Biomedical foams
阅读说明：本技术 生物医用泡沫 (Biomedical foams ) 是由 J·J·雅各布斯 C·斯坦利 于 2018-12-20 设计创作，主要内容包括：本公开提供了一种用于向鼻腔局部地施用活性剂并用于吸收流体排放物的泡沫鼻部敷料。该泡沫鼻部敷料包括发泡芯部和发泡壳体部,该发泡壳体部被设置成使得发泡芯部被至少部分地放置在发泡壳体部内。发泡壳体部具有大于80％的孔隙率并且包括第一相分离聚合物和活性剂。发泡芯部包括第二相分离聚合物,其中,第一相分离聚合物和第二相分离聚合物是相同的或不同的。本公开还提供了一种形成泡沫鼻部敷料的方法。(The present disclosure provides a foam nose dressing for topically applying an active agent to the nasal cavity and for absorbing fluid discharges. The foam nose dressing includes a foam core portion and a foam shell portion that is configured such that the foam core portion is at least partially disposed within the foam shell portion. The foaming shell portion has a porosity greater than 80% and includes a first phase separated polymer and an active agent. The foamed core comprises a second phase separating polymer, wherein the first phase separating polymer and the second phase separating polymer are the same or different. The present disclosure also provides a method of forming a foam nose dressing.)
1. A foam nose dressing for topically applying a medicament to a nasal cavity and for absorbing fluid discharge, the nose dressing comprising:
a foamed core comprising a first polyurethane, the foamed core comprising an amorphous segment and a crystalline segment and a hemostatic agent;
a foamed housing portion disposed such that the foamed core is at least partially disposed within the foamed housing portion, the foamed housing portion having a porosity greater than 80% and comprising a second polyurethane, the foamed housing portion comprising an amorphous segment and a crystalline segment, wherein the first polyurethane and the second polyurethane are the same or different;
a medicament placed in the foamed housing portion; and
the nasal dressing has an elongated shape extending from a first end to a second end, the nasal dressing having a first half adjacent to the first end and a second half adjacent to the second end, wherein a weight of the medicament in the first half of the foam nasal dressing is greater than a weight of the medicament in the second half of the foam nasal dressing.
2. The foam nose dressing of claim 1, wherein the medicament comprises a steroid and the foam shell portion comprises the steroid, and the foam core is substantially free of the steroid.
3. The foam nose dressing of claim 2, wherein the steroid includes at least one hydrogen atom bonded to a nitrogen, oxygen, or fluorine atom that is available to form hydrogen bonds with crystalline segments of the foaming shell portion.
4. The foam nose dressing of any preceding claim, wherein the foamed shell portion and the foamed core portion are bonded to each other via hydrogen bonding and have substantially no covalent bonds therebetween.
5. The foam nose dressing of any preceding claim, wherein the crystalline segments in the first polyurethane and/or the second polyurethane comprise the reaction product of 1, 4-butanediol and 1,4 isocyclohexylimide.
6. The foam nose dressing of claim 1, wherein molecules within the first and/or second polyurethane foam are arranged such that the crystalline segments and the amorphous segments are stacked in an alternating configuration, providing a three-dimensional cellular structure that is enhanced via hydrogen bonding between stacked crystalline segments.
7. The foam nose dressing of any preceding claim, wherein the foam core portion comprises the medicament at a first concentration and the foam housing portion comprises a second medicament at a second concentration that is the same or different from the medicament.
8. The foam nose dressing of any preceding claim, wherein the foam nose dressing further comprises a foam base at the second end, the foam shell portion and the foam core portion extending from the foam base toward the first end.
9. The foam nose dressing of any preceding claim, wherein the foam base portion and the foam housing portion cooperate to enclose the foam core portion and define an outer surface of the nose dressing.
10. The foam nose dressing of any preceding claim, wherein the first half comprises 50% of the volume of the first end and the foam nose dressing, and the second half comprises the remaining 50% of the volume of the second end and the foam nose dressing.
11. The foam nose dressing of any one of claims 8-10, wherein the foamed base and the foamed core are integral.
12. The foam nose dressing of any preceding claim, wherein the foamed core portion and/or the foamed shell portion comprises a hemostatic agent.
13. The foam nose dressing of claim 12, wherein the hemostatic agent includes at least one hydrogen atom bonded to a nitrogen atom and at least one hydrogen atom bonded to an oxygen atom, the hydrogen atoms operable to form hydrogen bonds with crystalline segments of the first and/or second polyurethane foams.
14. The foam nose dressing of claim 13, wherein molecules of the hemostatic agent and molecules of the second polyurethane foam are bonded to each other via hydrogen bonding and have substantially no covalent bonds therebetween.
15. The foam nose dressing of any one of claims 12-14, wherein the hemostatic agent is insoluble in the first polyurethane foam and/or the second polyurethane foam, and the drug is a steroid that is insoluble in the first polyurethane foam and/or the second polyurethane foam.
16. The foam nose dressing of any preceding claim, wherein the foam dressing does not have any internal cavity.
17. The nasal dressing of any preceding claim, wherein the first polyurethane foam and/or the second polyurethane foam is bioabsorbable.
18. The foam nose dressing of any preceding claim, wherein the volume of the foamed shell portion is from about 20% to about 40% of the total volume of the foam nose dressing.
19. The foam nose dressing of any preceding claim, wherein the foam core is placed entirely within the foam housing portion.
20. The foam nose dressing of any preceding claim, wherein the foamed core is cylindrical.
21. The foam nose dressing of any preceding claim, wherein the cross-section of the foamed shell portion has a square or rectangular shape and the same shape as the cross-section of the foamed base portion.
22. The foam nose dressing of any preceding claim, wherein the foamed core has a porosity of greater than 80%.
23. A method of forming a foamed nose dressing for topically applying a medicament to a nasal cavity and for absorbing fluid discharge, the method comprising:
providing a mould;
placing a spacer in the mold;
placing a first liquid comprising a first polyurethane and a drug in the mold, the first polyurethane;
wherein the first liquid and the spacer are in contact in the mold;
cooling the first liquid to freeze the first liquid;
removing the spacer from the frozen first liquid to expose a cavity in the frozen first liquid;
placing a second liquid comprising a second polyurethane and a hemostatic agent in the cavity of the frozen first liquid;
cooling the second liquid to freeze the second liquid; and
drying the frozen first liquid and the frozen second liquid to form the foam nose dressing.
24. The method of claim 23, wherein placing the second liquid in the cavity of the frozen first liquid is further defined as overflowing the cavity of the frozen first liquid with the second liquid.
25. The method of claim 24, wherein drying the frozen second liquid forms the foam core and forms a foam base such that the foam core and foam shell portions extend from the foam base.
26. The method of claim 25, wherein the foam base portion and the foam housing portion cooperate to enclose the foam core and define an outer surface of the foam nose dressing.
27. The method of any one of claims 23 to 26, wherein the foamed core portion is cylindrical and the foamed shell portion has a square or rectangular shape in cross-section.
28. The method of any one of claims 23-27, wherein the foaming housing portion is the only portion of the foam nasal dressing that contains the medicament.
29. A method of simultaneously treating inflammation and absorbing fluid discharges from the nasal cavity using a foam nasal dressing, the method comprising:
providing a foam nose dressing comprising:
a foamed core comprising a first phase separated polymer and a hemostatic agent;
a foaming housing portion configured such that the foaming core is at least partially disposed within the foaming housing portion, the foaming housing portion having a porosity of greater than 80% and comprising a second phase separating polymer, wherein the first phase separating polymer and the second phase separating polymer are the same or different;
wherein the nasal dressing has an elongated shape extending from a first end to a second end, the nasal dressing having a first half adjacent to the first end and a second half adjacent to the second end, the weight of the medicament in the first half of the foam nasal dressing being greater than the weight of the medicament in the second half of the foam nasal dressing;
compressing the foam nose dressing such that the foam dressing assumes an insertion configuration; and
positioning the foam nose dressing within the nasal cavity when the foam nose dressing is in the insertion configuration such that the second end of the foam nose dressing is further away from the user than the first end.
30. An elongate foam nose dressing for topical administration of a medicament to the nasal cavity and for absorbing fluid discharge, the foam nose dressing comprising:
a first foam having a porosity of greater than 80% and comprising a foamed base at a first end of the foam nose dressing and a foamed core extending from the foamed base toward a second end of the foam nose dressing, the foamed core comprising a first phase separated polymer comprising an amorphous segment and a crystalline segment; and
a second foam having a porosity of at least 80% and comprising a foamed housing portion extending from the foamed base portion to the second end, the foamed housing portion comprising a second phase separating polymer and a drug, the second phase separating polymer comprising amorphous and crystalline segments;
wherein the foam base and foam housing portions cooperate to enclose the foam core and define an outer surface of the nasal dressing;
wherein the first phase separating polymer and the second phase separating polymer are the same or different; and
wherein the foam nose dressing comprises the medicament in a volume defining the second end and does not comprise the medicament in a volume defining the first end.
31. The foam nose dressing of claim 30, wherein each of the first and second phase-separating polymers respectively corresponds to the formula:
-[R-Q1[-R′-Z1-[R"-Z2-R′-Z3]p-R"-Z4]q-R′-Q2]n- (I)
wherein R is selected from one or more aliphatic polyesters, polyetheresters, polyethers, polyanhydrides and/or polycarbonates, and optionally at least one R comprises a hydrophilic segment, R 'and R' are each independently C2-C8 alkylene optionally substituted with C1-C10 alkyl or C1-C10 alkyl group, with halide or protected S, N, P or O moieties and/or containing S, N, P or O in the alkylene chain, Z1-Z4 are each amide, urea or polyurethane, Q1 and Q2 are each urea, polyurethane, amide, carbonate, ester or anhydride, n is an integer from 5 to 500, p and Q are each 0 or 1, with the proviso that when Q is 0, r is at least one amorphous aliphatic polyester, polyether, polyanhydride and/or polycarbonate segment, optionally at least one crystalline polyether, polyester, polyetherester or polyanhydride segment.
32. The foam nose dressing of claim 30 or 31, wherein the foam shell portion and the foam core portion are bonded to each other via hydrogen bonding and have substantially no covalent bonds therebetween.
33. The foam nose dressing of any one of claims 30-32, wherein the first phase-separating polymer and/or the second phase-separating polymer comprise crystalline segments comprising the reaction product of 1, 4-butanediol and 1, 4-isocyclohexylimide.
34. The foam nose dressing of any one of claims 30-33, wherein the foamed core portion and/or the foamed shell portion comprises a hemostatic agent.
35. The foam nasal dressing of claim 34, wherein the hemostatic agent comprises at least one hydrogen atom bonded to a nitrogen atom and at least one hydrogen atom bonded to an oxygen atom, the hydrogen atoms operable to form hydrogen bonds with the first phase separating polymer and/or the second phase separating polymer.
36. The foam nasal dressing of claim 35, wherein molecules of the hemostatic agent and molecules of the first phase-separating polymer and/or the second phase-separating polymer are bonded to each other via hydrogen bonding and have substantially no covalent bonds therebetween.
37. The foam nasal dressing of any one of claims 30-35, wherein the drug is a steroid and the foam core is substantially free of the steroid.
38. The foam nasal dressing of claim 37, wherein the steroid includes at least one hydrogen atom bonded to a nitrogen, oxygen, or fluorine atom, the atom operable to form hydrogen bonds with the crystalline segments of the foamed shell portion.
39. The foam nasal dressing of claim 37, having:
the foam base being positioned at a first end of the nasal dressing and the foam core extending from the foam base toward a second end of the nasal dressing;
a steroid disposed in the foamed housing portion; and
chitosan placed in the foam core;
wherein the foam nose dressing comprises the steroid in a volume defining the second end and does not comprise the steroid in a volume defining the first end; and
wherein the foam nose dressing comprises the chitosan in a volume defining the first end and does not comprise the hemostatic agent in a volume defining the second end.
40. An elongate foam nasal dressing for topical administration of a medicament to the nasal cavity and for absorbing fluid discharge, the nasal dressing comprising:
a first foam having a porosity greater than 80% and comprising a foamed base at a first end of the nose dressing and a foamed core extending from the foamed base toward a second end of the nose dressing, the foamed core comprising a first phase separated polymer and a chitosan hemostatic agent; and
a second foam having a porosity of at least 80% and comprising a foamed shell portion extending from the foamed base portion to the second end, the foamed shell portion comprising a second phase separating polymer and a drug;
wherein the foam base and foam housing portions cooperate to enclose the foam core and define an outer surface of the nasal dressing;
wherein the first phase separating polymer and the second phase separating polymer are the same or different;
wherein the foam nose dressing contains a medicament in a volume defining the second end and does not contain the medicament in a volume defining the first end; and
wherein the foam nose dressing comprises the chitosan hemostatic agent in a volume defining the first end and does not comprise the chitosan hemostatic agent in a volume defining the second end.
Technical Field
The present disclosure relates to a biomedical foam article (e.g., a foam nose dressing) and a method of forming the biomedical foam article.
Disclosure of Invention
An exemplary foam nose dressing for topical administration of a medicament to the nasal cavity and for absorbing fluid discharge is provided. The foam nose dressing includes a foam core portion and a foam shell portion that is configured such that the foam core portion is at least partially disposed within the foam shell portion. The foamed core comprises a first polyurethane and includes amorphous and crystalline segments and a hemostatic agent. The foaming shell portion has a porosity greater than 80%, includes a second polyurethane, and includes amorphous and crystalline segments and a drug. In this example, the first polyurethane and the second polyurethane may be the same or different. The nasal dressing has an elongated shape extending from a first end to a second end. The first half is adjacent to the first end and the second half is adjacent to the second end, wherein the weight of the medicament in the first half of the foam nose dressing is greater than the weight of the medicament in the second half of the foam nose dressing.
In another example, a foam nose dressing for topically applying a medicament to a nasal cavity and for absorbing fluid discharge is elongate and includes a first foam and a second foam. The first foam has a porosity of greater than 80% and includes a foamed base at a first end of the foam nose dressing and a foamed core extending from the foamed base toward a second end of the foam nose dressing. The foamed core includes a first phase separated polymer including amorphous segments and crystalline segments. The second foam has a porosity of at least 80% and includes a foamed shell portion extending from the foamed base portion to the second end. The foamed shell portion includes a second phase separated polymer including amorphous segments and crystalline segments. In this example, the first phase separating polymer and the second phase separating polymer are the same or different. The foam base and foam shell portions cooperate to enclose the foam core and define the exterior surface of the nasal dressing. The foam nose dressing of this example contained a medicament in the volume defining the second end and no medicament in the volume defining the first end.
In yet another example, a foam nose dressing for topically applying a medicament to a nasal cavity and for absorbing fluid discharge includes a first foam and a second foam. The first foam has a porosity greater than 80% and includes a foam base at a first end of the nose dressing and a foam core extending from the foam base toward a second end of the nose dressing. The foamed core includes a first phase separated polymer and a chitosan hemostatic agent. The second foam has a porosity of at least 80% and includes a foamed shell portion extending from the foamed base portion to the second end. The foaming shell portion includes a second phase separating polymer and a medicament. In this example, the first phase separating polymer and the second phase separating polymer are the same or different. The foam base and foam shell portions cooperate to enclose the foam core and define the exterior surface of the nasal dressing. The foam nose dressing contains a medicament in the volume defining the second end and no medicament in the volume defining the first end. Further, the foam nose dressing includes a chitosan hemostatic agent in the volume defining the first end and no chitosan hemostatic agent in the volume defining the second end.
Also provided is a method of forming a foamed nose dressing for topically applying a medicament to the nasal cavity and for absorbing fluid discharges. The method includes providing a mold. The method also includes placing the spacer and the first liquid in a mold such that the first liquid and the spacer are in contact in the mold. The first liquid includes a first polyurethane and a drug. The method also includes cooling the first liquid to freeze the first liquid and removing the spacer from the frozen first liquid to expose the cavity in the frozen first liquid. The method also includes placing a second liquid in the cavity of the frozen first liquid. The second liquid comprises a second polyurethane that is the same or different from the first polyurethane. The method also includes cooling the second liquid to freeze the second liquid. The method also includes drying the frozen first liquid and the frozen second liquid to form a foam nose dressing that includes a foam core disposed at least partially within a foam housing portion.
Also disclosed is a method of simultaneously treating inflammation and absorbing fluid discharge from the nasal cavity using a foam nasal dressing. The method comprises the following steps: providing a foam nose dressing; compressing the foam nose dressing such that the foam assumes an insertion configuration; and positioning the foam nose dressing within the nasal cavity such that the second end of the foam nose dressing is further from the user than the first end when the foam nose dressing is in the insertion configuration.
Drawings
Advantages of the present disclosure will be readily understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
FIG. 1A is a perspective view of an example of a foam nose dressing;
FIG. 1B is a perspective view of the example of FIG. 1A along line BC, with the foaming housing portion shown in cross-section;
FIG. 1C is a cross-sectional view of the example of FIGS. 1A and 1B along line BC;
FIG. 2 is a top left side perspective view of an example of a foam nose dressing, with the foaming housing portion shown in cross-section;
FIG. 3 is a cross-sectional view of another example of a foam nose dressing;
FIG. 4 is a cross-sectional view of another example of a foam nose dressing;
FIG. 5 is a cross-sectional view of another example of a foam nose dressing;
FIG. 6 is a cross-sectional view of another example of a foam nose dressing;
FIG. 7 is a perspective view of the mold and spacer;
FIG. 8 is a cross-sectional view of the mold and spacer of FIG. 7;
FIG. 9 is a cross-sectional view of the mold of FIG. 8 including a frozen first liquid;
FIG. 10 is a cross-sectional view of the mold of FIG. 9 further including a frozen second liquid; and
FIG. 11 is a flow chart showing steps included in a method of simultaneously treating inflammation and absorbing fluid discharge from the nasal cavity with a foam nose dressing.
Detailed Description
In one example, the biomedical foam is a foam nose dressing for topically applying an active agent to the nasal cavity and for absorbing fluid discharge. As shown in fig. 1-6, the
In the context of the present disclosure, "being at least partially disposed within …" requires that some volume of the foaming
Of course, the
In many examples, the foam nose dressing 10 does not have any internal cavity. That is, the foam nose dressing 10 is substantially free of large voids (except for the relatively fine void/cell structure of the foam forming the foam nose dressing 10).
Referring now to the example of fig. 1-6, the foam nose dressing 10 of this example has an elongated shape extending from a distal or
Referring back to foaming
The foaming
As best shown in fig. 1A-C, the geometry of the foamed
In certain examples, such as those shown in fig. 1A-C, 5, and 6, when 100% of the foamed
Of course, when less than 100% of the foamed
Although the relative volume of the foamed
Referring now to the foamed
The porosity of the foamed
In examples where the foaming
The geometry of the foamed
Referring now to the
The foamed
The geometry of the foamed
In the example where the foamed
The foaming
Referring now to the first phase separating polymer, the second phase separating polymer and the third phase separating polymer, the term "phase separating polymer" as used herein refers to a polymer comprising a soft (amorphous) segment and a hard (crystalline) segment, the hard segment having a phase transition temperature of at least the body temperature of a mammal (typically 37 ℃ for humans) and exhibiting a phase separated morphology when a foam made from such a polymer is applied in the human or animal body for a sufficient period of time. In addition, polymers placed under temperature conditions comparable to those of the human or animal body exhibit phase separated morphology. Phase separated polymers are characterized by the presence of at least two immiscible or partially miscible phases having different morphologies under normal environmental conditions. Within one material, a rubber phase and a crystalline phase (at a temperature above the glass transition temperature of the amorphous phase and below the melting temperature of the crystalline phase) may be present or may be a glass phase and a crystalline phase (at a temperature below the glass transition temperature of the amorphous phase). Additionally, at least two amorphous phases may exist at temperatures between two phase transitions (e.g., one glass phase and one rubber phase). At temperatures above the highest phase transition, which is the melting or glass transition temperature, the liquid phase and the rubber phase or the two rubber phases, respectively, may form a phase-mixed morphology, or they may still be immiscible. The immiscible liquid and/or rubber phases generally result in a polymer having a phase separated morphology without the initial desired mechanical properties under normal environmental conditions.
The first phase separating polymer, the second phase separating polymer, and the third phase separating polymer may each be individually selected from the group consisting of polyesters, polyethers, polyhydroxy acids, polylactones, polyetheresters, polycarbonates, polydioxanes, polyanhydrides, polyurethanes, polyester (ether) polyurethanes, polyurethane ureas, polyamides, polyesteramides, polyorthoesters, polyaminoacids, polyphosphonates, polyphosphazenes, and combinations thereof. Such polymers are described in WO-A-99/64491, the entire content of which is incorporated herein by reference.
Without being bound by any particular theory, it is believed that the first phase separated polymer of the foamed
In certain examples, at least the
The term "biodegradable" as used herein refers to the ability of a polymer to act thereon, typically biochemically by living cells, organisms or parts of these systems, which includes hydrolysis as well as degradation and breakdown into chemical or biochemical products.
The term "bioresorbable" as used herein refers to the ability to be metabolized entirely by the human or animal body.
The term "amorphous" as used herein refers to segments present in a phase separated polymer wherein at least one glass transition temperature is lower than the temperature of the cavity into which the foam of the human or animal body is packed, and may also refer to a combination of amorphous and crystalline segments that are completely amorphous when packed in the human or animal body. For example, the PEG in the prepolymer may be crystalline in pure form, but when included in the R-block of the polyurethane of formula (I), it may be amorphous. The longer PEG segment may also be partially crystalline when included in the R segment of the polyurethane of formula (I), but will become amorphous ("dissolve") when placed in contact with water. Thus, such longer PEG segments are part of the soft segments of the phase separated polymer of formula (I), while the hard segments should remain crystalline in nature to provide sufficient support for the particular foam portion in a wet and packed state, at least for some time.
The term "crystalline" as used herein refers to segments that are crystalline when packed in a human or animal body, i.e., having a melting temperature that is higher than the temperature of the cavity into which the foam nose dressing 10 of the human or animal body is packed, that exist in phase separation.
As used herein, "hydrophilic segment" refers to a segment comprising at least one, preferably at least two, more preferably at least three hydrophilic groups, such as may be provided by C-O-C or ether, chain links. Thus, the hydrophilic segment may be provided by a polyether segment. The hydrophilic segment may also be provided by a polypeptide, poly (vinyl alcohol), poly (vinyl pyrrolidone), or poly (hydroxymethyl methacrylate). The hydrophilic segment is preferably taken from polyethylene glycol, such as polyoxyethylene, polypropylene glycol or polybutylene glycol. The preferred hydrophilic segment is a polyethylene glycol (PEG) segment.
The term "segment" as used herein refers to a polymeric structure having any length. In the field of polymer technology, long polymeric structures are often referred to as blocks, while short polymeric structures are often referred to as blocks. These conventional meanings are all understood to be included in the term "segment" as used herein.
In one particular example of the present application, the polymer conforms to the formula:
-[R-Q1[-R′-Z1-[R"-Z2-R′-Z3]p-R"-Z4]q-R′-Q2]n-(I)
wherein R is selected from one or more aliphatic polyesters, polyetheresters, polyethers, polyanhydrides and/or polycarbonates, and optionally at least one R comprises a hydrophilic segment, R 'and R' are each independently C2-C8 alkylene optionally substituted with C1-C10 alkyl or C1-C10 alkyl group, with halide or protected S, N, P or O moieties and/or containing S, N, P or O in the alkylene chain, Z1-Z4 are each amide, urea or polyurethane, Q1 and Q2 are each urea, polyurethane, amide, carbonate, ester or anhydride, n is an integer from 5 to 500, p and Q are each 0 or 1, with the proviso that when Q is 0, r is at least one amorphous aliphatic polyester, polyether, polyanhydride and/or polycarbonate segment, optionally at least one crystalline polyether, polyester, polyetherester or polyanhydride segment.
The simplest form of a phase separated polymer as shown by formula I corresponds to the following formula: -R-Q1-R' -Q2-, i.e. when Q is 0.
The amorphous segments are contained in the-R-moiety of the polymer according to formula (I). In the case of Q ═ l, the moiety Ql [ -R ' -Zl- [ R "-Z2-R ' -Z3] p-R" -Z4] Q-R ' -Q2 of the polymer according to formula (I) represents a crystalline segment. In this particular case, amorphous and crystalline segments are alternated, thereby providing hard segments with uniform block length.
As described above, R may represent a mixture of two or more different types of aliphatic polyesters, polyetheresters, polyethers, polyanhydrides, and/or polycarbonates, the mixture including both amorphous and crystalline types, such that both are included in a particular foamed part. In case a mixture of amorphous and crystalline R segments is provided in the polymer according to formula (I), optionally at least one hydrophilic segment is provided in at least one amorphous R segment.
R may be taken in particular from the cyclic monomers lactide (L, D or LD), glycolide, -caprolactone, -valerolactone, trimethylcarbonate, tetramethylene carbonate, l, 5-dioxan-2-one, p-dioxanone and combinations thereof and optionally polyethylene glycol, polypropylene glycol, polybutylene glycol and combinations thereof. In certain examples, R is an amorphous polyester taken exclusively from lactide and caprolactone, having a molecular weight between 1000 and 4000. In one example, R is about 25% by weight lactide, about 25% by weight-caprolactone, and about 50% by mass polyethylene glycol.
In the phase separated polymer according to formula (I), Ql and Q2 may be selected from amide, urea, polyurethane, carbonate or anhydride groups, while Zl to Z4 should be selected from amide, urea or polyurethane groups, such that at least 4 hydrogen bond forming groups are present in line in the crystalline segment. The group R 'in-Z2-R' -Z3-may be different from or similar to-Ql-R '-Zl-or-Z4-R' -Q2-.
As mentioned, R optionally comprises hydrophilic segments, and such hydrophilic segments may very suitably be ether segments, such as polyether segments which may be taken from such polyether compounds (e.g. polyethylene glycol, polypropylene glycol or polytetramethylene glycol). In addition, the hydrophilic segment included in R may be taken from a polypeptide, poly (vinyl alcohol), polyvinylpyrrolidone, or poly (hydroxymethyl methacrylate). The hydrophilic segment is preferably a polyether, such as poly (ethylene glycol), polypropylene glycol, or poly (butylene) glycol.
In certain examples, the amorphous segments comprise hydrophilic segments. The hydrophilic segment may comprise polyethylene glycol in an amount of 1 to 80 wt.%, more preferably 5 to 60 wt.%, even more preferably 20 to 50 wt.%, and most preferably 50 wt.%, based on the total weight of the hydrophilic segment.
In certain examples, the phase separated polymer is a polymer according to formula I, wherein R' is (CH)2)4R' is (CH)2)4Or R 'and R' are both (CH)2)4,. For example, Z1-Z4 may be polyurethane.
It should be understood that the foams described herein are comprised of a plurality of polymer chains, wherein each polymer chain comprises a phase separated polymer, such as polyurethane. In many examples, the foam is substantially free of any covalent cross-linking between polymer chains contained in the foam. In the context of the present disclosure, the term "substantially free of any covalent cross-linking" means that one polymer chain has less than 20, less than 10, less than 6, less than 4, or less than 2 covalent bonds with other polymer chains comprised in the foam. In some examples, the foam does not have any covalent crosslinks between the polymer chains contained in the foam. In other words, each polymer chain is not covalently cross-linked to any other polymer chain contained in the foam.
In some preferred examples, the phase separated polymer is a polyurethane foam comprising amorphous and crystalline segments, the crystalline segments being formed via hydrogen bonding. In such an example, the crystalline segments may comprise the reaction product of 1, 4-butanediol and 1, 4-isocyclohexylimide, while the amorphous segments in the polyurethane foam may comprise polyalkylene glycols, such as poly (ethylene glycol), polyesters (e.g., polyglycolide), or a combination of both.
The term "hydrogen bonding" as used herein refers to the partial electrostatic attraction between a hydrogen (H) atom-hydrogen bond donor-bound to a more electronegative atom (e.g., nitrogen (N), oxygen (O), or fluorine (F)) or group-and another adjacent electron-hydrogen bond acceptor-carrying a single electron pair. In polyurethanes, hydrogen bonding between carbonyl and N-H groups is one of the main driving forces for phase separation. Hydrogen bonding can be either intermolecular (occurring between separate molecules) or intramolecular (occurring between portions of the same molecule).
In such an example, the foams described herein include hard/crystalline segments and soft/amorphous segments. The hard segments are formed via hydrogen bonding between the polyurethane segments of each polymer chain. While not wishing to be bound by a particular theory, it is believed that the polyurethane segments of each polymer chain are particularly susceptible to hydrogen bonding with other polyurethane segments in adjacent polymer chains. Thus, during foam formation, the polyurethane segments of each polymer chain are hydrogen bonded to, and thus aligned with, the polyurethane segments of the other polymer chains contained in the foam. Since the polyurethane segment of each polymer chain is aligned with the polyurethane segments of the other polymer chains, the polyetherester segment of each polymer chain must be aligned with the polyetherester segments of the other polymer chains contained in the foam. The alignment of these polyetherester segments forms the soft segments of the foam. Thus, the foam exhibits a highly organized three-dimensional network structure of hard and soft segments due to hydrogen bonding between the polyurethane segments of each polymer chain.
Accordingly, the polyurethane foam of this preferred example includes crystalline segments formed via hydrogen bonding. Further, it is believed that crystalline segments comprising the reaction product of 1, 4-butanediol and 1, 4-isocyclohexylimide and amorphous segments comprising poly (ethylene glycol) form crystalline segments and amorphous segments that are "stacked" in an alternating configuration to provide a 3-dimensional porous structure that is enhanced via hydrogen bonding between the stacked crystalline segments.
In addition, the polyurethane foam of this preferred example readily interacts with other polymers (or moieties) to hydrogen bond because it includes crystalline segments comprising the reaction product of 1, 4-butanediol with 1, 4-isocyclohexylimide and amorphous segments comprising poly (ethylene glycol).
In many examples, each
In addition to porosity, pore size, and foam density, the combination of specific phase separated polymers in each specific foam section establishes the physical properties of the specific foam section. In particular, it is possible to obtain good compressibility, which means that the foam retains its structure (in particular its compressive strength) when it has absorbed a liquid (e.g. blood) or is filled with a liquid (e.g. blood). The mechanical properties, structural characteristics and chemical nature of the foam are determined primarily by the polymers present in the foam. This is advantageous because it provides a means to control and adjust mechanical properties, structural characteristics and chemistry by selecting suitable phase separated polymers.
The foaming
In one example, the foaming
The medicament included in each particular foam portion of the foam nose dressing 10 is located substantially within the cell walls of the foam. This is in contrast to foams that include a drug primarily within the interstices of the foam. Without wishing to be bound by theory, it is believed that drug release is uncontrolled and substantially instantaneous when the drug is substantially located in the void. In contrast, the porosity of a particular drug containing foamed portion affects the release rate of the active agent when the drug is located within the cell walls of the pores. The higher the porosity, the higher the release rate and vice versa. Without wishing to be bound by theory, it is believed that the increased porosity results in an increased degradation rate of the particular foam portion, and thus an increased release rate. In other words, degradation of a particular foam portion (e.g., the foaming housing portion 14) controls release rather than additives.
The release rate of an active agent from a particular foam portion of the foam nose dressing 10 containing the active agent can be expressed as the time required to release an amount of drug over an amount of time. Typically, it takes 8 hours to 1.5 days to release 50% of the active agent from the foaming
Typically, the active agent is a drug (i.e., any pharmaceutically active compound), an antibiotic, an anti-inflammatory agent, a corticosteroid, a hemostatic agent, an anti-allergen, an anticholinergic agent, an antihistamine, an anti-infective agent, an antiplatelet agent, an anticoagulant, an antithrombotic agent, an anti-scarring agent, an antiproliferative agent, a chemotherapeutic agent, an antineoplastic agent, a pro-healing agent, a decongestant, a vitamin, a hypertonic agent, an immunomodulator, an immunosuppressant, or a combination thereof. In one example, the active agent is a steroidal anti-inflammatory agent. It has been found that the relatively slow release of the active agent from the foaming
In some examples, the active agent is a molecule comprising at least one hydrogen atom bonded to a nitrogen, oxygen, or fluorine atom. This structure facilitates hydrogen bonding between the active agent and a phase separated polymer, such as a polyurethane foam comprising crystalline segments comprising the reaction product of 1,4 butanediol and 1,4 isocyclohexylimide and amorphous segments comprising poly (ethylene glycol). In other words, the active agent may advantageously include hydrogen atoms that may be used to form hydrogen bonds with the crystalline segments of the phase-separating polymer (e.g., polyurethane). Hydrogen bonding between the active agent and the phase separated polymer can help control and slow the release of the active agent.
In one example, the active agent is a steroidal anti-inflammatory agent. It has been found that the relatively slow release of the active agent from the phase separated polymer is particularly suitable for steroidal anti-inflammatory agents, such as corticosteroids. In some examples, the foaming
In another example, the active agent is a hemostatic agent. Of course, the foam nose dressing 10 may include an anti-inflammatory agent (e.g., a steroid) and a hemostatic agent. In various examples, the hemostatic agent includes at least one hydrogen atom bonded to a nitrogen atom and/or at least one hydrogen atom bonded to an oxygen atom, wherein the hydrogen atoms are operable to form hydrogen bonds with crystalline segments of the first and/or second polyurethane foams. In such an example, the molecules of the hemostatic agent and the molecules of the phase-separating polymer are bonded to each other via hydrogen bonding and have substantially no covalent bonds therebetween.
In certain examples, when the active agent is a hemostatic agent, it is believed that the interaction between the phase-separating polymer and the hemostatic agent in the foamed nose dressing 10 results in a synergistic effect with respect to hemostatic activity, particularly when a phase-separating polymer and a chitosan hemostatic agent are used. Hemostatic agents are described in U.S. patent application publication 2015/0320901, the entire contents of which are incorporated herein by reference, which includes their synergistic effect with phase-separated polymers.
In certain examples, the hemostatic agent is a chitosan hemostatic agent. The term "chitosan hemostatic agent" as used herein refers to chitosan or a salt or derivative thereof. Good results have been obtained with chitosan or chitosan ethyl ester.
Chitosan is a polysaccharide comprising D-glucosamine units (deacetylation units) and N-acetyl-D-glucosamine units (acetylation units). Chitosan can be prepared from chitin by deacetylating at least a portion of N-acetyl-D-glucosamine in chitin (poly-N-acetyl-D-glucosamine) by hydrolysis. The ratio of D-glucosamine units and N-acetyl-D-glucosamine units in chitosan is generally expressed as the degree of deacetylation. The degree of deacetylation is defined as the percentage of non-acetylated glucosamine units in the chitosan. Thus, this percentage corresponds to the molar percentage (mol%) of deacetylated units present in the chitosan. Without being bound by theory, it is believed that a higher degree of deacetylation improves hemostatic properties. The chitosan may have a degree of deacetylation of 1-100 mol%, 25-100 mol%, 50-100 mol%, 75-100 mol%, 85-100 mol%, 90-100 mol%, 5-50 mol%, 10-35 mol%, or 10-25 mol%. The above values also apply to chitosan present in chitosan salts as well as to chitosan derivatives (which have acetylated and deacetylated units, just like chitosan itself). In other non-limiting examples, all values and ranges of values within and including the above range endpoints are expressly contemplated herein. Without being bound by theory, it is believed that a higher degree of deacetylation improves the hemostatic properties of chitosan.
Suitable chitosan salts are those having chitosan ions with a net positive charge. Thus, a suitable chitosan salt may be a salt consisting of chitosan cations and coexisting anions. For example, the chitosan haemostat may be a salt of chitosan with an organic acid, especially a carboxylic acid, such as succinic acid, lactic acid or glutamic acid. The chitosan salt may for example be selected from the group comprising nitrates, phosphates, glutamates, lactates, citrates, acetates and hydrochlorides of chitosan.
Typically, the chitosan derivative is a chitosan molecule in which one or more of the hydroxyl and/or amine groups present in the chitosan have been substituted. For example, one or more hydroxyl groups may be substituted to obtain an ether or ester. The amine groups may be substituted to obtain amino groups, although this generally results in a decrease in hemostatic activity. Thus, the amine groups of chitosan are typically unsubstituted.
The chitosan haemostat may comprise or be derived from chitosan derived from animal, plant or shellfish. These sources give similar good results in terms of the hemostatic effect described above. In addition, synthetic chitosan may also be used.
Other examples of suitable chitosan salts are chitosan esters of glutamate, succinate, phthalate or lactate, chitosan derivatives comprising one or more carboxymethyl cellulose groups, carboxymethyl chitosan. Other suitable examples of chitosan derivatives are chitosan with quaternary groups (like N-trimethyl chloride, N-trimethylene ammonium). In addition, biologically active excipients, such as calcitonin or 5-methylpyrrolidone, may be used.
The chitosan hemostatic agent may have a molecular weight in the range of about 1-1000 kDa.
In various examples, the chitosan hemostatic may have a molecular weight in the range of about 1-1000kDa, 1-500kDa, 1-250kDa, 1-100kDa, 10-1000kDa, 10-500kDa, 10-250kDa, 10-100kDa, 30-80kDa, 50-1000kDa, 50-500kDa, 50-350kDa, 50-250kDa, 100-minus-plus-1000 kDa, 100-plus-750 kDa, 100-plus-500 kDa, 100-plus-250 kDa, 150-plus-500 kDa, 200-plus-1000 kDa, 200-plus-750 kDa, 200-plus-500 kDa, 225-plus-275 kDa, 200-plus-300 kDa, 210-plus-390 kDa, 90-1000kDa, 190-plus-1000 kDa, 290-plus-1000 kDa or 390-plus-1000 kDa. In other non-limiting examples, all values and ranges of values within and including the above range endpoints are expressly contemplated herein.
In one example, as best shown in fig. 1A-C, a foam nose dressing 10 for topically applying an active agent to the nasal cavity and for absorbing fluid discharge includes a first foam having a porosity greater than 80%. The first foam includes a foamed
In certain examples, the foaming
In certain examples, when the active agent is a hemostatic agent, the foaming portion (i.e., the foaming
The amount of the haemostat may be at least 0.1 wt%, preferably at least 2 wt%, more preferably at least 5 wt% of the total weight of the foam portion comprising the haemostat. Notably, even relatively small amounts of hemostatic agent are sufficient to provide the desired hemostatic properties for the foam nose dressing 10. Further, the amount of the hemostatic agent is typically less than 99 weight percent, less than 50 weight percent, or less than 35 weight percent of the total weight of the foam portion. Since the hemostatic activity of the foam nose dressing 10 is nearly dependent on the hemostatic agent, high concentrations are generally neither necessary nor preferred.
The haemostatic agent is preferably present in the foam in the form of particles, in particular polymer particles. Examples of suitable particles are amorphous, crystalline and gelatinous particles. The haemostat may also be a liquid, especially when highly viscous. In the case of hemostatic particles, the particles may have a size of 1-1000 μm. Preferably, the particles are less than 150 μm. Particularly good results have been obtained with particles of 5-90 μm. Small particles have many advantages. First, the structure of the foam is less affected by the presence of small particles than large particles. Second, small hemostatic particles have a smaller tendency to aggregate than large particles. In addition, small particles can be used to obtain good dispersions. Finally, the small particles do not settle when the foam is prepared, so that a uniform distribution within the foam can be achieved, if desired.
The hemostatic particles may be of any suitable shape, but are preferably substantially spherical. The particles are preferably solid. Suitable solid particles to be used are generally insoluble and hydrophilic.
In some examples, the chitosan hemostatic agent is uniformly distributed within the
In a first non-limiting example, a foam nose dressing 10 for topically applying an active agent to the nasal cavity and for absorbing fluid discharge includes a
In a second non-limiting example, a foamed
In a third non-limiting example, a foam nose dressing 10 for topically applying a medicament to the nasal cavity and for absorbing fluid discharges is elongate. In this example, the foam nose dressing 10 includes a first foam having a porosity greater than 80%. The first foam includes (or forms) a foamed
In a fourth non-limiting example, a foam nose dressing 10 for topically applying a medicament to the nasal cavity and for absorbing fluid discharges is elongate. In this example, the foam nose dressing 10 includes a first foam having a porosity greater than 80%. The first foam includes (or forms) a foamed
Without departing from the broadest scope of the present disclosure, it will be understood that the biomedical foam described above in connection with the foam nasal dressing 10 may also be used in other biomedical foam applications, such as foams for ear dressings or for atrial tamponade. When the biomedical foam is a foam ear dressing or atrial tamponade, the foam includes a foamed
The present disclosure also provides a method of forming a foam nose dressing 10, as shown in fig. 7 and 8, that includes providing a
As also shown in fig. 7 and 8, the method further includes placing the
The method further includes placing a first liquid comprising a first phase separated polymer and an active agent in the
The method also includes cooling the first liquid to freeze the first liquid. The cooling of the first liquid may be performed at any suitable temperature that is capable of freezing the first liquid.
The method further includes removing the
The method further includes placing a second liquid in the cavity 32 of the frozen first liquid. The second liquid includes a second phase separating polymer that is the same as or different from the first phase separating polymer. The second liquid may optionally include an active agent (e.g., a hemostatic agent) and a solvent.
The method also includes cooling the second liquid to freeze the second liquid. The cooling of the second liquid may also be performed at any suitable temperature that is capable of freezing the second liquid. As best shown in fig. 10, freezing the second liquid can produce a frozen core 12 'and a frozen base 20', wherein the frozen core 12 'is placed entirely within the frozen housing portion 14'. In addition, the frozen housing portion 14 ' and the frozen base portion 20 ' may cooperate to enclose the frozen core 12 '.
The method further includes drying the first and second frozen liquids to form a foam nose dressing 10, the foam nose dressing 10 including a foamed core portion 12 'disposed at least partially within a foamed housing portion 14'. In other words, drying the frozen first liquid forms the foaming housing portion 14 'and drying the frozen second liquid forms the foaming core 12'. Suitable methods of forming, cooling, and drying the first and second liquids are described in U.S. patent application publication No.2015/0320901, which is incorporated herein by reference in its entirety.
In certain examples, the drying is performed by reducing the pressure and increasing the temperature such that any solvent present in the first frozen liquid and the second frozen liquid is sublimated from the phase separated polymer. In some examples, the temperature increase may be in part from the latent heat of sublimation of solvent molecules, and may result in up to 90%, 95%, or 100% sublimation of the solvent. The entire freeze-drying process may last from about 1 hour to 24 hours or more. Typically, the entire freeze-drying is performed for about 15 hours.
In certain examples, placing the second liquid in the cavity 32 of the frozen first liquid is further defined as overflowing the cavity 32 of the frozen first liquid with the second liquid. When the cavity 32 is filled in this way, the "overflow" may form the foamed base 20' after the process is completed. Thus, in these examples, the foamed core 12 'and foamed base 20' have the same chemical composition, porosity, foam density and are unitary. Further, the foaming core portion 12 ' and the foaming shell portion 14 ' extend from the foaming base portion 20 '.
In certain examples, the method further includes placing a third liquid in the
When a solvent is included in the first liquid, the second liquid, and/or the third liquid, suitable solvents include polar solvents having a freezing point in the range of about 0-50 ℃. This solvent can be removed by drying. Such suitable solvents include organic solvents such as acetic acid, benzene, cyclohexanecarboxylic acid, nitrobenzene, phenol, l, 4-dioxane, 1,2, 4-trichlorobenzene, dimethyl sulfoxide (DMSO), and combinations thereof. In one example, the solvent used is 1, 4-dioxane.
In certain examples, when the active agent is not soluble in the phase separated polymer or solvent, the method includes an additional step to ensure that the active agent is homogeneously mixed into the particular foam part. When the active agent is not soluble in the phase separation polymer and/or the solvent, the active agent is typically a particle. These additional steps are described in U.S. patent No.9,422,389, the entire contents of which are incorporated herein by reference.
In one example, homogeneous mixing is achieved by performing a cooling step such that the temperature of the first and/or second liquid is reduced at a high rate (typically within 10 s) to below the freezing point (crystallization temperature) of the liquid.
These cooling rates will depend on the type of solvent or solvents used and the rate at which the drying process is used to enable sublimation of the solvent or solvents from the foam. When the temperature of the polymer/particle mixture is below the freezing point (crystallization temperature) of the solvent or solvents, the solvent crystallizes. Sublimating the one or more solvents results in a foam comprising uniformly distributed particles.
In a particular example, the first and/or second liquid is frozen within 60 seconds and the one or more solvents are subsequently sublimated to form a foam comprising a uniform distribution of particles.
In another alternative example, the phase separated polymer/particle mixture may also be refrozen by cooling the first and/or second liquids to freeze the first and/or second liquids and then at least once raising the temperature above the freezing point of the one or more solvents to melt the partially frozen phase separated polymer/particle mixture and lowering the temperature; and subsequently drying the frozen first and second liquids by sublimation of the one or more solvents to form a foam comprising a uniform distribution of the particles to achieve uniform mixing of the particles into the foam.
The size of the particles used also affects their distribution within the foam. The use of ultra-fine particles in the process results in good particle distribution throughout the foam and minimizes particle agglomeration. However, the use of larger sized particles is less desirable because it results in an increased likelihood of coagulation or agglomeration of the particles in the foam. The coagulation of particles in the foam can cause the foam to become brittle, which would make them unsuitable for use.
The particles are preferably solid. Suitable solid particles to be used are insoluble and hydrophilic and may be organic, inorganic or a mixture of both. The particle size is generally from 1 to 1000. mu.m, preferably from 1 to 150. mu.m, even more preferably from 15 to 120. mu.m. The particles may have any suitable shape, but are preferably substantially spherical.
The particles may be an anticoagulant, antibacterial, antifungal, antiseptic, or other suitable drug. Preferably, the particles may be smooth particles having a size of about 20-30 μm or coarse particles having a size of about 60-115 μm.
In addition to forming a uniform distribution of the insoluble drug in a particular foamed portion, a layer of the insoluble drug may also be formed in a particular foamed portion. In these examples, the first or second liquid is cooled to the freezing point of the one or more solvents included therein within 60s to 600 s; and subsequently drying the polymer/particle mixture by sublimation of the one or more solvents to form a foam comprising one or more layers of particles. In these examples, the particles are generally lighter than the solvent or solvents and do not rise to the top as one would expect, rather than the particles forming a layer underneath the foam.
In a first non-limiting example, a method for forming a foam nose dressing 10 is provided. The method includes providing a
Referring now to fig. 11, a method of simultaneously treating inflammation and absorbing fluid discharges from the nasal cavity using the foam nasal dressing 10 is also disclosed. The method comprises the following steps: providing a foam nose dressing 10; compressing the foam nose dressing 10 such that the foam dressing assumes an insertion configuration; and positioning the foam nose dressing 10 within the nasal cavity with the foam nose dressing 10 in the insertion configuration such that the
The various steps of compressing the foam nose dressing 10 such that the foam dressing assumes an insertion configuration and positioning the foam nose dressing 10 within the nasal cavity when the foam nose dressing 10 is in the insertion configuration such that the
A method of simultaneously treating inflammation and absorbing emissions from the nasal cavity using a foam nose dressing 10 may utilize a foam nose dressing 10, the foam nose dressing 10 including a
One or more of the above values may vary by 5%, 10%, 15%, 20%, 25%, etc., as long as the variation remains within the scope of the present disclosure. Each member may be selected individually or in combination (reply on) and provide sufficient support for a particular example within the scope of the appended claims. The subject matter of all combinations of the independent claims and the dependent claims (both singly and multiply) is expressly contemplated herein. The disclosure is illustrative and includes words of description rather than limitation. Many modifications and variations of the present disclosure are possible in light of the above teachings, and the disclosure may be practiced otherwise than as specifically described herein.
All combinations of the foregoing examples throughout the disclosure are expressly contemplated herein in one or more non-limiting examples even if such disclosure is not described in a single paragraph or section above. In other words, an explicitly contemplated example may include any one or more of the elements described above, selected and combined from any portion of the present disclosure.
It will also be understood that any ranges and subranges taken in describing the various examples of the disclosure individually have been collectively within the scope of the appended claims, and are understood to describe and contemplate all ranges including all and/or some values therein, even if such values are not explicitly written herein. Those skilled in the art will readily recognize that the enumerated ranges and subranges sufficiently describe and enable various examples of the present disclosure, and that such ranges and subranges can be further delineated into relevant halves, thirds, quarters, fifths, and so on. As but one example, a range of "from 0.1 to 0.9" may be further delineated into a lower third (i.e., 0.1 to 0.3), a middle third (i.e., 0.4 to 0.6), and an upper third (i.e., 0.7 to 0.9), which are individually and collectively within the scope of the appended claims and may be individually and/or collectively selected and provide sufficient support for specific examples within the scope of the appended claims. Further, with respect to language that defines or modifies a range, such as "at least," "greater than," "less than," "not greater than," and the like, it is to be understood that such language includes subranges and/or upper or lower values. As another example, a range of "at least 10" inherently includes a sub-range from at least 10 to 35, a sub-range from at least 10 to 25, a sub-range from 25 to 35, and so forth, and each sub-range may be individually and/or collectively chosen and provides sufficient support for the particular example within the scope of the appended claims. Finally, various numbers within the disclosed ranges may be chosen and provide sufficient support for specific examples within the scope of the appended claims. For example, a range of "from 1 to 9" includes a plurality of individual integers (e.g., 3) and individual numbers (e.g., 4.1) including decimal points (or fractions) that may be selected and provide sufficient support for a particular example within the scope of the appended claims.
Several examples have been discussed in the foregoing description. However, the examples discussed herein are not intended to be exhaustive or to limit the disclosure to any particular form. The terminology that has been used is intended to be in the nature of words of description rather than of limitation. Many modifications and variations are possible in light of the above teaching, and the disclosure may be practiced otherwise than as specifically described.
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