U.S. patent number 3,826,258 [Application Number 05/224,138] was granted by the patent office on 1974-07-30 for gradual release medicine carrier.
Invention is credited to Samuel V. Abraham.
United States Patent |
3,826,258 |
Abraham |
July 30, 1974 |
GRADUAL RELEASE MEDICINE CARRIER
Abstract
A medicament carried within a perforate or semipermeable shell
is gradually released, as by dissolution into body fluids, to
provide effective therapy with reduced concentration and dosage.
The medicament may be in dry powdered form. For treatment of the
eye, the carrier comprises a capsule less than 1 millimeter in
diameter which is placed in the conjunctival sac or mounted in a
contact lens. The capsule may be colored for easy location and
removal, may be absorbable by the body, or may gradually swell to
allow washout by the tears. For glaucoma treatment, less than 1
milligram of pilocarpine or phospholine in a single sustained
release capsule may be an adequate daily dosage. In another
embodiment a soft contact lens itself may serve as the medicine
containing carrier. For burn, ulcer, or wound treatment, the
carrier may be of planar configuration or incorporated in a film
forming spray comprising many minute particles or capsules each
containing a medicament. The resultant film will protect the tissue
from exposure, will provide sustained release medication, and may
be absorbable to eliminate the need for removal with concomitant
damage to newly formed granulation tissue.
Inventors: |
Abraham; Samuel V. (Encino,
CA) |
Family
ID: |
22839408 |
Appl.
No.: |
05/224,138 |
Filed: |
February 7, 1972 |
Current U.S.
Class: |
424/427;
604/295 |
Current CPC
Class: |
A61K
9/0051 (20130101); A61F 9/0017 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61F 9/00 (20060101); A61m
031/00 () |
Field of
Search: |
;128/260,268,261,249,248,172.1 ;424/19,21,22 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Waltman and Kaufman, "Use of Hydrophilic Contact Lenses to Increase
Ocular Penetration of Topical Drugs," Investigative Opthalmology 9,
No. 4, pp. 250-255. .
Dabezies, "Contact Lenses and Their Solutions: ... Principles,"
Eye, Ear, Nose & Throat Monthly, Vol. 45, 3-1966, pp. 82-84
& 112. .
Sedlacek, "Possibilities of Application of Eye Drugs with the Aid
of Gel-Contact Lenses," Czech. Oftalmologia, Vol. 21, 6-1965, pp.
509-512. .
Gasset and Kaufman, "Therapeutic Uses of Hydrophilic Contact
Lenses," American Journal of Opthamology, Vol. 69, 2-1970, pp.
252-259..
|
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: McGowan; J. C.
Attorney, Agent or Firm: Flam & Flam
Claims
Intending to claim all novel, useful and unobvious features is
shown or disclosed, the applicant claims:
1. For sustained release medicinal therapy of the eye:
a sealed, disposable, ampoule-like dropper prepackaged to contain a
very small number of gradual release medicine carriers in a saline
or antiseptic solution, each carrier having a hollow casing
containing a medicament in dry powdered form, said casing being
non-allergenic, having a tear-equivalent pH, and being perforated
by orifices to allow the entry of tear fluids, the number and size
of said orifices establishing the gradual release rate of said
medicament by dissolution into said tear fluids, each carrier
having no dimension greater than about 1 millimeter to permit
non-irritating disposition of said carrier in the conjunctival sac
of the eye, said ampoule-like dropper facilitating delivery of said
carriers into said conjunctival sac for intimate tear fluid
exchanging delivery of said medicament to the eye.
2. A prepackaged ampoule-like dropper according to claim 1 wherein
said casing is absorbable by tissue of said conjunctival sac over a
time duration commensurate with or greater than the total release
period of said medicament.
3. A prepackaged ampoule-like dropper according to claim 1 wherein
said carrier is colored to aid finding the emptied casing for
removal from said conjunctival sac.
4. A prepackaged ampoule-like dropper according to claim 1 wherein
said casing gradually swells in the presence of tears to a size
sufficient to be washed from said conjunctival sac by said
tears.
5. A prepackaged ampoule-like dropper according to claim 1 wherein
said medicament comprises less than 1 milligram of pilocarpine or
phospholine, said medicament being a sufficient daily dosage for
the sustained release treatment of glaucoma.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to gradual release medicine carriers
and particularly to a capsular medicament carrier useful for
prolonged release therapy of the eye and adapted for placement in
the conjunctival sac and to other carriers for treatment of
superficial body areas.
2. Description of the Prior Art
It is well known that the effectiveness of some medicinal agents is
increased when the agent is released slowly into the host. This is
particularly true of the eye, where the constant washing by tears
tends to dilute and flush away a medicine dropped onto the cornea.
A substantial portion of the actual medicament is lost, and the
remaining therapeutic portion is present at the eye for a
relatively short period of time.
Sustained release therapy, wherein a small amount of medicine is
released over a prolonged period of time, significantly decreases
both the concentration of medicament required and the total daily
dosage. Such therapy is of value to patients who are sensitive
either to the medication itself or to the preservative, vehicle or
stabilizer used with the agent. For eye treatment, sustained
release therapy is useful for continuous control of intraocular
pressure or other ocular conditions (infections, etc.).
The reduced dosage and concentration achievable with sustained
release therapy is illustrated by the pilocarpine treatment of
open-angle glaucoma. To simulate gradual release of the medication,
patients were administered 100 drops of pilocarpine over a 5 hour
period. The results were compared with the response of patients
given the conventional dosage of two or three drops per day of 1%
to 4% pilocarpine. On a sustained release basis, the minimum
effective dosage was found to be between 10 and 30 micrograms per
hour, equivalent to a 24 hour dose of 240 to 720 micrograms. This
is significantly less than the total dose of from 1500 micrograms
per day for a patient receiving 1% pilocarpine three times daily to
6000 micrograms in a patient receiving 4% pilocarpine three times
daily. The investigators reported that "If a suitable method of
prolonged release pilocarpine therapy could be developed, most
patients with wide-angle glaucoma would require a total 24-hour
dose between 10 and 25 times less than that they are currently
using." (See "Simulated Sustained Release Pilocarpine Therapy and
Aqueous Humor Dynamics" by S. Lerman and B. Reininger,
OPHTHALMOLOGY DIGEST, Sept., 1971.)
In the past, some sustained release medicine carriers have been
suggested, but none is useful for eye therapy. Typical is the
polysiloxane (silicone rubber) implant shown in the U.S. Pat. No.
3,279,996 to D.M. Long, Jr. et al. That device comprises a tube
about 1 centimeter in length, fabricated of certain silicone rubber
material (typically dimethylpolysiloxane), and containing a drug
which is soluble in and capable of diffusing through the silicone
rubber at a constant rate. The carrier containing a relatively
large supply of the medicament, is implanted in the living body.
Drug molecules are removed from the polymer wall by body fluids and
tissue absorption, this process continuing indefinitely or until
the medicinal substance has been consumed completely. The agents
used include anti-coagulants, anti-infectives, anesthetics, and
hormones. Sustained release drug application through polysiloxane
implants also shows improved effectiveness over conventional
therapy. For example, invivo experiments were performed with rats
using the steroid hormonal preparation megestrol acetate. These
experiments show that sustained release of the hormone through a
polysiloxane implant is 6 to 25 times more effective than
subcutaneous injections in producing comparable biological effect.
(See C. Chang and F. Kinel, "Sustained Release Hormonal
Preparations: Biologic Effectiveness of Megestrol Acetate" in
STEROIDS, Vol. 12, No. 6, Dec., 1968.)
While effective therapeutically, silicone rubber implants are
inapplicable for eye usage. An objective of the present invention
is to provide a gradual release medicine carrier of sufficiently
small size as to be placed in the conjunctival sac, or incorporated
in a contact lens worn by the patient. Techniques for carrier
insertion and disposal of the emptied capsule are set forth. Other
embodiments for burn, ulcer, wound and implant therapy are
discussed.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a
sustained release medicine carrier comprising a capsule having a
perforate or semipermeable shell and containing a medicament which
is gradually released through the shell. Alternatively, the
medicament may be impregnated in the capsule. For eye therapy, the
capsule preferably is less than 1 millimeter in diameter,
permitting deposit of the capsule in the conjunctival sac. The
medicament, which may be in a dry, powdered form, dissolves in the
tears to effectuate prolonged release into the eye. The capsule may
be inert or have a pH matching that of the tears.
To facilitate insertion, one or more capsules may be prepackaged in
a dropette. Coloring facilitates location of the emptied capsule
for removal from the conjunctival sac. Alternatively, the capsule
may be absorbable, or may swell so as to be washed from the eye by
tears after some period of time.
In other embodiments, the sustained release medicine carrier may be
inserted in a contact lens, or the corneoscleral lens itself may
function as the medicament container. For burn, ulcer and wound
treatment, very small medicament containing capsules or
medicine-impregnated particles may be incorporated in a spray
forming a film over the body area being treated. The film may be
absorbable and applied in layers, with the rate of absorption
controlling the medicament release rate. Preformed, absorbable,
gradual release medicament containing structures such as thin pads
or implants also are envisioned. Alternatively, the medicaments may
be incorporated in linquets, pellets, microspansules, ointments,
suppositories, or chewable tablets, each facilitating gradual
release of the medicament.
BRIEF DESCRIPTION OF THE DRAWINGS
A detailed description of the invention will be made with reference
to the accompanying drawings wherein like numerals designate
corresponding parts in the several figures. These drawings, unless
described as diagrammatic or unless otherwise indicated, are to
scale.
FIGS. 1 and 2 are greatly enlarged perspective views, partly broken
away, of gradual release medicine carriers for eye therapy and
respectively using a perforate shell and a semipermeable
membrane.
FIG. 3 is a pictorial view showing insertion of a gradual release
medicine carrier into the conjunctival sac of the eye.
FIG. 4 is a perspective view of a prolonged release medicine
carrier mounted in a contact lens.
FIG. 5 illustrates the manner in which a soft contact lens may be
used as a medicament carrier.
FIG. 6 is a perspective view of a pad-shaped gradual release
medicine carrier useful, e.g., for burn treatment.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following detailed description is of the best presently
contemplated modes of carrying out the invention. This description
is not to be taken in a limiting sense, but is made merely for the
purpose of illustrating the general principles of the invention
since the scope of the invention is best defined by the appended
claims.
Structural and operational characteristics attributed to forms of
the invention first described shall also be attributed to forms
later described, unless such characteristics are obviously
inapplicable or unless specific exception is made.
A gradual release medicine carrier 10 useful for eye therapy is
shown in FIG. 1. Referring thereto, the carrier or capsule 10
comprises a casing or shell 11 which may be, but is not necessarily
spherical. Contained within the shell 11 is a medicament 12,
typically in dry, powdered form. The shell 11 is perforated to
allow body fluids such as tears to enter the capsule interior 13.
The medicament 12 dissolves in such fluid and flows out through the
perforated shell 11 in solution.
The medicine release rate is established by the size, shape and
number of the shell 11 perforations. By way of example, a capsule
10 may have just a few relatively large openings 14 of V- or
Y-shape. Such shape establishes a substantial flow area, but
prohibits foreign bodies such as dust in tears from entering the
capsule 10. Alternatively, the shell 11 may be perforated by
multiple tiny holes or micropores 15. In another embodiment the
medicament may be impregnated in the capsule shell or the capsule
may be solid with the medicament impregnated throughout.
In the alternative embodiment of FIG. 2, the capsule 20 includes a
shell 21 having the characteristics of a semipermeable membrane.
Body fluid diffuses through the membrane 21 into the capsule
interior 23 where it comes in contact with the dry, powdered
medicament 12. The medicine dissolves, and the solution flows back
out through the shell 21 at a rate established by the membrane
characteristics. Alternatively, a liquid medicament may be
contained in the capsule 20, and the semipermeable membrane
selected for preferred outward diffusion of the medicine. The shell
21 may comprise a dialysis membrane.
Preferably the diameter of each capsule 10, 20 is sufficiently
small so that there is no irritation or discomfort when the carrier
is situated in the conjunctival sac of the eye. A diameter of less
than about 1 millimeter is satisfactory. The shell 11, 21 may be
inert or may have a pH of about 7.2, equal to that of a tear, and
should be non-allergenic.
FIG. 3 illustrates delivery of the capsule 10, 20 to the
conjunctival sac 25 of a patient 26. Many of the capsules 10, 20
may be packaged in a bottle, in a saline or antiseptic solution.
The capsules may be colored for ease of visability. An eyedropper
is used to remove one or two capsules from the bottle for deposit
into the sac 25. Since the capsules 10, 20 are small, it may be
difficult to pick up only one or two in a dropper. This problem is
alieviated by prepackaging a very small number (i.e., one or two)
capsules 10, 20 in an individual, disposable dropette 27 or
ampoule-like dropper. In use, the dropette 27 is opened and the
contents deposited into the conjunctival sac 25 as the lid 28 (FIG.
3) is held away from the eye 29.
While the capsule 10, 20 is within the conjunctival sac 25, the
medicament 12 will dissolve in the patient's tears and flow onto
the eye 29. Prolonged release of the medicine is achieved, so that
the amount of medicament 12 employed may be very small. For
example, in the treatment of glaucoma the medicament 12 may
comprise powdered crystals of pilocarpine or phospholine. When
gradually released from the carrier 10, 20, less than 1 milligram
of such powder may constitute a day's supply. As discussed earlier,
this is significantly less than the amount required for effective
therapy using the conventional liquid drop application. Moreover,
as the pilocarpine or phospholine is maintained in dry powder form,
no preservative is required, eliminating the chance of allergic
reaction to such preservatives. Similarly, no preservative may be
required if the medicament is impregnated in the capsule.
When all of the medicament 12 has been released to the eye 29, the
capsule 10, 20 is removed from the sac 25 by flushing the eye with
water, or by use of a cue tip. If the shell 11, 21 is colored, the
capsule readily can be located for removal.
The need to remove the emptied capsule 10, 20 from the sac 25 can
be eliminated by making the shell 11, 21 of a material absorbed by
the body. For example, the perforated shell 11 may be made of a
synthetic polyglycolic acid polymer which hydrolyzes in the human
body. Sutures made of such synthetic material are sold commercially
by the Lederle Laboratories, Pearl River, N.Y., under the trademark
DEXON. Certain colloidal materials such as collagen fibrils may be
formed into a shell 11 absorbably in the body. Alternatively, the
semipermeable shell 21 may comprise absorbable gut of the type used
for dialysis membranes. Such material is absorbed in the body by
proteolysis, a protein cleavage process.
An alternative approach to the capsule removal problem is to form
the shell 11, 21 of a material which will swell when immersed in
tears. In the course of a day, as the medicament 12 is dispensed,
the shell will swell sufficiently so as to be washed from the eye
by the tears present in the sac 25. A swelling gelatin material
satisfactory for use at the eye is described in the Mar., 1968
issue of ARCH OPHTHAL, on page 289. This gelatin is absorbed by the
body, but only after periods much longer than a day.
Rather than placing the gradual release medicine carrier in the
conjunctival sac, the capsule 10, 20 may be situated in a contact
lens. Thus (FIG. 4) a contact lens 35 may include a capsule
receiving notch or recess 36 in a peripheral edge 37 of the lens. A
capsule 10, 20 is injected into the recess 36. When the lens 35 is
placed on the eye, tears will enter the recess 36; the medicament
12 will dissolve in the tears and flow onto the eye 29 as
before.
The use of the invention with soft contact lenses is of particular
interest. The hydrophilic corneoscleral lens, composed of a
cross-linked hydrophilic polymer of 2-hydroxyethyl methacrylic acid
has the known disadvantage that bacteria tend to grow in the
interstices of the plastic. As a result, such lenses normally must
be boiled in saline each day for sterilization, or kept in a
sterilizing solution overnight with questionable results. Such
daily sterilization could be eliminated by mounting in the lens a
capsule 10, 20 containing an antibacterial agent instead of or in
addition to a medicament.
Another disadvantage of soft contact lenses is that ocular
preservatives such as benzalkonium chloride and chlorbutanol drops
might concentrate within the interstices of the lens. This problem
is completely eliminated by the use of a carrier 10, 20 which
contains the medicament without any preservative.
As the cost of soft contact lenses is reduced, it is likely that
disposable lenses will become available. The medicament carrier 10,
20 could be mounted in such a disposable lens at the time of
manufacture. The user would purchase the daily disposable lenses by
prescription specifying the appropriate medication.
In yet another embodiment, a disposable, soft contact lens itself
may serve as the medicament shell. Thus in FIG. 5, the soft contact
lens 40 contains a chamber 41 containing the medicament 12,
injected during manufacture. The region 41 is perforated, as for
example, by micropores 42 analogous to the openings 15 in the
embodiment of FIG. 1. Controlled release of the medicine is
achieved directly from the lens 40.
For the treatment of burns, ulcers and wounds, the carrier 45 (FIG.
6) may comprise a pad of minimal thickness but relatively large
length and width. The casing 46 of the pad 45 is analogous in
composition and function to the shell 11 or 12 described above, and
surrounds a hollow interior 47 containing a medicament 48.
Preferably the casing 46 is of absorbable material. When placed on
a burn or open wound the medicament 48 slowly will be released.
Eventually the casing 46 itself will be absorbed. The slow release
of medication provides the benefits of lowered dosage and
concentration, while the absorbability feature eliminates the pain
usually associated with bandage removal. The pad need not be
hollow, but may have the medicament impregnated throughout.
By making the capsules 10, 20 of very small size, they may be
combined with a film forming plastic material and applied to a
wound area in the form of a spray. Alternatively the spray may
comprise small particles of a film forming material impregnated
with the medicament. Such particles may consist of a polyglycolic
acid intermediary, a colloidal protein, collagen fibrils or other
absorbable material.
The film thus formed in situ will be conformal with the wound, and
will have the desirable gradual medicine release characteristics
described above. In addition, the film will protect the tissue from
exposure, decreasing pain and reducing the chance of toxic
reactions. The medicament may include an antiseptic to prevent
infection.
Additional benefits result from using an absorbable film forming
material. The rate of medicament release may be determined by the
absorption rate. Additional layers may be sprayed on to affect the
dosage and replenish the medication. Further, use of such an
absorbable film eliminates the problem, associated with removal of
conventional wound coverings, of pulling off newly formed
granulation tissue.
Suitably packaged forms of the invention, for example linguets or
suppositories, can be placed in the mucus membrane of the eye, oral
or nasal cavity, vagina or rectum to achieve gradual release of
medicament.
* * * * *