U.S. patent application number 15/618339 was filed with the patent office on 2017-09-28 for methods for manufacturing implants.
This patent application is currently assigned to ProMed Pharma, LLC. The applicant listed for this patent is ProMed Pharma, LLC. Invention is credited to James H. ARPS, Matthew Petersen.
Application Number | 20170273900 15/618339 |
Document ID | / |
Family ID | 55436467 |
Filed Date | 2017-09-28 |
United States Patent
Application |
20170273900 |
Kind Code |
A1 |
ARPS; James H. ; et
al. |
September 28, 2017 |
METHODS FOR MANUFACTURING IMPLANTS
Abstract
Pharmacologically active implants, in particular subcutaneous
implants, intrauterine devices, and intravaginal rings, are
provided herein. Methods for forming an active
ingredient-containing core are described. Methods for laminating an
active ingredient-containing core to form a rate-controlling sheath
are also described.
Inventors: |
ARPS; James H.; (Chanhassen,
MN) ; Petersen; Matthew; (Minneapolis, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ProMed Pharma, LLC |
Plymouth |
MN |
US |
|
|
Assignee: |
ProMed Pharma, LLC
Plymouth
MN
|
Family ID: |
55436467 |
Appl. No.: |
15/618339 |
Filed: |
June 9, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14847782 |
Sep 8, 2015 |
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15618339 |
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62047344 |
Sep 8, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B29K 2105/0035 20130101;
A61K 31/567 20130101; B29L 2031/7148 20130101; A61K 9/0036
20130101; B29C 48/157 20190201; A61K 47/34 20130101; A61K 31/57
20130101; B29L 2031/754 20130101; A61K 47/32 20130101; B29C 51/12
20130101; B29C 48/04 20190201; B29K 2067/046 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/567 20060101 A61K031/567; A61K 31/57 20060101
A61K031/57; A61K 47/32 20060101 A61K047/32; A61K 47/34 20170101
A61K047/34; B29C 51/12 20060101 B29C051/12 |
Claims
1. A method of forming a pharmacologically active homogenous core
matrix mixture, the method comprising: combining one or more
polymers with one or more active ingredients to form a mixture; and
mixing the mixture sufficient to impart heat and until a homogenous
mixture is achieved; wherein heat imparted to the mixture is
sufficient to melt the polymer without substantially altering the
pharmacological properties of the active ingredient.
2. The method of claim 1, wherein mixing is accomplished via a dual
asymmetric mixer.
3. The method of claim 1, wherein mixing is contactless.
4. The method of claim 1, wherein the homogenous mixture has a
material uniformity of less than +/-5%.
5. The method of claim 1, further comprising combining the one or
more polymers and one or more active ingredients with one or more
of an opacifier or a dye.
6. The method of claim 1, further comprising cooling the
mixture.
7. The method of claim 5, further comprising processing the cooled
mixture to achieve a mean particle diameter of less than 2
inches.
8. The method of claim 1, wherein the one or more active
ingredients comprises one or more of estradiol, ethinyl estradiol,
etonogestrel, progesterone, ethisterone, norethisterone acetate,
norethynodrel, levonorgestrel, or gestodene.
Description
BACKGROUND
[0001] This application claims benefit of U.S. Provisional
Application No. 62/047,344, filed on Sep. 9, 2014 and which
application is incorporated herein by reference. A claim of
priority is made.
[0002] Solid drug delivery implants are utilized to provide
sustained release of an active agent or drug over a period of days,
weeks, months, or years as an attractive alternative to more
conventional dosage forms, such as oral or parenteral dosages. A
few examples of such products include subcutaneous "rod" implants,
intrauterine devices, and intravaginal rings (IVRs). In order to
provide consistent and constant drug release rates a preferred
approach is to embed the drug within a polymer matrix of material
and encapsulate it within a polymer membrane or sheath to provide a
barrier for controlled drug diffusion and release. Typically the
drug is incorporated into the polymer by a hot melt extrusion
process to produce drug-doped pellets. These pellets are then
extruded to form the drug-filled core, and a rate-controlling
sheath is coextruded over the drug-filled core. Drug-filled cores,
and appurtenant sheaths, are extruded in lengths, typically with
circular cross-sections. When continuous implant shapes are
desired, the sheathed cores must be cut to length and the ends must
be welded together.
[0003] In cases where a very thin (<0.5 mm, frequently 0.10 mm
or less) sheath thicknesses are advantageous or required, control
of thickness during extrusion can be problematic and required
expensive in-line process control and equipment. The extrusion
process also subjects the drug to significant thermal loads which
can cause a range of deleterious effects, including chemical
degradation of the drug and/or matrix and sheath components,
crystallization within the polymer matrix. Further, the process
often demands relatively large amounts of material resulting in
wasted active ingredients and polymer material. Additionally,
coextrusion equipment and subsequent process steps (e.g. welding
into rings) can also be expensive and engender process
inefficiency.
SUMMARY
[0004] In general, this disclosure describes techniques for
manufacturing active ingredient cores. Techniques further describe
methods for laminating active ingredient cores to form a
rate-controlling sheath. In particular, this disclosure describes
techniques for manufacturing subcutaneous implants, intrauterine
devices, and intravaginal rings (IVRs), although it should be noted
that the techniques of this disclosure are generally applicable to
pharmacologically active implants.
[0005] According to an example of the disclosure, a method of
forming a pharmacologically active homogenous core matrix mixture
comprises combining one or more polymers with one or more active
ingredients to form a mixture; and mixing the mixture sufficient to
impart heat and until a homogenous mixture is achieved; wherein
heat imparted to the mixture is sufficient to melt the polymer
without substantially altering the pharmacological properties of
the active ingredient.
[0006] According to another example of the disclosure, a method of
forming a rate-controlling release membrane over a
pharmacologically active core comprises positioning a core between
two layers film; applying one or more of heat and pressure to the
core and film layers such that each film layer mechanically
combines with one or more of the ring-shaped core and the opposite
membrane film; and trimming excess film to form a sheath having a
substantially uniform thickness.
[0007] The details of one or more examples are set forth in the
accompanying drawings and the description below. Other features,
objects, and advantages will be apparent from the description and
drawings, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The accompanying drawings illustrate non-limiting example
embodiments of the invention.
[0009] FIG. 1 illustrates a cross sectional side view of a
ring-shaped implant, according to one or more embodiments of this
disclosure.
[0010] FIG. 2 illustrates a method for forming an inner core,
according to one or more embodiments of this disclosure.
[0011] FIG. 3A illustrates a method for laminating an inner core,
according to one or more embodiments of this disclosure.
[0012] FIG. 3B illustrates a perspective view of an inner core
being positioned between sheath materials, according to one or more
embodiments of this disclosure.
[0013] FIG. 3C illustrates a perspective view of a post-combining
product, according to one or more embodiments of this
disclosure.
[0014] FIG. 3D illustrates a cross-sectional view of a
post-combining product, according to one or more embodiments of
this disclosure.
[0015] FIG. 3E illustrates a cross-sectional view of a
post-combining product with excess material identified, according
to one or more embodiments of this disclosure.
DETAILED DESCRIPTION
[0016] The present invention is described with reference to the
attached figures, wherein like reference numerals are used
throughout the figures to designate similar or equivalent elements.
The figures are not drawn to scale and they are provided merely to
illustrate the invention. Several aspects of the invention are
described below with reference to example applications for
illustration. It should be understood that numerous specific
details, relationships, and methods are set forth to provide an
understanding of the invention. One skilled in the relevant art,
however, will readily recognize that the invention can be practiced
without one or more of the specific details or with other methods.
In other instances, well-known structures or operations are not
shown in detail to avoid obscuring the invention. The present
invention is not limited by the illustrated ordering of acts or
events, as some acts may occur in different orders and/or
concurrently with other acts or events. Furthermore, not all
illustrated acts or events are required to implement a methodology
in accordance with the present invention.
[0017] This disclosure provides novel solid drug delivery implants
and methods of manufacture therefor. As used herein, "implants" can
refer to an object which contacts the body of an animal or human,
or an object which is positioned within an organ or an orifice. For
example, an implant can be positioned within a mouth, within a
vagina, underneath an epidermis, or within a uterus. Examples of
bodily positions are non-limiting; embodiments provided herein can
be utilized throughout a body as necessary or advantageous.
Implants can include subcutaneous implants, intrauterine devices,
and intravaginal rings (IVRs).
[0018] FIG. 1 illustrates a cross-sectional side view of an implant
100, comprising an inner core 110 and a rate-controlling sheath
120. Inner core 110 can comprise one or more polymer excipients and
at least one active ingredient. The polymer fraction forms a matrix
throughout which the one or more active ingredients are dispersed.
In many embodiments, the active ingredient is substantially
uniformly dispersed, such as having a material uniformity less than
+/-5%, less than +/-4%, less than +/-3%, less than +/-2%, or less
than +/-1%. Polymers can include thermoplastics such as
thermoplastic urethanes, polyethylene terephthalate polyesters,
silicone thermoplastics, LTV silicone elastomers, and polyamides.
Specific examples of polymers can include polyoxymethylene,
thermoplastic copolyester elastomer (TPC-ET), polyethylene
homopolymer, poly(vinyl acetate) homopolymer, poly(lactic acid)
homopolymer, poly(caprolactone), polypropylene, poly(ethylene
oxide), poly(styrene), poly(vinyl chloride) poly lactic-co-glycolic
acid, and ethylene vinyl acetate (EVA). EVA comprises ethylene and
vinyl acetate, with a weight percent (wt. %) of vinyl acetate
ranging from about 5 wt. % to about 40 wt. %, about 7 wt. % to
about 34 wt. %, or about 9 wt. % to about 28 wt. %.
[0019] Active ingredients can include any pharmacologically active
agents, such as contraceptive hormones. Contraceptive hormones can
include estradiol, ethinyl estradiol, etonogestrel, progesterone,
ethisterone, norethisterone acetate, norethynodrel, levonorgestrel,
or gestodene, although others are similarly suitable as would be
recognized by one of skill in the art after review of this
disclosure. Inner core 110 can further comprise opacifiers, such as
barium sulfate, or dyes.
[0020] Inner core 110 can have a cross-sectional shape which is
circular, or polygonal. In some embodiments, a cross-sectional
shape is chosen to accommodate manufacturing processes or
equipment. The overall shape of the inner core 110 can be tubular
or rod shaped, or a continuous shape. A continuous shape can
include a circle, oval, triangle, square, or other polygons. Shapes
can include a mixture of straight and curved edges, such as a
semi-circle. Shapes can include irregular geometries which can be
in some embodiments designed to match the contour of an implant
positioning location within a body.
[0021] Rate-controlling sheath 120 can comprise one or more
polymers, such as those suitable for the inner core 110.
Rate-controlling sheath 120 can comprise a similar composition to
the polymer fraction of the inner core 110. In some embodiments,
rate-controlling sheath 120 and inner core 110 share at least one
common polymer component. Composition of the rate-controlling
sheath can be determined based on permeability of one or more
active ingredients. In some embodiments, the compositions of the
rate-controlling sheath 120 is selected such that the rate
controlling-sheath 120 can melt. Accordingly, in some embodiments,
polymers such as silicone are not suitable for the rate-controlling
sheath 120. In some embodiments, the rate-controlling sheath has a
thickness of between about 1 mil to about 25 mils (about 0.0254 mm
to about 0.635 mm).
[0022] As shown in FIG. 2, a method 200 of forming an inner core
can comprise low-heat mixing 210 inner core components to form a
mixture, processing 220 the mixture after mixing, and forming the
inner core 230. Inner core components can be supplied for mixing in
powdered, pelleted, or liquid forms. One or more objectives of
mixing 210 include removing air bubbles from the mixture,
homogenizing the mixture to achieve suitable uniformity, elevating
the temperature of the mixture above a melting point of at least
one polymer. "Melting point" as used herein can refer to a melting
point or a glass transition temperature. Homogenizing the mixture
includes evenly dispersing the one or more active ingredients
throughout the mixture. Mixing 210 can be accomplished via
asymmetric mixing, wherein friction of mixing imparts heat on the
mixture such that at least one polymer exceeds its melting
point.
[0023] Asymmetric mixing advantageously imparts sufficient heat
onto the mixture, while the heat of the mixture remains below a
damaging heat threshold. Active ingredients, such as estradiol, can
be heat sensitive, and appreciable chemical degradation of an
active ingredient can define a damaging heat threshold. Asymmetric
mixing is contactless, and relies on the movement of the vessel to
initiate rapid spinning and shearing of a mixture contained within
a vessel. As used herein, "contactless" describes the relationship
between a mixture and a mixer wherein the only component contacting
the mixture is the vessel. This is in contrast to other mixing
methods, which use paddles, screws, or other mixing elements to
which contact and mix a mixture. Asymmetric mixing can include dual
asymmetric mixing. Speed and duration of mixing is controlled to
achieve mixing objectives.
[0024] An advantage of this approach is that a range of mix sizes
is easily attainable by choosing the appropriate mix vessel for the
mix size and cleaning can be minimized or eliminated entirely due
to minimal contact surfaces. In some cases the heat and shear loads
on fragile polymers or active ingredients can be reduced relative
to other methods due to the rapid mixing. Vessels can be composed
of a range of materials, including polypropylene, thermoplastic
polyurethanes, glass, metals such as stainless steel or aluminum,
polyethylene, polytetrafluoroethylene, or other suitable container
materials. The vessel can comprise a number of materials which are
disposable or reusable. Dual planetary mixers can be used. Examples
of mixers include FlackTek SpeedMixers.TM. and Thinky mixers.
[0025] Processing 220 can include allowing the mixture to cool
under ambient conditions, or cooling the mixture using
refrigerants, liquid nitrogen, or the like. Processing 220 can
further comprise forming the cooled mixture into powders, granules,
pellets, or pieces. An objective of processing 220 is to achieve a
particle size which is suitable for forming 230 the inner core. In
some embodiments a suitable particle diameter is less than 3
inches, less than 2 inches, or less than 1 inch. Forming the inner
core 230 can comprise injection molding, although other methods can
be suitable. An objective of forming the inner core 230 includes
remaining below a damaging heat threshold.
[0026] As shown in FIG. 3A, a method 300 of laminating an inner
core can comprise positioning 310 an inner core between two
surfaces of rate-controlling sheath material, combining 320 the
inner core and sheath material, and trimming 330 excess sheath
material. FIG. 3B shows an inner core 110 being positioned 310
between sheath materials 121 and 122. Sheath materials, such as 121
and 122, can be supplied in films with varying thicknesses. In some
embodiments, sheath materials comprise a single sheet (not picture)
which is folded about an inner core 110. Combining 320 the inner
core and sheath material can comprise thermal and/or pressure
lamination.
[0027] The use of lamination to create dosage forms for
pharmaceuticals is novel in the industry, as coextrusion has been
the manufacturing method of choice due to familiarity of the
technology. In instances where lamination has been employed, the
same has been used solely to affect surfaces properties (e.g.,
wear, resistance, feel, etc.) of products. Lamination can be
preferable to coextrusion as it is time efficient, heat and
material efficient, and allows for superior operating temperature
management and control and uniformity of sheath thickness.
Controlling sheath uniformity and thickness is critical as it
directly impacts drug release rates and overall implant efficacy
and safety. Lamination additionally allows for thinner sheaths to
be manufactured, increasing functionality of implants (e.g., drug
release rates and use duration). Further, lamination encapsulates
an inner core ring as a whole, rather than utilizing a welded joint
which can affect drug release rate.
[0028] Lamination according to method 300 can be conducted at high
pressures, such as at 15 to 20 tons of force. Temperature can
include temperatures above the film material's melting point. For
example, when EVA is a film component, temperatures of 100-120 C
can be used. In many embodiments, an operating temperature exceeds
the melting point of one or more polymers by less than about 1% of
the melting point temperature, less than about 2.5% of the melting
point temperature, less than about 5% of the melting point
temperature, or less than about 10% of the melting point
temperature. When one or more films contain multiple polymer
components, a temperature can be chosen to exceed the melting point
of one polymer component, of a plurality of polymer components, or
all polymer components. A temperature can also be chosen such that
the melting point of a core component is not exceeded. When a
temperature is used which exceeds the melting point of a core
component, lamination process time and/or compressing pressure can
be chosen to complement the process temperature in order to avoid
chemical degradation and/or physical deformation of the core. Films
can combine by one or more of adhering to the opposite film, or
adhering to the inner core 110.
[0029] FIG. 3C illustrates a post combining 320 product 325. FIG.
3D illustrates a cross-sectional view of a post-combing 320 product
325 which comprises an inner core 110 and a rate-controlling sheath
120. FIG. 3E illustrates a cross-sectional view of a post-combining
320 product 325, wherein excess sheath material 125 is identified.
Excess material 125 can be defined as material not substantially
contributing to an extrapolated contour of the core. Excess
material can also be defined as material which does not provide a
consistent sheath thickness. Trimming 330 excess sheath material
can be accomplished using a die cutting system, or other suitable
means.
EXAMPLE
Manufacture of Prototype Vaginal Ring for Contraception
[0030] Approximately 50 g of ethylene vinyl acetate (28% vinyl
acetate content) polymer (pellets or granules) was measured into a
150 mL cylindrical container after which 50-250 mg of sex hormones
such as ethinyl estradiol and/or etonorgestrel powder or opacifier
such as barium sulfate were added. The container was placed in a
dual asymmetric mixer (Flaktek SpeedMixer) and mixed for 2-10
minutes at up to 3000 RPM. Upon removal the EVA had melted
(estimated temperature 100-120.degree. C.) and the drug was
uniformly dispersed throughout the melt. Drug content analysis
performed using inductively coupled plasma--optical emission
spectroscopy revealed that material uniformity was approximately
+/-2%.
[0031] After the melt was allowed to cool, the material was
processed into granular materials suitable for injection molding by
cooling the polymer and processing using with an IKA bladed mill.
When EVA was used, the polymer was cooled using liquid nitrogen
before and/or during milling. Following milling, particle size was
generally less than 0.75 in diameter, though many smaller particles
were present.
[0032] After milling, this ground material was transferred to an
injection molding press and vaginal ring cores with an outer
diameter of .about.55 mm and a cross section diameter of .about.5
mm were molded at approximately 175.degree. C. and at .about.5 tons
of pressure. The mold was held at .about.60.degree. C. during the
molding operation and was further cooled 30-40.degree. C. with or
without a chiller after injection over .about.5 minutes prior to
removal of the ring. The ring was then placed between two sheets of
EVA film (4-5 mils thick, 9% vinyl acetate content), placed in a
mold and compressed at 15-20 tons of force at temperatures
sufficient to adhere the laminating layers to one another and the
core ring (generally at 100-120.degree. C. for EVA). Excess
material was cut and trimmed, leaving a core-sheath ring.
[0033] The photographs below shows the overall ring prior to
trimming as well as a cross section showing the distinct core and
sheath domains. The cutting and trimming operating is ultimately
expected to be carried out using an automated die cutting system.
Much larger batches of material (up to 5 kg) can be mixed at a time
using scaled up dual asymmetric planetary mixing equipment and
different geometries are accessible using appropriate molds (for
example, rod-shaped) and the same fundamental molding and
lamination process. Additionally, it is anticipated that the same
process should also be applicable to other thermoplastic
elastomers, particularly thermoplastic polyurethanes.
* * * * *