer surface by narrow pore
necks, the mean diameters of the cavities in section being over
twice as large as the mean internal widths of the necks of the
pores, and the internal width of the necks of the pores being
preponderantly less than 0.1 .mu.m, and (ii) a drug or
pharmaceutically active substance is embedded or contained in the
cavities.
Inventors: |
Baukal; Werner (Kronberg,
Taunus, DT), Kinkel; Heinz-Joachim (Schwalbach,
Taunus, DT), Robens; Erich (Friedrichsdorf,
DT), Walter; Gerhard (Steinbach, DT) |
Assignee: |
Battelle-Institut e.V.
(Frankfurt am Main, DT)
|
Family
ID: |
23455337 |
Appl.
No.: |
05/369,404 |
Filed: |
June 12, 1973 |
Current U.S.
Class: |
424/468; 424/469;
424/484; 514/770 |
Current CPC
Class: |
A61K
9/2009 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 027/12 () |
Field of
Search: |
;424/19-23,357 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Christen & Sabol
Claims
What is claimed is:
1. A carrier system for a drug which allows the sustained and
prolonged release of the drug which consists of
i. a porous carrier aluminium oxide material which is insoluble or
only slightly soluble in the body which is in dried jelly lump form
which disintegrates into small particles and which contains inkwell
pore cavities which are connected to the outer surface by narrow
pore necks, the mean diameters of the inkwell pore cavities in
section being over twice as large as the mean internal widths of
the necks of the inkwell pores, and the internal width of the necks
of the inkwell pores being preponderantly less than 0.1 .mu.m
and
ii. a drug or pharmaceutically active substance which is embedded
or contained only in said inkwell pore cavities, and which jelly
has been formed by stirring together dropwise a mixture of aluminum
isoproponate dissolved in benzene and a mixture of water and
isopropanol, both mixtures containing the drug almost to the point
of saturation, and drying the jelly which formed, to a lump which
disintegrates into small particles.
Description
BACKGROUND OF THIS INVENTION
1. Field of this Invention
The invention relates to a carrier, depot or bonding system for a
drug which allows sustained release of the drug and which can be
administered orally, externally or by implantation. The carrier
material consists of physiologically innocuous, inorganic or
organic materials which are totally or almost non-reabsorbable in
the body. For its properties as a carrier of active pharmaceutical
substances what is decisive is the special porous structure. It
comprises so-called inkwell pores, i.e. it contains cavities
connected to the outer surface of the bonding substance by passages
(pore necks) which are narrow in relation to their diameters. The
drug is embedded in the cavities.
2. Prior Art
Sustained release preparations make it possible for the dosage of a
drug to be accurately controlled over a long period of time and for
a plurality of active substances to be released on a set time
schedule. A number of methods of obtaining sustained release are
already known. For example, the drug may be enclosed in a capsule
which will dissolve in the body after a certain amount of time or
which allows the drug to diffuse through its porous wall. In the
case of microincapsulation, the drug is enclosed in a large number
of very small membrane capsules. Tablets may be coated with
lacquers to achieve delayed release. The drug may be suspended in
water, oil or buffer solutions. The drug may be etherified or
esterified to put it in a form in which it is difficult to
reabsorb. If the drug is applied as a crystal suspension or a
crystal implant, its release will be delayed because its surfaces
will be small relative to the amorphous substance. Absorption of
the drug in carrier materials which can swell, such as gelatin,
cellulose or certain plastics also delay release. If the drug is
bonded by adsorption to large surfaces, release will be slow due to
the low speed of desorption, as, e.g., in the case of the adsorbate
innoculate or vaccine, a result of admixture with aluminium
hydroxide. If a powdered drug is compressed together with powdered
plastics, a porous tablet will form in which the plastic material
will partly cover the surface of the powdered drug and will delay
its release (see British Pat. No. 808,014, German Pat. No.
1,201,950 and U.S. Pat. No. 3,279,996).
BROAD DESCRIPTION OF THIS INVENTION
The problem solved by this invention was the developement of a
carrier, bonding or depot system for sustained release preparations
which has the following advantages as compared with known carrier
means: (1) it is adapted to incorporate various solid or liquid
drugs, independent of their chemical nature, solubility and
mechanical or thermal stability, and (2) the rate at which the drug
is released from the carrier substance into the body remains
constant over a selectable period of time independently of the
amount of stored drug or varies in accordance with a schedule or
program.
According to this invention, these requirements are fulfilled when
the drug, medicament or pharmaceutically active substance is
incorporated in a porous carrier substance which is insoluble or
only slightly soluble in the body (human and/or animal) and when
the pores of the carrier substance each have an inkwell shape. In
the literature (see, e.g., G.J. Gregg and K.S.W. Sing, "Adsorption,
Surface Area and Porosity": London, Academic Press (1967), page 145
ff), inkwell pores are pores which, in the simplest case, comprise
a cavity which opens towards the outside through a narrow neck.
With these pores two essential parameters can be chosen
independently of one another: (i) the volume of the cavity and (ii)
the dimensions (internal width and length) of the neck of the pore.
If the volume of the neck is small relative to the volume of the
cavity, the amount which can be stored in the pores will depend
virtually only on the volume of the cavity, while the timing of the
release or temporal course of delivery into a surrounding medium
will be affected predominately by the dimensions of the pore neck.
The pore systems having inkwell pores which are used in this
invention are composed of a plurality of pores of different shapes
and sizes, and the cavities are frequently interconnected and open
to the outer surface of the porous substance through a plurality of
necks. Pore systems of such very complex construction can be
described, in their adsorption behavior action, as an inkwell
shape, if the diameters of the cavities are on the average more
than twice as large as the associated pore necks. This invention
involves or uses only those inkwell pores in which the necks are
within the micro- and mesopore range, i.e., having internal widths
or diameters of less than 0.1 .mu. m down to the diameter of only a
few atoms diameters (see, e.g., D.H. Everett and R.H. Ottewill,
(eds.), "Surface Area Determination" London, Butterworths (1970)
page 63).
For the sustained release preparation according to this invention,
a porous carrier material which is insoluble or only slightly
soluble in the body is used. The dimensions of the pores in such a
material is virtually invariable during the period or time of
application, so the rate at which the stored drug is discharged
(rate of delivery) remains constant so long as the concentration in
the cavities does not drop.
After the application or taking of a sustained release preparation
comprised of an insoluble carrier substance having inkwell pores
and a drug incorporated therein, body fluid first enters the pores
and dissolves the drug or mixes with it. The drug then diffuses
outwardly via the pore necks filled with body fluid while more body
fluid diffuses inwardly. The drug initially has saturation
concentration in the cavities and almost zero concentration outside
(in the body). With regard to the timing of the release of drug
when the starting processes are over, one should distinguish
between the following two cases:
1. The active substance is soluble only to a limited extent in the
body fluid and forms a separate phase. In this case the
concentration of active substance in the solution in the cavity,
and with it the rate of release or delivery, will remain constant
until the separate phase has disappeared. It will then
decrease.
2. The active substance can be mixed with the body fluid in any
ratio. The concentration of active substance and the rate of
release or delivery will then decrease continuously. The neck of
the pore acts as a resistance to or check on the flow of active
substance and lengthens the period of release.
If the dimensions of the necks in the pore system vary widely, the
pores with short and wide necks will empty first, while the
concentration in the other pores will remain constant for longer.
The rate of release from such a pore system will decrease with the
passage of time. With a suitable combination, provision can be made
for the drugs to be released with any timing, e.g., in
approximately linear progression. By mixing pore systems of
different types, filled with different active substances,
programmed release of combinations of active substances also are
obtained.
The rate of discharge from a carrier system with inkwell pores can
be estimated from their dimensions, as demonstrated by the
following example. The composition is taken to be a tablet with a
volume of 100 mm.sup.3 less the cavity volume V of 10 mm.sup.3. The
cavities are connected to the surface by a = 10.sup.8 not very
different pore necks with a mean cross-sectional area of A = 10
nm.sup.2 and a mean length of 0.1 .mu.m. The concentration of
active substance in the cavities when the starting processes are
over is c.sub.2 = 0.1 .mu.mol/mm.sup.3, while the concentration
c.sub.1 in the body in the vicinity of the tablet is 0. Assuming a
coefficient of diffusion of D = 10.sup..sup.-9
m.sup.2.s.sup..sup.-1, then according to Fick's Law the following
is obtained, in simplified form, for the rate of release n (see,
e.g., C.D. Hodgman, "Handbook of Chemistry and Physics", 44 ed.,
Cleveland, Chemical Rubber Publishing 1961, page 2274), : ##EQU1##
If the active substance has a molecular weight M of 200 and a
density .delta. of 10.sup.6 g.m..sup..sup.-3, then, assuming that
the concentrations remain constant (Case 1), the period of
discharge t will be: ##EQU2## The rate of discharge of active
substance would accordingly remain constant for longer that 1/2
day, given low solubility.
With a = 10.sup..sup.-6 and 1 - 10 .mu.m, one would obtain n -
10.sup..sup.-12 mol.s.sup..sup.-1 and a period of release t of 1.6
years.
Solids with an inkwell pore structure are known, they are used, for
example, as adsorbents, catalysts or catalyst carriers. Suitable
materials which can be used as the carrier material having an
inkwell pore structure include oxides, ceramic and metallic
materials and plastics which are physiologically innocuous. The
preparations may be used as a powder or in a compact or compacted
form, such as, tablet form.
Oxides such as silicon oxide, aluminium oxide, zirconium oxide,
etc., can be prepared in highly porous form from the corresponding
hydroxide gel by dehydration and drying at an elevated temperature
(see, e.g., R.E. Kirk and D.F. Othmer, "Encyclopedia of Chemical
Technology", Vol. 12, page 345 ff., New York, Interscience
Publishers (1954); and E. Robens and G. Sandstede, "Z.
Instrumentenkunde" 75 (1967), page 177). In another process (see
K.S. Mazdiyasny, C.T. Lynch and J.S. Smith, J. Am. Ceramic Soc. 48
(1965), pages 372 - 375) alcoholates dissolved in organic solvents
are converted, by hydrolysis and subsequent drying, into oxides
with crystallites and pores in the sub-micron range,
Metallic anc ceramic substances as well as plastics can be sintered
together to form porous bodies by compressing powders, with a
simultaneous or subsequent heat treatment. Porous structures of the
desired type can be obtained by thermal disintegration of hydrates
or salts, e.g., in the thermal decomposition of nickel formate
dihydrate (P.G. Fox, J. Ehretsmann and C.E. Brown, J. Catalysis 20
(1971), pages 67 - 73). The Raney process may be used to prepare
metallic powders of very high micro-porosity. A metal alloy is
first produced and one component of the alloy is then dissolved
out. The remaining metal re-crystallizes, and micro-crystallites
and corresponding pore systems are formed (see. e.g., H. Krupp, H.
Rabenhorst, G. Sandstede, G. Walter and R. McJones, J.
Elektrochemical Soc. 109 (1962), pages 553 - 557). Porous plastics
can be made by various, already-known methods, e.g., by using one
of the freeze drying techniques. In the processes mentioned herein,
the pore structure can be modified by varying the manufacturing
conditions.
The active substance may be deposited by steeping the bonding
material in the liquid or molten drug. It may be necessary first to
cleanse the material of substances (such as water) which have been
embedded in the cavities during manufacture. This can be done,
e.g., by drying under vacuum at an elevated temperature. Solid
drugs may be dissolved and incorporated or placed in the bonding
material by steeping the latter in the solution. The solvent can
then be removed by vaporization. If the drug is vaporizable or
sublimable, it may be deposited or placed in the cavities by
condensation out of the gas phase. Finally, the drug may be mixed
with the starting materials before the preparation of the carrier
material. As the carrier material is made, the drug becomes
enclosed in the pores which are formed.
Preparations made in this way can be used in powder form. The
powder may be processed as an emulsion in a liquid in which the
drug is insoluble or compressed into tablets. The carrier material
in pellet or tablet form may be coated in a known manner with
lacquers in order to achieve a further delay in the action of the
drug.
As used herein the term drug includes medicaments, drugs,
pharmaceutically active substances, etc.
The drug can be, for example: laxatives, such as, oxyphenisatin
acetate; vitamins and nutrients; parasympatholytics, such as
homatropine methylbromide or phenobarbital; hormones; steroids;
anti-infectives; analgesics, such as, phenacetin, aspirin and
caffeine; narcotics; anesthetics; sedatives and tranquilizers, such
as, chlordiazepoxide HCl and diazepam; antihallucinatory agents;
sympathominetics; hypo-allergenic agents; antigens; antihistamines,
such as, bromodiphenhydramine hydrochloride, methapyrilene fumarate
and chlorpheniramine maleate; vasoconstrictors; antibiotics;
enzymes; anticoagulants, vasodilators; lipotropic agents; cerebral
stimulants; bronchodilators; muscle relaxants; diuretics; etc.
The carrier material consists of physiologically harmless inorganic
or organic materials which cannot be absorbed or only very slightly
absorbed in the body. Its special porous structure is critical for
its use as a carrier of pharmaceutically active ingredients. It
contains so-called inkwell pores, that is to say it contains
cavities or hollow spaces, which are connected by channels (necks
of the pores), which are narrow in relation to their diameter of
the main cavity bodies, with the outside surface of the carrier
material. The drug is housed in the hollow spaces.
DETAILED DESCRIPTION OF THIS INVENTION
In the following examples and throughout the rest of this document,
all parts, percentages and ratios are on a weight basis unless
otherwise stated or obviously so to one ordinarily skilled in the
art.
EXAMPLE 1
Benzoic acid in silica gel
An excess quantity of waterglass solution was stirred drop by drop
into dilute hydrochloric acid at 50.degree.C. A jelly formed, which
was washed free of electrolyte and dried first at 100.degree.C.,
then at 300.degree.C. A piece of the resultant lumps of silica gel
was de-gassed under vacuum and, again under vacuum, impregnated
with molten benzoic acid (as a sample drug). The lump was then
compressed in polyethylene powder in such a way that the silica gel
was completely sheathed with a porous film of polyethylene. The
tablet was put into water and the timing of the variation in
conductivity resulting from the escape of benzoic acid was
measured. A uniform increase in conductivity was observed over
several hours.
EXAMPLE 2
1-Propyl-1-cyclohexyl-2-methylaminopropane-hydrochloride in
aluminium oxide
By the method of Mazdyiasni, Lynch and Smith,
aluminium-iso-propylate was dissolved in benzene, and a mixture of
water and iso-propanol were added dropwise while stirring. Both
mixtures contained the drug almost to the point of saturation. The
jelly which formed was dried at 100.degree.c. As in Example 1 the
rate of discharge was ascertained by measuring the conductivity,
and the lump disintegrated into small particles. As first there was
a strong discharge of the drug, which changed to a slow discharge
after about a quarter of an hour. A constant rate of discharge
could be observed for 2 days.
The initial strong discharge was decreased by washing and then
drying the lump of the preparation.
* * * * *