U.S. patent application number 10/337233 was filed with the patent office on 2003-09-04 for controlled release pharmaceutical composition.
Invention is credited to Dunne, Josephine, Gutierrez-Rocca, Jose, Rios, Saul A..
Application Number | 20030165562 10/337233 |
Document ID | / |
Family ID | 25150058 |
Filed Date | 2003-09-04 |
United States Patent
Application |
20030165562 |
Kind Code |
A1 |
Gutierrez-Rocca, Jose ; et
al. |
September 4, 2003 |
Controlled release pharmaceutical composition
Abstract
A sustained/prolonged release pharmaceutical dosage form is
disclosed. The form comprises a hard shell capsule and a
formulation comprising (a) a water insoluble medicament, (b) a high
melting fatty ester, (c) a low viscosity oil, (d) a cellulosic
polymer, and (e) a non-ionic surfactant.
Inventors: |
Gutierrez-Rocca, Jose;
(Miami, FL) ; Dunne, Josephine; (Plantation,
FL) ; Rios, Saul A.; (Miramar, FL) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Family ID: |
25150058 |
Appl. No.: |
10/337233 |
Filed: |
January 6, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10337233 |
Jan 6, 2003 |
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09790239 |
Feb 21, 2001 |
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6524615 |
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Current U.S.
Class: |
424/458 ;
424/750; 424/757; 424/776 |
Current CPC
Class: |
A61K 9/4866 20130101;
A61K 9/4858 20130101 |
Class at
Publication: |
424/458 ;
424/750; 424/757; 424/776 |
International
Class: |
A61K 009/54; A61K
035/78 |
Claims
We claim:
1. A sustained/or prolonged release pharmaceutical unit dosage form
comprising a hard shell capsule and a formulation comprising: (a) a
water insoluble medicament; (b) a high melting fatty acid ester
selected from the group consisting of glyceryl behenate, glyceryl
palmitostearate and glyceryl stearate; (c) a low viscocity oil
selected from the group consisting of corn oil, cottonseed oil,
menhaden oil, safflower oil, sesame oil, shark-liver oil, soybean
oil, olive oil and saturated polyglycolized glycerides; (d) a
cellulosic polymer selected from the group consisting of methocel A
series, methocel E series, methocel K series, and ethocel P series;
low-substituted hydroxypropyl ether cellulose polymers selected
from the group consisting of LH11, LH22, and LH30; and (e) a
non-ionic surfactant.
2. A pharmaceutical unit dosage form according to claim 1 wherein
the high melting fatty acid ester comprises from about 10% to about
50% by weight of the total weight of the formulation.
3. A pharmaceutical unit dosage form according to claim 2 wherein
the high melting fatty acid ester comprises from about 15% to about
35% by weight of the total weight of the formulation.
4. A pharmaceutical unit dosage form according to claim 3 wherein
the high melting fatty acid ester comprises about 25% by weight of
the total weight of the formulation.
5. A pharmaceutical unit dosage form according to claim 1 wherein
the oil comprises about 40% to about 60% by weight of the total
weight of the formulation.
6. A pharmaceutical unit dosage form according to claim 5 wherein
the oil comprises about 50% by weight of the total weight of the
formulation.
7. A pharmaceutical unit dosage form according to claim 1 wherein
the cellulosic polymer comprises from about 1% to about 5% by
weight of the total weight of the formulation.
8. A pharmaceutical unit dosage form according to claim 7 wherein
the cellulosic polymer comprises from about 3% by weight of the
total weight of the formulation.
9. A pharmaceutical unit dosage form according to claim 1 wherein
the surfactant comprises about 1.0% to about 10% by weight of the
total weight of the formulation.
10. A pharmaceutical unit dosage form according to claim 9 wherein
the surfactant comprises from about 2% by weight of the total
weight of the formulation.
11. A pharmaceutical unit dosage form according to claim 1 wherein
the high melting fatty acid ester comprises from about 10% to about
50% by weight, the oil comprises about 46% to about 61% by weight,
the cellulosic polymer comprises from about 1% to about 5% by
weight and the surfactant comprises from about 1.0% to about 10% of
the total weight of the formulation.
12. A pharmaceutical unit dosage form according to claim 11 wherein
the higher melting fatty acid ester comprises from about 15% to
about 35% by weight of the total weight of the formulation.
13. A pharmaceutical unit dosage form according to claim 12 wherein
the higher melting fatty acid ester comprises about 25% by weight,
the oil comprises about 51% by weight, the cellulosic polymer
comprises about 3% by weight, and the surfactant comprises about 1%
of the total weight of the formulation.
14. A pharmaceutical unit dosage form according to claim 1 wherein
the water insoluble medicament comprises about 20% by weight of the
total weight of the formulation.
15. A pharmaceutical unit dosage form according to claim 1 wherein
the high melting fatty acid ester comprises about 10% to about 50%
by weight, the oil comprises from about 46% to about 61% by weight,
the cellulosic polymer comprises from about 1% to about 5% by
weight, and the surfactant comprises from about 1.0% to about 10%
by weight, and the water insoluble medicament comprises about 20%
by weight of the total weight of the formulation.
16. A pharmaceutical unit dosage form according to claim 15 wherein
the high melting fatty acid ester comprises about 25% by weight,
the oil comprises about 51% by weight, the cellulosic polymer
comprises about 3% by weight, and the surfactant comprises about
2.0% and the water insoluble medicament comprises about 20% by
weight of the total weight of the formulation.
17. A pharmaceutical unit dosage form according to claim 1 wherein
said water insoluble medicament is a medicament selected from the
group consisting of hydroxyzine pamoate, nifedipine, nimodipine,
nisoldipine, nicardipine, amlodipine, atorvastatin, simvastatin and
lovastatin, genfibrozil, fenofibrate and clofibrate
18. A pharmaceutical formulation comprising a water insoluble
medicament selected from the group consisting of hydroxyzine
pamoate, nifedipine, nimodipine, nisoldipine, nicardipine,
amlodipine, atorvastatin, simvastatin, lovastatin, genfibrozil,
fenofibrate and clofibrate associated with, (a) a high melting
fatty acid ester selected from the group consisting of glyceryl
behenate, glyceryl palmitostearate and glyceryl stearate; (b) an
oil selected from the group consisting of corn oil, cottonseed oil,
menhaden oil, safflower oil, sesame oil, shark-liver oil, soybean
oil, olive oil, wheat grain oil and a low viscocity polyglycolized
glyceride; (c) a cellulosic polymer selected from the group
consisting of methocel E series, methocel A series, ethocel P
series, methocel K series, low substituted hydroxypropyl ether
cellulosic polymers, selected from the group consisting of LH11,
LH22 and LH30; and (d) a non-ionic surfactant.
19. A pharmaceutical unit dosage form according to claim 18 wherein
the higher melting fatty acid ester comprises from about 10% to
about 50% by weight of the total weight of the formulation.
20. A pharmaceutical formulation according to claim 19 wherein the
high melting fatty acid ester comprises from about 15% to about 35%
by weight of the total weight of the formulation.
21. A pharmaceutical formulation according to claim 20 wherein the
high melting fatty acid ester comprises from about 25% by weight of
the total weight of the formulation.
22. A pharmaceutical formulation according to claim 18 wherein the
oil comprises about 46% to about 61% by weight of the total weight
of the formulation.
23. A pharmaceutical formulation according to claim 22 wherein the
oil comprises about 51% by weight of the total weight of the
formulation.
24. A pharmaceutical formulation according to claim 18 wherein the
cellulosic polymer comprises from about 1% to about 5% by weight of
the total weight of the formulation.
25. A pharmaceutical formulation according to claim 24 wherein the
cellulosic polymer comprises from about 3% by weight of the total
weight of the formulation.
26. A pharmaceutical formulation according to claim 18 wherein the
high melting fatty acid ester comprises from about 10% to about 50%
by weight, the oil comprises about 46% to about 61% by weight, the
cellulosic polymer comprises from about 1% to about 5% by weight
and the surfactant comprises from about 1.0% by weight of the total
weight of the formulation.
27. A pharmaceutical formulation according to claim 18 wherein the
high melting fatty acid ester comprises about 25% by weight, the
oil comprises about 51% by weight, the cellulosic polymer comprises
about 3% by weight, and the surfactant comprises from about 1.0% by
weight of the total weight of the formulation.
28. A process for the preparation of a sustained/prolonged release
pharmaceutical unit dosage form comprising the steps of: (a)
fluidizing a high melting fatty acid ester, (b) granulating the
fluidized fatty acid ester, an oil, a cellulosic polymer, a
surfactant and a water insoluble medicament; (c) transferring the
fluidized granulate to a hard shell capsule.
29. A process according to claim 28 wherein the water insoluble
medicament is selected from the group consisting of hydroxyzine
pamoate, nifedipine, nimodipine, nisoldipine, nicardipine,
amoldipine, atorvastatin, simvastatin, lovastatin, genfibrozil,
fenofibrate and clofibrate.
30. A process according to claim 28 wherein the high melting fatty
acid ester is fluidized at a temperature in the range of about
75.degree. to 80.degree. C.
31. The process according to claim 28 wherein the fluidized
granulate is transferred to a hard shell capsule at a temperature
of about 70.degree. C.
32. A pharmaceutical unit dosage form according to claim 1 wherein
the hard shell capsule comprises hydroxypropyl methylcellulose.
33. A process according to claim 28 wherein the hard shell capsule
comprises hydroxypropyl methylcellulose.
34. A modulated release pharmaceutical construct which comprises a
matrix of a material selected from the group consisting of (a) a
high melting fatty acid ester, (b) an oil, (c) a cellulosic polymer
and (d) a mixture of any of the foregoing, and a water insoluble
medicament associated with said matrix.
35. The construct as defined in claim 34 wherein the matrix further
comprises a surfactant added to said material.
36. The construct as defined in claim 34 wherein the matrix
comprises a mixture of said material (a) through (c).
37. The construct as defined in claim 34 wherein the matrix is
formed from a mixture comprising said ester selected from the group
consisting of glyceryl behenate, glyceryl palmitostearate and
glyceryl stearate; said oil selected from the group consisting of
corn oil, cottonseed oil, menhaden oil, safflower oil, sesame oil,
shark-liver oil, soybean oil, olive oil, wheat grain oil; and a low
viscosity polyglycolized glyciride and said polymer selected from
the group consisting of methocel A series, methocel E series,
methocel K series, ethocel P series, a low substituted
hydroxypropyl ether cellulosic polymer selected from the groups
consisting of LH11, LH22 and LH30.
38. The construct as defined in claim 37 wherein said mixture
further comprises a surfactant comprising a non-ionic
surfactant.
39. The construct as defined in claim 34 wherein said water
insoluble medicament is a medicament selected from the group
consisting of hydroxyzine pamoate, nifedipine, nimodipine,
nisoldipine, nicardipine, amoldipine, atorvastatin, simvastatin and
lovastatin, genfibrozil, fenofibrate and clofibrate.
40. A sustained release pharmaceutical composition comprising: a
construct comprising a component selected from the group consisting
of (a) a high melting fatty acid ester, (b) an oil, (c) a
cellulosic polymer and (d) a mixture of any of the foregoing, and a
water insoluble medicament associated with said construct;
41. A sustained release/prolonged release pharmaceutical unit
dosage form comprising: (a) a hard shell capsule; (b) a carrier
construct having a matrix of a material selected from the group
consisting of (a) a high melting fatty acid ester, (b) an oil, (c)
a cellulosic polymer and (d) a mixture of any of the foregoing, and
a water insoluble medicament associated with said matrix.
42. A process for preparing a sustained/prolonged release
pharmaceutical unit dosage form, which comprises: (a) fluidizing a
carrier comprising a component selected from (a') a high melting
fatty acid ester, (b') an oil, (c') a cellulosic polymer and (d') a
mixture of any of the foregoing components, to form a carrier
solution; (b) adding a water insoluble medicament to said carrier
solution to form a medicament solution; (c) transferring said
medicament solution to a hard shell capsule to solidify said
medicament solution to form the dose having a component matrix with
said medicament associated therewith.
Description
BACKGROUND OF THE INVENTION
[0001] One of the most frequently utilized methods to extend the
duration of drug action in the body is by modification of the
pharmaceutical dosage form. This is usually achieved with single or
multicomponent matrix systems such as granules, pellets, tablets or
a combination of the above where the drug delivery is mainly
controlled by diffusion or erosion mechanisms.
[0002] Another commonly used procedure to sustain or control the
rate of drug release is by utilizing polymer coating technology.
Polymers with pH dependent or independent properties are coated
onto the different dosage forms utilizing fluid bed or conventional
coating equipment.
[0003] The delivery systems described above, traditionally have
been used to manufacture many of the available pharmaceutical
dosage forms in the market. However, for drugs that present a low
melting point or are metastable at room temperature the only
available solid oral unit dosage form has been the soft gelatin
capsule.
[0004] Soft gelatin encapsulation is rather a complex process and
usually requires the services of an outside contractor. However,
many pharmaceutical companies would prefer to keep development
activities in-house for reasons of confidentiality and control over
the development process. With the new advances in pharmaceutical
equipment technology it is now possible to formulate drug
substances into semi-solid, liquid or paste-like form for filling
into hard-shell two piece capsules. This type of formulation
technology demonstrates an alternative for the difficult to
manufacture soft gelatin technology and the ability to maintain the
development activities in-house.
[0005] There are several advantages that can be obtained by
formulating drugs in liquids and/or semisolid (molten) formulations
to be filled into hard shell two piece capsules. These are the
ability to formulate with low melting point materials, low-dosed or
highly potent drugs, compounds that are oxygen- or moisture
sensitive, and for drugs that require bioavailability
enhancement.
[0006] Many of the liquid formulations in hard-shell capsules
provide an immediate or fast release. This is usually achieved as a
result of the immediate release of the contents due to the fast
disintegration time of the gelatin at body temperature. Other
formulations utilize sustained release liquid-filled release
capsules utilizing thermosoftening matrices. The excipients most
frequently utilized are the Gelucires.RTM., Gattefosse.RTM.,
France, since they are available as semisolids with a wide range of
melting points and HLB values. This variety allows flexibility in
mixing, adequate filling viscosity, different degrees of
bioavailability enhancement and a sustained drug release from the
semisolid matrix.
[0007] High melting glycerides have frequently been used as
lubricants when formulating tablets or capsules. Lubricants have a
great effect on the aspect of the finished product and the ejection
of the tablet out of the die is improved. Lubricants are usually
hydrophobic substances and when used in high amount can alter the
desegregation time of the tablet thus delaying the bioavailability
of the active ingredient.
[0008] The incorporation of lubricants (waxes, HMG) into tablet
matrices has been a popular method to prolong drug release. For
example, sustained release acetaminophen tablets with glyceryl
behenate, Klucel HXF, hydroxy propyl cellulose (HPC), a swellable
water-soluble polymer, and Carbopol.RTM. 934, a crosslinked
polymer, has been prepared. It was observed that all tablets
containing a sustained release agent exhibited some degree of
prolonged drug release in vivo as compared to regular tablets. It
was also noted that from all sustained release agents evaluated,
glyceryl behenate provided the slowest release.
[0009] Glyceryl behenate as a potential controlled release wax
matrix in spheres and tablets has been evaluated (10, 30 and 50%).
At the 10% level no sustained action was observed. However, as the
levels of glyceryl behenate increased a significant slower release
of the drug was obtained. The results indicated that glyceryl
behenate exhibited the potential to create a controlled release
matrix.
[0010] Sustained release preparations have also been achieved from
other high melting glycerides (glycerol palmitostearate and
glyceryl monostearate). For example the release of theophylline
embedded in a glycerol palmitostearate matrix containing varying
amounts of mannitol and/or hydroxypropyl methyl cellulose 4000
(HPMC) was evaluated. The release of theophylline was modulated by
varying the fraction of HPMC and/or mannitol used. When both HPMC
and mannitol were used the matrix system developed followed a
first-order dissolution release.
[0011] In general, natural, synthetic and/or semi-synthetic
polymers such as cellulose or acrylics derivatives, have been used
in high quantities (>10%) to retard the release of many
pharmaceutical active ingredients. Such polymers are not usually
recommended to be utilized in small quantities to retard the
release of API.
SUMMARY OF THE INVENTION
[0012] A controlled release pharmaceutical formulation is
disclosed. The formulation comprises a matrix construct of a
component selected from a high melting point fatty acid ester, an
oil, a polymeric cellulose derivative, and a mixture of any of the
foregoing, having a selected medicament associated therewith.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The accompanying drawing illustrates the invention. In such
a drawing:
[0014] FIG. 1 is a graphical representation of the in vitro release
of lovastatin using Compritol 888;
[0015] FIG. 2 is a graphical representation of the in vitro release
of lovastatin using Precirol ATO5;
[0016] FIG. 3 is a graphical representation of the in vitro release
of hydroxyzine pamoate using low HLB sufactant;
[0017] FIG. 4 is a graphical representation of the in vitro release
of hydroxyzine pamoate using high HLB surfactant; and
[0018] FIGS. 5 and 6 are graphical representations of the
dissolution profiles of nifedipine.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention relates to a sustained or modulated
pharmaceutical formulation comprising (1) a selected water
insoluble medicament or drug, (2) a suitable construct with which
the drug is associated, i.e. is encapsulated therewithin or being
part of the construct. The construct provides a modulated release
of the associated, e.g. encapsulated, drug to the body of a
patient, e.g. a human being or another animal, when the construct
is administered e.g. orally, to the patient.
[0020] As used herein the term "a water insoluble medicament, drug
or active ingredient" includes such medicament drug or active
ingredient that is (1) a sparingly soluble in water, i.e. 1 part
solute into about 30 to about up to about 100 parts of water; (2)
"slightly water soluble", i.e. 1 part of solute into about 100 to
up to about 1,000 parts of water; (3) "a very slightly water
soluble", i.e. 1 part of solute into about 1000 to up to about
10,000 parts of water; and (4) "practically water insoluble", i.e.
1 part of solute to at least about 10,000 parts of water; as
defined in USP XXII.
[0021] The formulation is intended to be administered orally to the
patient in a dosage form comprising a hard shell capsule filled
with the formulation.
[0022] Suitable therapeutic medicament categories of drugs or
medicaments are those which are water insoluble and include
cardiovascular drugs, antiallergics, analgesics, bronchodilators,
antihistamines, antitussives, antifungals, antivirals, antibiotics,
other pain medicaments, antiinflamatories, etc. Particularly
suitable medicaments include hydroxyzine pamoate; dihydropyridine
calcium channel blockers, e.g. nifedipine, nimodipine, nisoldipine,
nicardipine, amoldipine, etc.; statins e.g. atorvastatin,
simvastatin, lovastatin, etc., anticonvulsants, e.g. phenytoin,
carbamezepine, etc.; analgesics, e.g. ibuprofen, naproxen,
indomethacin, etc. steroids, e.g. prednisone, prednisolone,
hydrocortisone, etc.; fibrates, e.g. gemfibrozil, fenofibrate,
clofibrate, etc.; vitamins, e.g. vitamins A, D, E and K, etc.
[0023] For purposes of the formulations of this invention, which
are intended for incorporation into a hard shell capsule unit
dosage form, the biotherapeutic medicament or drug is associated
with the construct carrier with which it is destined to be
combined. By "associate" or "associated" is meant that the water
insoluble medicament is present as a matrix or a part of the matrix
along with the component making up the construct or is encapsulated
within the carrier matrix, or is on the surface of the carrier
matrix.
[0024] A suitable construct is selected. Such a construct is one
which will incorporate or encapsulate the selected medicament and
provide a controlled or modulated release of the medicament
therefrom to the sites of action or application to the patient's
body, e.g. to the hepatobiliary receptors of the human being or
other animal.
[0025] A suitable carrier construct comprises a material or
component selected from the group comprising a high melting fatty
acid ester, such as for example glyceryl behenate, gyceryl
palmitosterate and glycerylstearate; low viscocity oils, e.g.
vegetable oils, hydrogenated vegetable oils, corn oil, cottonseed
oil, menhaden oil, safflower oil, sesame oil, shark-liver oil,
soybean oil, olive oil and wheat germ oil; saturated,
polyglycolyzed, glycerides, a cellulosic polymer, e.g. methocel E
series, methocel A series, methocel K, series ethocel P series,
low-substituted hydroxypropyl ether cellulose polymers, L H series
methocel and a mixture of any of the foregoing.
[0026] A most preferred cellulosic polymer is a methylcellulose
polymer having a structure, 1
[0027] which are commercially available from the Dow Chemical
Company, Midland, Mich., under the tradename"METHOCEL". e.g.
METHOCEL A. Another most preferred cellulosic polymer is a
hydroxypropoxyl methyl cellulose polymer having a structure, 2
[0028] which are commercially available (Dow Chemical Company)
under the designations METHOCEL E, METHOCEL F, METHOCEL and
METHOCEL K brand products. Preferably, the formulation comprises a
mixture of at least two of the foregoing components.
[0029] The dosage form comprising a hard shell capsule utilizes the
formulation, i.e. the construct or the matrix having the medicament
associated therewith. Preferably, the sustained/prolonged release
pharmaceutical unit dosage form comprises the matrix or construct
formulated from a mixture of the above-described materials or
components.
[0030] The high melting fatty acid esters (high melting glycerides)
of the formulation and the sustained/prolonged release capsule unit
dosage forms of the present invention comprise esters of fatty
acids and polyhydric alcohols, such as glycerol, melting at
elevated temperatures within the range of from about 50.degree. to
about 80.degree. C. The melting points of fatty acid esters of
behenic acid (docosanoic acid), palmitostearic acid and stearic
acid and glycerol fall within this range and are suitable for the
formulations and unit dosage forms of the present invention. Other
high melting fatty acid esters, that is, fatty acid esters melting
within the range (about 50.degree. to about 80.degree. C.), may be
employed in the formulations and dosage forms.
[0031] The oils of the formulations and the sustained/prolonged
release capsule unit dosage forms of the present invention comprise
triglycerides of fatty acids having short (12 to 14 carbon atoms),
medium (16 to 18 carbon atoms) and long (18 to 22 carbon atoms)
carbon chains and no, or up to 6 double bonds. Exemplary fatty
acids are lauric acid (12 carbon atoms, no double bonds), myristic
acid (14 carbon atoms, no double bonds), palmitic acid (16 carbon
atoms, no double bonds), palmitoleic acid (16 carbon atoms, one
double bond), stearic acid (18 carbon atoms, no double bonds),
oleic acid (18 carbon atoms, 1 double bond), linoleic acid (18
carbon atoms, 2 double bonds), eicosapentaenoic acid (20 carbon
atoms, 5 double bonds ("EPA") and docosahexanoic acid (22 carbon
atoms, 6 double bonds), which are found in various animal and
vegetable oils listed in the Table below.
1TABLE Super Refined .RTM. Oils and the Associated Typical Fatty
Acid Distribution (%) Super Refined Product Myristic Palmitic
Palmitoleic Stearic Oleic Linoleic Linolenic EPA DHA Corn 1 10 0 3
30 55 0 0 0 Cotton- 1 24.5 0 2.5 17 55 <1 0 0 seed Menhaden 8.5
23 12.5 3 12.5 2 <1 12 8.5 Olive 0 11.5 1 2 75 9.5 0 0 0 Peanut
0 7.5 1 4.5 62 20 0 0 0 Safflower 0 7 0 3 15 75 0 0 0 Sesame 0 8 0
4.5 43 41 0 0 0 Shark-liver 2 12 7 4 30 6 5 4 4 Soybean 0 9 0 4 24
52 8 0 0 Wheat- 0 13.5 0 3.5 19 54.5 7 0 0 germ
[0032] The cellulosic polymers of the formulations and
sustained/prolonged release capsule unit dosage forms of the
present invention comprise glucose polysaccharide ethers having
multiple glucose units and methyl, ethyl, hydroxyethyl,
hydroxypropyl or hydropropyl methyl substitution. Exemplary
cellulosic polymers having methylether substitution are the
Methocels, i.e., methocel E10, methocel A4M, methocel K15M,
methocel K100LV and methocel K100M, and the Ethocels, for example,
ethocel P20 and low-substituted hydroxypropyl ether cellulose
polymers LH11, LH22 and LH30.
[0033] Surfactants which may optionally be employed with the
formulations and sustained/prolonged release capsule unit dosage
forms of the present invention, comprise polysorbates, such as
ethers of polyoxyethylene sorbitan and fatty acids. Exemplary
surfactants are polysorbate 80 and polyoxyethylene 20 sorbitan
monoleate, polyoxyxethylene alkyl ethers of the Brij- or Volpo
series, Cremophor RH, Cremophor EL, polyoxyethylene sorbitan fatty
acid esters of the Tween- or Crillet series, polyoxyethylene
stearates of the Cerosynt- or Myrj series, lecithin, poloxamers,
d-2-tocophenyl polyethylene glycol 1000 succinate (Vitamin E TPGS)
and saturated polyglycolized glycerides (Labrasol, Labrafil and
Gelucires), polyoxyethylene castor oil derivations, such as
polysorbate 80 which is preferred.
[0034] The release of the insoluble or partially water soluble
active ingredient or drug of the pharmaceutical unit dosage forms
of the present invention is sustained over a prolonged period of
about 24 hours. The sustained release of the water insoluble
medicament from a hard shell capsule is dependent upon the type and
amount of medicament, the high melting fatty acid ester, cellulose
polymer and a surfactant (if employed).
[0035] The most preferred formulation comprises a water insoluble
medicament, and a mixture comprising glyceryl behenate as the fatty
acid ester, an oil, a cellulosic polymer, such as for example, a
methyl or ethyl ether of a cellulose, e.g., a methocel or an
ethocel, and polysorbate 80 surfactant.
[0036] Optionally, pharmaceutically acceptable excipients,
compatible with the requirements for filling the capsules that the
formulation be in the fluid state, i.e., a liquid or semi solid, at
the filling temperature, may be included in the formulation. Such
excipients comprise a surfactant, such as for example polysorbate
80; stabilizers/antioxidants, such as for example butylated
hydroxytoluene, propyl gallate, vitamin E, ascorbic acid and
ethylene diamine tetraacetic acid; solubilizers, such as for
example N-methyl-2-pyrrolidone, citrate esters, e.g., Citroflex 2,
acetylated monoglycerides, e.g., Triacetin and Mygliols; viscosity
modifiers, such as for example polyethylene glycols, e.g. PEG, and
silica derivatives, e.g., silicon dioxide; and fillers such as for
example hydrocarbons, e.g., paraffin and mineral oil. Preferably,
combined with the component or components of the carrier and the
drug is a surfactant, such as polysorbate 80.
[0037] The release of water insoluble medicaments from the unit
dosage formulation generally depends on the type and amount of the
high melting fatty acid in the formulation and varies substantially
with the type and amount thereof. For example, the release of
lovastatin from a formulation containing the same cellulose
(methocel) component over a prolonged period of about 24 hours, is
fastest with Precirol AtO5, slowest with Compritol 888. The release
of Lovastatin/Ethocel from a formulation of the precirol is
moderately faster as the same formula containing compritol and
ethocel.
[0038] The release of water insoluble medicament from a unit dosage
formulation is markedly dependent on the type and amount of the
cellulosic polymer. For example, lovastatin, compritol, is released
considerably faster from a formulation of Methocel K100M than
Ethocel P20. Similarly, lovastatin/precirol is released from a unit
dosage formulation faster when the formulation contains Methocel
K100M than Ethocel P20.
[0039] The formulations of the water insoluble medicaments of the
present invention are useful for encapsulation in hard shell
capsules for oral administration for the treatment of various
diseases and disorders, for example, lovastatin, as an
antilipidimic, or nifedipine as an antihypertensive agent,
hydroxyzine pamoate as a antihistamine. The drugs are readily
available from commercial suppliers.
[0040] The high melting fatty acid esters, the oils, the cellulosic
polymers and surfactants and other excipients of the formulations
of the present invention suitable for encapsulation in hard shell
capsules are generally available from commercial sources. The water
insoluble medicaments are also commercially available.
Pharmaceutically acceptable acids and bases required for salt
formation of water insoluble medicaments are available from
suppliers such as Aldrich Chemical Company, Milwaukee, Wis.
[0041] The sustained/prolonged release pharmaceutical unit dosage
forms are prepared by fluidizing matrix carrier material or
components, e.g. a high melting fatty acid ester, an oil, a
cellulosic polymer or a mixture of the foregoing, to provide a
formulation, to which is added the medicament which dissolves
therein, which is then filled into a hard shell capsule, while in
the fluid state, and, generally, allowed to solidify in the
capsule. The filling of the hard shell capsule is conveniently
performed by a capsule filling machine for liquid filling of the
type available, for example, from Robert Bosch GmbH, (Hofligen and
Kars GKF/L Series), Germany, Harro Hoefleger GmbH, (KFM/L Series),
Germany, or Zanasi Nigris SpA (AZ 20/L Series), Italy. The hard
shell capsules are generally sealed by one of several methods. The
filled capsule may be sprayed with a water alcohol mixture to seal
the cap to the body of the container. Alternatively, the cap may be
sealed to the body of the container by a bonding process, which
entails passing the cap over a revolving wheel immersed in a water
gelatin or a cellulose bath and then passing the capsule through a
drying chamber to seal the gap between the cap and the body of the
capsule with dried gelatin or cellulose. The bonding is generally
performed on commercially available machines manufactured by Robert
Bosch GmbH and Zanasi Nigris SpA, makers of capsule filling
machines.
[0042] Empty hard shell capsules are commercially available from
the Capsugel Division of Warner-Lambert Co., Greenwood, S.C., and
from Shionogi Qualicaps, Whitsett, N.C., in various sizes to
accommodate the dosage requirements for the treatment of disease or
disorder states. For example, size 0 may be employed for unit
dosage forms for potent drug formulations whereas size 000 would be
required for a less potent drug, depending on the amounts of the
components of the formulation and excipients.
[0043] Gelatin and hydroxypropylmethylcellulose (HPMC) capsules may
be used as containers for the formulations.
Hydroxypropylmethylcellulose capsules are preferred.
[0044] The following examples are illustrative and do not define
the scope of the invention described and claimed herein.
EXAMPLES
General Example
[0045] The sustained/prolonged release formulations of the present
invention are generally prepared by heating the matrix component or
components until liquid (a melt), usually at the capsule filling
temperature (70-90.degree. C.) and adding the water insoluble
medicament to the melt. The amount of water insoluble medicament
utilized in all formulations is about 20% of the total amount of
the formulation. Size #0 Hard-Shell hydroxypropylmethylcellulose
capsules are utilized since they are heat resistant. In order to
assure proper mixing and to reduce the amount of air entrapped with
stirring (vortex created), batches containing a minimum of 50 grams
are prepared. A general formulation is illustrated below.
2 Ingredients % Qty (g) Medicament 20.0 10.00 High Melting
Glyceride 25.0 12.50 Surfactant 1.0 0.50 Cellulose Polymer 3.0 1.50
Vegetable oi 51.0 25.50 Total 100.0 50.00
Example 1
[0046] Soybean oil, polysorbate 80, and Compritol 888 in the
amounts shown in Table 1 were weighed and placed in a glass beaker.
The mixture was heated to 75-80.degree. C. until the contents
melted by immersing the beaker into a water bath heated by a
Hot-Plate. The melt in the amount shown in Table 1 below was
stirred with a laboratory mixer fitted with a straight blade
propeller to disperse the ingredients and create an homogeneous
melt. To the melt, Methocel E or Ethocel 10P was slowly added with
heating and stirring. After addition of the Methocel E 10P was
complete, the melt was cooled to approximately 70.degree. C., and
then cooled at approximately 70.degree. C., the water insoluble
medicament lovastatin, was slowly added, and the melt was stirred
until uniform. Capsules size 0 were filled with 500 mg of melt,
with a pipette. The filling weights of each capsule were recorded
to guarantee consistency. The melt was all regular type maintained
at approximately 70.degree. C. during the filling process. The
release of the medicament, lovastatin, was then determined.
[0047] The dissolution release of the formulations was determined
by the USP Basket Method (Apparatus 1). By this method, samples are
tested in a 40 mesh basket rotating at 100 RPM. Release media were
used in a volume of 900 Ml per dissolution vessel, maintained at
37.degree. C. Double distilled deionized water with 1% sodium
dodecyl sulfate was generally used as the dissolution media. Nine
samples of 3.0 ml each were automatically collected at 2, 4, 6, 8,
10, 12, 14, 20 and 24 hours. The absorbency of the samples was
measured at the peak wavelength in the ultraviolet spectrum with
Hewllet Packard model 8453 spectrophotometer. The absorbency values
were converted to percentages of added medicament that was
released.
[0048] FIG. 1 shows the in vitro release of lovastatin using
Compritol 888 and different cellulose products in the capsule
system. The Methocel products differ in their chemical substitution
attached to its cellulose backbone. The chemical substituents are
hydroxypropoxyl and methoxyl groups. The methoxyl substituent
provides more hydrophobicity and does not contribute to a great
extent to the hydrophilic nature of the cellulose polymer thus
having minimal influence on the rate of polymer hydration. On the
other hand, the more hydrophilic hydroxypropoxyl group does
contribute greatly to the rate of polymer hydration. Consequently,
Methocel K products have the fastest rate of hydration than the
other polymers due to its higher amount of the hydroxypropoxyl
groups and a lower amount of the hydrophobic methoxyl group.
Methocel E has a higher content of methoxyl group than
hydroxypropoxyl groups attached thus providing a slower rate of
hydration. Ethocel is a water insoluble polymer, with the same
cellulose backbone and no water hydrating properties. The polymer
is only organosoluble. The results show that for all formulas
evaluated a sustained release of the drug was obtained. The fastest
hydrating polymers provided a faster release thus allowing
modulation of the sustained release effect. (Methocel K>Methocel
E>Ethocel).
3 TABLE 1 Formula/ Ingredients 1 2 3 Lovastatin 20.0 20.0 20.0
Compritol 888 25.0 25.0 25.0 Methocel E10P 3.0 Methocel K100M 3.0
Ethocel P20 3.0 Olive Oil 51.0 51.0 51.0 Polysorbate 80 1.0 1.0
1.0
EXAMPLE 2
[0049] Following the procedure of Example 1, using the amounts of
the components shown in Table 2 below, hard shell capsules of the
formulations were obtained. The release of the medicament was
determined by the procedure of Example 1, and the results are
recorded graphically in FIG. 2.
[0050] FIG. 2 shows the in vitro release of lovastatin using
Precirol ATO5 and different cellulose based products in the capsule
system. Precirol ATO5 has a lower melting point than Compritol 888
due to shorter fatty acid chains. Compritol 888 which is glyceryl
behenate contains a 22 carbon fatty acid length chain. Precirol
ATO5 is an equal mixture of the palmitate and sterate, 16 and 18
carbon units respectively. The use of a lower melting glyceride
resulted in faster dissolution profiles of the water insoluble
lovastatin. For systems containing the fast hydrating Methocel
polymers, lovastatin was completely released in 4 hours. For
systems containing the non-hydrating Ethocel a sustained release of
the lovastatin was obtained over 24 hours. It is clearly
demonstrated that the dissolution release is dependent on the type
of polymer used.
4 TABLE 2 Formula/ Ingredients 1 2 3 Lovastatin 20.0 20.0 20.0
Precirol ATO 5 25.0 25.0 25.0 Methocel E10 P 3.0 Methocel K100M 3.0
Ethocel 3.0 Olive Oil 51.0 51.0 51.0 Polysorbate 80 1.0 1.0 1.0
Example 3
[0051] This example illustrates the release of the active
pharmaceutical ingredient hydroxyzine pamoate. In order to optimize
the inclusion of this water insoluble salt in the capsule semisolid
matrix, several surfactant classes and levels were evaluated (1-10%
by weight). At levels lower than 2% by weight significant sample to
sample variabilities were observed in the dissolution profiles
indicating that the matrix was not well dispersed or a
non-homogeneous mixture was obtained. Since excessive amounts of
surfactant are not recommended for oral intake, the smallest amount
which provides minimal sample to sample variability was evaluated
(2% by weight level). These formulations listed in Table 3 below
were prepared by melting the Compritol 888 with Labrasol and the
specified surfactant in a suitable size beaker. The temperature of
the mixture was kept at 75-80.degree. C. with the aid of a heated
plate and water bath. The mixture was constantly mixed until it
became homogeneous. Once the mixture was homogeneous and free of
any agglomerates, the cellulose polymer was added slowly to the
melt with continuous mixing. The temperature of the mixture was
then lowered to approximately 70.degree. C. Once the mixture cooled
to approximately 70.degree. C., the hydroxyzine pamoate was slowly
dispersed. The final melt was mixed well until uniform. Utilizing
an appropriate pipette HPMC Capsules (#0) were filled with 500 mg
of the melted mixture. The liquefied melt immediately solidified at
room temperature. The actual filling weights were recorded for each
capsule. Empty capsules were tared and balance zeroed. The melt
mixture was maintained at approximately 70.degree. C. during the
filling operation.
[0052] The results of combinations utilizing a low HLB surfactant
are shown in FIG. 3. The results utilizing a high HLB surfactant
are shown in FIG. 4.
5TABLE 3 Formula/ Ingredients 1 2 3 4 Hydroxyzine Pamoate 20.0 20.0
20.0 20.0 Compritol 888 25.0 Methocel K100 3.0 3.0 Methocel E10 P
Ethocel 3.0 3.0 Precirol ATO 5 25.0 Labrasol 51.0 51.0 51.0 51.0
Polysorbate 80 2.0 2.0 2.0 2.0
Example 4
[0053] This example further illustrates the modulated sustained
release behavior of nifedipine. Nifedipine is a calcium channel
blocking agent indicated for the management of hypertension and
other cardiovascular diseases. Extended release tablets are
available at 60 and 90 mg doses. In order to adjust for the proper
and recommended dosing, the filled weight of the capsules was
reduced to 450 mg. At a 20% medicament level each capsule will
contain a total of 90 mg nifedipine. The procedures used to
manufacture the capsules were the same as those described in
Example 1. The formulation and the percentages for each are
described in Table 4--below. The dissolution profiles demonstrating
the modulated sustained release effect of the capsule matrix and
the effect of the polymer and surfactant combinations are seen in
FIGS. 5 and 6.
6TABLE 4 Formula/ Ingredients 1 2 3 4 Nifedipine 20.0 20.0 20.0
20.0 Compritol 888 25.0 Methocel K100 3.0 3.0 Methocel E10 Ethocel
3.0 3.0 Precirol ATO 5 25.0 Labrasol 51.0 51.0 51.0 51.0
Polysorbate 80 2.0 2.0 2.0 2.0
* * * * *