EP3829536A1 - Formulation pharmaceutique et système et procédé d'administration - Google Patents
Formulation pharmaceutique et système et procédé d'administrationInfo
- Publication number
- EP3829536A1 EP3829536A1 EP19768952.4A EP19768952A EP3829536A1 EP 3829536 A1 EP3829536 A1 EP 3829536A1 EP 19768952 A EP19768952 A EP 19768952A EP 3829536 A1 EP3829536 A1 EP 3829536A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- recited
- pharmaceutical formulation
- sustained release
- water
- release system
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
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- A61L2400/00—Materials characterised by their function or physical properties
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
Definitions
- Products that are current benchmarks for rheological performance in dental surgery and tooth extraction applications include SURGIFOAM ® Absorbable Gelatin Sponge and SURGIFOAM ® Absorbable Gelatin Powder, each being examples of sterile porcine gelatin absorbable sponges or powders intended for hemostatic use by applying to a bleeding surface ("Surgifoam").
- GELFOAM ® Dental Sponges (absorbable gelatin sponge, USP) is a medical device also intended for application to bleeding surfaces as a hemostatic.
- sustained release formulations designed to release a drug at a predetermined rate and to maintain a constant drug level for a specific period of time with minimal side effects.
- the basic rationale behind a sustained release drug delivery system is to optimize the biopharmaceutical, pharmacokinetic and
- opioid overdose deaths including those involving opioids
- Drug overdose deaths continue to increase in the United States. Deaths from drug overdose are up among both men and women, among all races, and among adults of nearly all ages. Two out of three drug overdose deaths involve an opioid.
- Opioids are substances that work in the nervous system of the body or in specific receptors in the brain to reduce the intensity of pain. Overdose deaths from opioids, including prescription opioids, heroin, and synthetic opioids like fentanyl have increased almost six times since 1999. In 2017, drug overdoses of all types averaged 21.7 per 100,000 with opioids alone killing more than 47,000 people, and with opioids representing 67.8% of all drug overdose deaths.
- 2018/0169080 describe sustained release formulations for dental applications.
- the contents of U.S. Patent Nos. 8,253,569 and 9,943,466 and U.S. Patent Application Pub. No. 2018/0169080 are incorporated herein by reference in their entirety.
- a sustained release pharmaceutical formulation for pain management comprises an active ingredient, and a water-miscible and hygroscopic network-forming material, the active ingredient being dispersed within the water-miscible and hygroscopic network-forming material.
- the pharmaceutical may comprise a hydrophobic component, wherein the active ingredient dispersed within the water-miscible and hygroscopic network-forming material are together dispersed in hydrophobic component.
- the pharmaceutical formulation may be combined with a reinforcing member for providing a system for sustained release of the pharmaceutical formulation for pain management.
- the active ingredient has a weight percent of less than 60% of the pharmaceutical formulation.
- the active ingredient may be present in an acidic form or a basic form.
- the active ingredient may comprise an anesthetic.
- the anesthetic may be bupivacaine, including an acidic form, a basic form, or a mixture of acidic and basic forms.
- the active ingredient is selected from an analgesic like acetaminophen.
- the active ingredient is selected from non-steroidal anti-inflammatory drugs (NSAID) analgesics.
- the NSAID may be ibuprofen, naproxen, meloxicam, ketoprofen, or mixtures thereof.
- the active ingredient is a mixture of anesthetics and analgesics.
- encapsulating material may also comprise an oligomeric material.
- the encapsulated particles can be prepared using a spinning disc spray dry process or an emulsion process.
- the network-forming material has a weight percent of 5% to 25% of the pharmaceutical formulation.
- the network-forming material may comprise a polymer, including either collagen or gelatin.
- the gelatin may have a Bloom value of 50 to 325, a viscosity of 1.5 to 7.5 mPa-s, and a mesh value of between 8 and 400.
- the sustained release pharmaceutical formulation and system may further comprise a pH modulator.
- the pH modulator can be an acid, such as citric acid.
- the acid has a weight percent of up to 5% of the pharmaceutical formulation.
- the pH modulator may also be a base, such as di sodium citrate. The base has a weight percent of up to 5%.
- the sustained release pharmaceutical formulation and system may further comprise a surfactant, an antiemetic, anti-infective, or chemotherapeutic agent.
- the hydrophobic component is an oil, a wax, or mixtures thereof.
- the hydrophobic component is selected from mineral oil, isopropyl palmitate, caprylic triglyceride, coconut oil, carnauba wax, beeswax, paraffin wax or mixtures thereof.
- the water-miscible and hygroscopic network-forming material does not gel for at least a time period of 24 hours after being suspended within the hydrophobic component.
- a method for delivering a sustained release pharmaceutical formulation for pain management at a target site of a patient comprises the steps of providing a pharmaceutical formulation, including an active ingredient, a water-miscible and hygroscopic network-forming material, the active ingredient dispersed in the water-miscible and hygroscopic network-forming polymer, and a hydrophobic liquid mixed with the water-miscible and hygroscopic network-forming polymer including the dispersed encapsulated active ingredient.
- the pharmaceutical formulation is deployed at the target site.
- the target site may be a tooth extraction socket.
- Another embodiment of a method of delivering a sustained release pharmaceutical formulation for pain management at a target site of a patient comprises the steps of providing a pharmaceutical formulation, including an active ingredient, and a water-miscible and hygroscopic network-forming material, the active ingredient dispersed in the water-miscible and hygroscopic network-forming polymer, an active ingredient encapsulated in a polymer, blending water with the water-miscible and hygroscopic network-forming polymer including the dispersed encapsulated active ingredient, and deploying the blend at the target site, such as a tooth extraction socket.
- acetaminophen/aspirin/caffeine/salicylamide aspirin/caffeine, acetaminophen/aspirin/caffeine, acetaminophen/caffeine/pyrilamine, acetaminophen/diphenhydramine,
- chemotherapeutic agents such as bleomycin sulfate, cetuximab, docetaxel, erbitux (Cetuximab), Hydrea (Hydroxyurea), Hydroxyurea, Keytruda (Pembrolizumab), Methotrexate, Nivolumab, Opdivo (Nivolumab), Pembrolizumab, Taxotere (Docetaxel), and Trexall (Methotrexate) are preferred adjunct active ingredients
- the sustained release pharmaceutical formulation preferably comprises gelatin having mesh values between about 8 and 400, but more preferably between about 18 and 230, and even more preferably between 35 and 140.
- the reinforcing member When the reinforcing member is in the form of a flexible textile sheet or scaffold, its geometric shape as well as its weight percentage in the delivery system can have a significant effect on the mechanical properties and on the tactile handling characteristics of the delivery system.
- Suitable tactile characteristics have been observed when pharmaceutical formulations are impregnated into the interstitial spaces of flexible textile sheets or scaffolds having thicknesses of between 0.01 cm and 0.1 cm, and topical surface areas of between 0.5 cm 2 and 15 cm 2 , and more preferably between 1 cm 2 and 9 cm 2 , and even more preferably between 5 cm 2 and 7 cm 2 .
- Suitable tactile characteristics have also been observed when the delivery system comprises a cellulose textile as a reinforcing member at a weight percentage of up to 15% by weight.
- the mass of fiber per topical square centimeter is between 0.005 g/cm 2 to 0.05 g/cm 2 , and more preferably between 0.008 g/cm 2 to 0.02 g/cm 2 .
- the mass of fiber per topical square centimeter is a relative indicator of the bulk density of the reinforcing member, which can be calculated by dividing the average weight of the member by its topical surface area. It has also been found that one or more geometric configurations of the reinforcing member can be used alone or in combination to form the formulation-impregnated delivery system.
- the reinforcing scaffold for a dry powdered mixture provides sufficient binding and mechanical support (i.e., cohesive integrity) before hydration.
- a fibrous cellulosic material e.g., SafeGauze, SURGICEL ® Original, FIBRILLAR, NU-KNIT and SNoW.
- the non-hydrated binder system could be allowed to hydrate in vivo, or it could be pre-hydrated and masticated before insertion into the tooth extraction socket. If the binder is allowed to hydrate in vivo, it must retain enough mechanical integrity to resist erosion until it hydrates with fluids in the tooth extraction socket.
- the non- hydrated binder when impregnated into a reinforcing member (i.e., a cellulosic textile), would resist erosion to a greater degree than a non-reinforced binder system, and thus may be a preferable alternative for in vivo hydration.
- hemostatic fibrous reinforcement material in the delivery device simultaneously provides many desirable features.
- the fibrous reinforcement facilitates initial composite reinforcement of the pharmaceutical formulation during manufacturing, during storage, and during initial deployment.
- the fibrous reinforcement allows for the optional use of lower network-forming material levels in the formula thereby expanding the upper limit for dispersed active ingredient and drug dosage, and for the optional use of lower levels of higher molecular weight network-forming materials in the binder phase of the formulation thereby providing reduced viscosity for ease of manufacturing and for higher initial compliance for handling efficacy.
- Use of multiple fiber types can impart combinations of desirable characteristics, including faster initial wetting and better initial adhesion during deployment from the more soluble fiber member, and longer-term composite integrity during the in vivo use period associated with dynamic changes in properties owing to inter-diffusion of tooth extraction socket fluids with the device from the less soluble fiber member.
- dry powders of bupivacaine-loaded PLGA microspheres and gelatin would be masticated with water to be delivered as a compliant dough-like material in end use for a desirable bupivacaine release profile.
- Volume restriction for the application estimated to be ca. 0.55 cc causes the dosage of bupivacaine to be severely limited by the occupied volume fraction of binder and water.
- Higher levels of bupivacaine loading in the PLGA microspheres are desirable for achieving useful bupivacaine delivery dosages, higher than the 20% w/w level that was used in the prior art since this level would only lead to maximum dose deliveries of less than 60 mg.
- Lower binder levels are required to maximize the microsphere content and hence the bupivacaine delivery dosage, which is a constraint that weakens the composite and necessitates not only better network forming binders, but higher levels of volume-occupying water for plasticization.
- Lower binder levels necessitate higher molecular weight network-forming gels that are susceptible to time-dependent reductions in compliance owing to diffusion-rate limitations which impact the time required for the network to reach its equilibrium state. Diffusion rates and time-dependent compliance behavior are further confounded by both the particle size distribution of the microspheres, which affects the bupivacaine time-release profile, and by the size of gelatin particulates. From a mechanical property perspective, it is desirable to maximize the smaller particle size fraction while simultaneously balancing the overall distribution to achieve the desired bupivacaine release profile since smaller particles will release faster than larger ones.
- release profile targets will be end use specific, it should be understood that there will be several adjustable factors besides PLGA surface-to-volume ratios that can also conceivably be used to modulate and control the time-release profiles of bupivacaine and the like.
- citric acid a Bronsted acid
- di-sodium citrate a Bronsted base
- Citric acid was observed to enhance binder system network formation of the network-forming material.
- these types of compounds can be optionally and separately microencapsulated, which would attenuate their availability for acid-base interactions with bupivacaine in its acidic form or its free-base form.
- these types of formulation levers it can be appreciated that one could achieve targeted bupivacaine release profiles while simultaneously employing higher fractions of high surface-to-volume particles if so desired. For example, with the combined use of these levers, one could potentially use a higher fraction of 3.4 um particles than would otherwise be viable.
- water may be used as a plasticizer to hydrate and to masticate blends of the powder ingredients to yield a compliant dough-like mixture (e.g., water + bovine gelatin with PLGA- encapsulated BUP as described in Example 12).
- a compliant dough-like mixture e.g., water + bovine gelatin with PLGA- encapsulated BUP as described in Example 12.
- water is the primary liquid ingredient in the pharmaceutical formulation, and the mechanical integrity of the formulation is achieved by virtue of gelation and network formation prior to the deployment.
- oils with optional waxes are used as liquid carriers to suspend hygroscopic, water absorbing network-forming materials, such as gelatin powders together with other dispersed ingredients, including PLGA-encapsulated BUP, free (non-encapsulated) BUP, and citric acid, to name a few.
- the hydrophobic pharmaceutical formulation achieve their initial mechanical cohesive integrity through a mechanism that is independent of gelled network formation.
- the formulation can then be used to disperse active ingredients, and it can then be impregnated into a fibrous textile which serves as a reinforcing scaffold forming a delivery device before its deployment.
- the reinforced device is therefore made to have cohesive integrity and compliance which renders it as sufficiently acceptable for use by the clinician during its deployment.
- liquids besides mineral oil such as caprylic triglyceride and isopropyl palmitate, are more polar than mineral oil, and they have at least some capacity for hydrogen bonding. However, their polarity and H-bonding characteristics are insufficient to cause gelation of the gelatin particulates that are suspended within them. Thus, although these types of liquids have permanent dipoles and therefore have some capacity for hydrogen bonding, they are poor plasticizers for gelatin.
- a pharmaceutical formulation or delivery device comprised of such liquids may be referred to as "hydrophobic".
- fluids can permeate into the matrix phase through a combination of macroscopic and microscopic diffusion mechanisms.
- Macroscopic diffusion can occur through permeable boundaries that are present from defects like void elements arising from entrapped air between partially bonded matrix polymer particulates (e.g., gelatin particulates), or from matrix polymer that is partially delaminated from the surfaces of weakly bonded elements or components that are dispersed within the matrix.
- Defects sites near these boundary regions become particularly susceptible to localized stress- induced tensile and shear types of failures.
- the ensuing number of internal cohesive failure events can begin to increase and even to accelerate from excessive strains at weak junctures, for example at cell walls of macroscopic voids, at the interfaces of weakly bonded particulates, etc.
- the cycle continues as more macroscopic pathways develop for the macroscopic ingress of even more fluids, leading to a further increase in the number of pathways for molecular level diffusion, which then leads to an increase in the number of swollen volume elements, which then leads to the further development of more localized stresses.
- the cascade continues, culminating in an acceleration in the rate of occurrence of ultimate failure events.
- an additive manufacturing process is used to meter and convey the formulation onto a web or discrete sheets of fibrous material, such as the cellulose hemostat, then the formulation could be propelled from a three dimensional printer nozzle or printer jet onto the web or discrete sheets, resulting in vehicle impregnated composites of the desired geometric size for the application, and then the resulting delivery device can be packaged for storage prior to deployment.
- Three-dimensional printing would also result in the creation of customized dose and dosage forms impregnated into the reinforcing member if so desired.
- a pharmaceutical formulation is possible with a low melting wax, or with an oil/wax blend, or with a low Tg polymer (lower than the Tg of the PLGA).
- a simple pressing process may be used to consolidate the textile with the PLGA spheres under ambient conditions.
- gelatin may be omitted from the formulation to thereby allow the cellulose to become the binder when it hydrates. Omission of the gelatin would make more "room” for bupivacaine loaded PLGA microspheres.
- oils are can be premixed with a wax at elevated temperatures above the melt temperature of the wax to form solutions.
- the solutions are then allowed to cool, causing a portion of the wax to recrystallize into micro-crystallites, which then remain suspended within the oil carrier.
- the resulting mixtures of oil and wax have higher viscosity tha n neat oil and are therefore desirable for use in formulating sta ble dispersions of particulates that can resist settling over time.
- the rate of cooling can be used to modulate the size of the resulting micro crystallites, with fast cooling generally leading to smaller crystallites, and with slow cooling or annealing leading to larger crystallites.
- oils or mixtures of oils could also be used in combination with a wax at ratios of total oil to wax that are sufficient for enabling certain desirable physical attributes, including melting point depression of the wax, increase in compliance of the resulting mixture, compressibility of the resulting mixture for textile impregnation, temperature-dependent viscosity of the resulting mixture, % PLGA and % gelatin loading in the mixture, and the like.
- hydrophobic formulations have been observed to have rheological characteristics that are conducive to the use of a sigma-blade blending process for preparing mixtures under ambient conditions, whereby the PLGA powders and gelatin particulates could be added to form dough-like mixtures in a batch or semi-continuous batch process.
- melt-recrystallization steps could also be optionally employed to produce stiffer or less stiff mixtures upon cooling.
- shear mixing of hydrophobic formulas could be performed with the intent of generating shear-induced heat. The resulting process temperature could be controlled and maintained at temperatures of less than the Tg of PLGA, and the mixture could then be directly dispensed onto a textile for impregnation while cooling.
- a wax or wax-mixture is typically employed at levels such that the total oil to wax ratio facilitates the achievement and control of certain desirable physical attributes or property characteristics, including, for example: 1) melting point depression of the wax; 2) an increase or decrease in the compliance of the resulting vehicle; 3) an increase in the cohesive integrity of the vehicle; 4) an increase or decrease in the viscosity of the resulting vehicle, such that dispersed ingredients within the vehicle remain dispersed without settling; 5) achievement of vehicle compliance with minimal elastic recovery to facilitate textile-impregnation processes; 6) achievement of a temperature- dependent viscosity characteristics that are conducive to shear mixing processes for vehicle manufacturing; 7) achievement of the ability to control or maximize the % PLGA and hence the % BUP in the vehicle, which can increase the dosage potential of the vehicle if so desired; and 8) achievement of the ability to control or maximize the % gelatin loading in the vehicle if so desired.
- the typical oil to wax w/w ratio for satisfying these purposes can be in the range of 0.01/1 (still solid wax-like
- the target dosage range for bupivacaine was estimated to be between a level approaching possible toxicity on a high-delivery side and a level representing clinical usefulness on a low-delivery side.
- the upper limit of BUP was estimated to be 360 mg over a 4-day period (90 mg/day x 4).
- the theoretical formulation composition for the upper limit and the lower limit for the % gelatin binder and the % of dispersed PLGA microspheres were observed to be dictated by the bupivacaine target dosage level.
- Table 1-5 DOE DRAFT-1 calculations of pertinent composition information based on the constraints presented in Table 1-4. Although placebo PLGA microspheres were used in preparing samples, calculations were performed to estimate a theoretical dosage of BUP delivery to a tooth extraction socket of 1 cc volume, assuming that the PLGA microspheres were loaded with 50% BUP by weight.
- EXAMPLE 2 Design of a controlled release device for delivering BUP within a volume-restricted end use application.
- diffusion rates and time-dependent compliance characteristics are further confounded by both the particle size distribution of the microspheres, which also affects the bupivacaine time-release profile, and by the particle sizes of the gelatin particulates.
- sample #10 which was made exclusively with 3.4-micron particles, was unique in that it exhibited the best physical properties. Specifically, sample #10 exhibited the highest relative cohesive strength and homogeneity of all the samples. This observation was consistent with the DOE-space trend analyses.
- the dispersed PLGA particles augment the mechanical properties of the hydrated gelatin network.
- the PLGA particles do not simply behave as dispersed filler particles which deteriorate mechanical properties or provide no improvement. Instead, they behave as reinforcing fillers which improve mechanical properties. This means that they not only perform a primary function of encapsulating active ingredients for controlled-release, they also perform a beneficial secondary function of reinforcing the hydrated binder matrix, with smaller PLGA particle sizes having a more pronounced positive effect.
- the PLGA microspheres will not only provide a first diffusion barrier for the release of BUP or other active ingredients, but its reinforcing presence in the matrix will also affect the compliance of the hydrated gelatin polymer itself, which in turn will further augment diffusion rates of BUP through the gelled matrix phase once the BUP has already diffused from the dispersed PLGA microspheres and into the gelled matrix. Also, from a macroscopic perspective, the mechanical reinforcement of the gelled gelatin binder by PLGA particles will also increase the resistance to erosion of the formulation within the end use application.
- PLGA microspheres made via an emulsion process provide qualitatively lower formula viscosities than their spinning-disc/spray-dried counterparts. In essence, this equates to a higher PLGA loading potential during mixing, which is also directionally preferred for achieving higher bupivacaine dosages, but only to the degree that adequate compliance and cohesive strength can be maintained.
- the emulsion particles (42.1 um) are thus preferred for the present application to the degree that larger particles are needed to achieve targeted release profiles.
- release profile targets will be end use specific, it should be appreciated from these teachings that there will be several adjustable factors besides PLGA surface-to-volume ratios that can also conceivably be used to modulate and control the time-release profiles of bupivacaine and the like.
- citric acid a Bronsted acid
- di-sodium citrate a Bronsted base
- Citric acid was observed to enhance binder network formation. From this perspective, these types of compounds can serve dual functions. They can be used to modulate the physical properties of the binder system, and their activity can also be exploited for the dual purpose of modulating the solubility of the bupivacaine free base.
- a completely wet and flowable/compliant amalgam was formed with only a 1/1 w/w ratio of liquid oil to gelatin.
- a hydrophilic binder component e.g., GLBG
- EXAMPLE 6 Preparation of a system using a cellulose textile impregnated with a formulation comprising GLBG, PLGA, and mineral oil.
- the long leg of the rectangular textile was then folded over and onto the Formula #14B mixture, and the assembly was gently kneaded to insure filling of the interstitial spaces of the textile on both sides of the fold.
- the resulting structure was nearly square (approximately 1.8 cm x 1.7 cm), comprising an impregnated textile folded over and onto itself with both sides being cohesively held together by the Formula #14B impregnated therein.
- Example 6 The delivery system from Example 6, comprising a single textile impregnated with 0.6 g of Formula #14B, was folded over three times and was kneaded again to insure filling of the interstitial spaces with the Formula #14B mixture. The resulting composite was permitted to age for 1 month under ambient conditions. No changes in relative compliance or compressibility were observed after this period of aging.
- the entire matrix of textile and Formula #14B was observed to consolidate, and it was easily kneaded into various shapes.
- the delivery system exhibited high compliance and formability. This suggests that the impregnated textile could be added directly to the tooth extraction socket to hydrate in place, or it could alternatively be hydrated with water first, and then placed into the tooth extraction socket.
- EXAMPLE 8 Formulations comprising wax, oil, GLBG, and PLGA for impregnating into a cellulose textile.
- Identifying a wax-type, determining the optimum weight ratio of wax to oil, and the optimum level of wax plus oil for textile-impregnation required consideration of several factors, including: 1) the compliance characteristics of the resulting formulation; 2) the cohesive strength of the formulation; 3) the hydration rate of the formulation upon exposure to fluids in vivo; 3) the time-dependent mechanical property characteristics of the formulation during the in vivo hydration process; 4) the conduciveness of the formulation to textile impregnation during manufacturing (e.g., solvent-free, minimal pressure, minimal temperature, textile wettability, etc.); 5) the optional capacity for the formulation to be pre-hydrated with water before insertion into the tooth extraction socket if so desired; and 6) the capacity for the formulation to be delivered with or without a fibrous textile reinforcing component.
- GLBG was added to the 19-2 gel from Part-1 to form sample 23-2.
- the resulting 23-2 amalgam provides the same effective weight ratio of oil-phase to gelatin that was used in creating Formula #14B from Example 5, where 0.2039 g mineral oil was added to 0.1022 g BG.
- the weight ratio of oil phase (wax + oil) to gelatin was 1.995.
- formulations compromising hydrophobic components can be made to have tactile characteristics that are equivalent to those of other commercially acceptable devices.
- equivalent characteristics can be achieved with significantly less water per unit weight of device.
- this water-absorbing feature also offers the opportunity for controlled dilution of the formulation, if so desired. For example, if the formulation is manufactured with an upper-limit dosage of active bupivacaine ingredients, it can then be diluted to reduce dosages to the degree necessary for the patient, simply by adding more water to a single type of manufactured unit.
- EXAMPLE 9 Drug delivery devices comprising cellulose materials impregnated with formulations compromising hydrophobic components for in vivo applications.
- the materials used for the hydrophobic formula preparation included the following:
- the 19-2 MO/BW premix (83.33% by weight mineral oil + 16.67% by weight beeswax) as described in Example 8 was prepared. Solid beeswax and liquid mineral oil were weighed and placed together inside of tared aluminum weighing pans. The mixture was heated over a hot plate having a surface temperature of 175°C while stirring with a metal spatula until the wax was melted to yield a yellowish homogeneous solution. Mix time was about 30 to 45 seconds until the wax was melted. At that point, the solution was removed from the hot plate and was allowed to set idle under ambient conditions. Within 10 minutes, the solution became an opaque heterogenous dispersion of uniformly suspended wax micro-crystallites. The mixture had the consistency of a soft spreadable gel.
- option-2 could be formulated to also achieve this objective since the formulations comprising hydrophobic components can be made sufficiently compliant without the need for mastication with fluids.
- option-4 there are several added advantages of using option-4 that not only help to meet the handleability needs of clinicians, but also provide synergistic performance characteristics that satisfy other clinical needs. For example, by reinforcing the formulation with fibrous material, a composite is created wherein the formulation is mechanically reinforced, thus facilitating the optional use of a formulation that is formulated with less binder phase and with more PLGA particles than would otherwise be possible without fiber reinforcement. This helps to satisfy the need for higher drug dosage deployment when so desired, without experiencing the deleterious effects on cohesive strength that would otherwise accompany any diminution in the percentage of binder.
- the reduction in the binder results in a decrease in cohesive strength, which can be more than compensated for by the use of fiber reinforcement.
- Fiber reinforcement can also facilitate the use of higher oil levels in the formulation.
- the use of lower viscosity formulas for ease of manufacturing and for ease of deployment in vivo can be achieved without experiencing the deleterious effects on cohesive strength that would otherwise accompany any reduction in the higher molecular weight components of the binder phase.
- the fibrous products that were used in this example are described in Table 9-2.
- the sample of SafeGauze was in the form of a rectangular textile and served as a geometric template for fashioning the other comparative fibrous materials.
- Each of the comparative fibrous materials were purposely pre-cut to have rectangular dimensions similar to those of the SafeGauze product, and then the samples were weighed to determine the relative differences in bulk density among the product types. These data are provided in Table 9-3.
- Table 9-4 Summary of relative differences among the fiber types after pre-cutting to the same x-y dimensions of the as-received SafeGauze product.
- Hybrid devices that were made with two fiber types, such as SG and SO, exhibited combined behaviors with macroscopically visible regions where blood had become more homogeneously dispersed than in samples made with SG alone, but also with regions that were more heterogeneous than those observed in samples made with SO or NK alone.
- One advantage of diffusion-assisted mixing is that the resulting in vivo composite becomes more homogeneous, and from a mechanical property perspective, this can help to dissipate internal cavity stresses over a larger volume fraction of the socket, thereby helping to minimize surface stresses that could disrupt protective scab formation. In this sense, it also becomes possible for the composite to become an integral component of the protective scab itself, wherein the radial gradient in composition between the tissue surface and the center of the cavity becomes more homogeneous.
- the diffusion characteristics and hence the chemical efficacy can be made to vary quite substantially.
- the free-base form of BUP may be much slower to protonate, a process which renders it more water soluble, which would have the effect of slowing the bulk rate of release, and thereby the effect of reducing the bio-availability of the drug at any given time.
- heterogeneous vesicles larger in scale than the micron-sized PLGA particles can be allowed to persist for the purpose of facilitating longer-term release.
- the heterogeneous vesicles could even be used to impart mechanical benefits like stress dissipation.
- the resulting morphology would be analogous to that of many impact-modified materials such as certain polymeric blends (e.g., impact modified polystyrene with a polybutadiene dispersed phase), which benefit from stress-dissipation owing to their dispersed components.
- impact-modified materials such as certain polymeric blends (e.g., impact modified polystyrene with a polybutadiene dispersed phase), which benefit from stress-dissipation owing to their dispersed components.
- a formulation designated as 12019-23-2 was made using caprylic triglyceride in place of mineral oil (Croda, Inc.; CAS # 65381-09- 1; Columbus Circle, Edison, NJ; tradename Crodamol GTCC). Again, apart from the type of oil, the compositions and relative weight percentages of all ingredients were the same as those used in preparing Formula 14C-2.
- Molecular level diffusion can occur via one or more of the following pathways in any combination, including for example: 1) water or other fluids entering the mother device; 2) active ingredients or other components dissolving and egressing from the mother device; 3) water diffusing into macro fragments that have been eroded away from the mother device; 4) active ingredients or other components leaching from macro fragments that have been eroded away from the mother device; or 5) components egressing from PLGA microspheres, including, microspheres that remain suspended within the mother device, microspheres contained within macroscopic fragments of the mother device, or microspheres that have become freely dispersed within the supernatant water- phase.
- Hydrophilic sample compositions preparations, and procedures.
- a mixed PLGA particle size distribution like that from formula #7 is one approach, a single PLGA particle size distribution was employed in this example for facilitating simple relative comparisons of cohesive integrity, release rates, and relative compliance characteristics when comparing the two formulations.
- methacrylate cuvettes (Fisher brand) were used to limit cuvette absorption within the range of detection for absorbance measurements on a Tecan infinite M200 Spectrometer within the range of 230-1000 nm. Given the lack of absorbance at higher wavelengths, spectrometer readings were typically measured between 250-350 nm. A wavelength step size of 2 nm with a bandwidth between 5-9 nm was used, and with 25 flashes, which was the number of incident light exposure and detection occurrences that were signal averaged at each wavelength. After each absorbance measurement, the supernatants were collected and added back to the original glass vials, such that the total volume in the elution experiment did not change except for minor loss due to residual supernatant in the pipette or UV cuvette.
- BUR free base has low solubility in water, the mildly acidic conditions insured that the BUR became protonated as the hydrochloride salt (BUP-HC!), rendering it as completely soluble under these conditions.
- BUP-HCI is known to be a strong ehromophore with a documented UV absorption maximum at 262 nm
- the level of BUR that was released from 918-li was already at a high enough level to saturate the detector.
- the level of BUR released from 918-1B was lower, and it was still within the range of instrumental detection.
- the amount of BUR that was released from both samples was high enough within 24 hours to saturate the UV detector.
- each of the 1 ml aliquots was used for UV absorption spectral analyses, and the relative levels of dissolved BUP were monitored as a function of time for each of the supernatant samples.
- the differential in maximum dosage is similar when volume is taken into consideration.
- the higher active ingredient dosage per unit weight of a formulation with hydrophobic ingredients translates to a higher delivery dosage of BUP per unit volume than would otherwise be possible with a comparable device.
- This unanticipated benefit provides an expanded opportunity to create formulations with higher net dosage delivery levels for use over protracted periods of time during end use if so desired.
- BUP-HCI is known to be a strong chromophore with a reported UV absorbance maximum of 262 nm (Cordova, A., Eur. Cbem. Bulk, 2012, 2(8), 554-557).
- the evolution of absorption in the 260-270 nm range is strongly influenced by the protonation of BUP and by its subsequent dissolution vs. time.
- Figures 12a, 12b, and 12c provide an alternative representation of the same data.
- Figure 13 provides the evolution of the absorbance intensity as a function of time for each of the device types. This plot is presented with a natural log time scale to better illustrate the large differences in the rates of egress among the device types. For illustration purposes, each of the data sets were empirically fit to a simple exponential growth function. The function and best fit parameters are provided in Table 12- 6. These trends illustrate the relative difference in release rates afforded by 1) the morphological distribution of the BUP, and by 2) the relative hydrophobicity of the formulation. For example, the trends reveal that the relative release rate of BUP increases with the use of hydrophilic components, and then decreases when the BUP is encapsulated by PLGA. Specifically, the relative BUP release rate was observed to trend as follows: 918-li > 918-1B ⁇ 14C-3B2 > 14C-3A.
- a formulation with hydrophobic ingredients containing BUP without PLGA encapsulation can be used to achieve similar results to those of a formulation with hydrophilic ingredients containing BUP that is encapsulated within PLGA microspheres.
- the estimated BUP elution concentration [BUPj t was ratioed against the total theoretical concentration [BUP] theoretical , thereby allowing for comparison of relative BUP elution rates among the various samples.
- Table 12-7 Relative absorption of supernatants from hydrophobic devices at 270 nm vs. time (hrs.) during the pH 2 water-soak experiment, including the estimated [BU P] at each time interval, and the estimated fraction of eluted BUP based on an initial theoretical concentration of BUP that was available from the device (i.e., 17.13 mg/ml for the hydrophobic devices as reported in Table 12-5).
- the absorption from the devices containing BUP were corrected for background contributions from non-BU P ingredients that may have dissolved (e.g., SO, GLBG) or dispersed (e.g., PLGA, MO, BW) as a function of time during the soak experiment. These contributions were roughly estimated from the absorbance of the 14C-3A Placebo at 270 nm. Note that when the absorbance correction resulted in a negative value, the correction was denoted as zero (marked with an asterisk). When measured absorbance values were at or approaching the saturation point of the detector, the effective BU P concentration was denoted as greater than the calculated value, but less than the theoretical maximum of ⁇ 17 mg/ml (also denoted with an asterisk).
- hydrophobic ingredients are best suited for formulations wherein the intention is to achieve longer-term usage in the end application.
- PLGA encapsulation was observed to attenuate the relative BUP release rate. Surprisingly however, the relative release rate from a more hydrophobic formulation containing BUP without PLGA encapsulation was observed to be similar to that of a more hydrophilic formulation wherein the BUP was encapsulated within PLGA
- EXAMPLE 13 Formulations compromising hydrophobic ingredients and containing mixtures of encapsulated and non-encapsulated ingredients.
- More hydrophobic formulations like those described in Example 12 were prepared for this example.
- the objectives were to demonstrate various methods that can be used to control BUP release from a more hydrophobic formulation, to demonstrate methods by which the maximum dosage level of BUP can be raised to even higher levels, and to demonstrate formulation flexibility that allows for the incorporation of additional dispersed ingredients, such as pH modulators, without adversely affecting rheological characteristics and release characteristics.
- compositions were mixed and were used to impregnate two orthogonally arranged Surgicel Original (SO) textiles for the purpose of forming control-release delivery devices.
- SO Surgicel Original
- the compositions of the formulations and devices are provided in Tables 13-1 and 13-2, respectively.
- the devices were then subjected to pH-2 water-soak testing at 37 degrees C and, using methodology similar to that which was described in Example 12, UV spectroscopy was used to estimate the relative concentration of BUP that had diffused or eluted into the supernatants as a function of time.
- the concentration of BUP at each time increment was estimated by using a two-step procedure.
- Figure 14 displays a relative absorbance vs. time comparison of placebo devices 14C-3E (with citric acid) and 14C-3A (without citric acid).
- the detector saturation condition was reached more slowly with delivery systems that employed PLGA-encapsuiated BUP microparticles (i.e., in devices made without the use of freely dispersed BUP).
- the maximum upper time-limit before detector saturation in these cases was approximately 96 hours (i.e., 4 days).
- the estimates of [BUP] appeared to be slightly negative at short soak times (e.g., at times of less than 8 hours for systems formulated with PLGA-encapsuiated BUP). This was an artifact of over correction from the 14C-3E placebo device, which appeared to provide a slightly higher degree of short-time non-BUP component dissolution than comparable devices that were formulated with PLGA-encapsuiated BUP.
- Figure 16 illustrates the relative rates of BUP elution (mg/ml/hour) together with the data ranges used for establishing the best linear fitting parameters.
- This graph reveals that the fastest releasing delivery system eluted ⁇ 12% of its theoretical [BUP] reservoir within about 12 to 24 hours, whereas the slowest releasing systems released approximately 7 to 8% of their theoretical [BUP] within approximately 4 days intermediate devices (i.e., those containing mixtures of freely dispersed BUP and PLGA-encapsulated BUP) had released 8-10% of their theoretical [BUP] within approximately 2 days.
- rheo-mechanical properties are also affected by other factors, including for example, the particle size distributions of the dispersed particulates, the total surface to volume ratio of particulates within the formulation matrix and within the delivery device, the weight and volume ratios of the formulation to cellulose fibers in the delivery device, the number and diameters of fibers that constitute a bundled-fiber strand, the knit or weave density of the fibers and fiber bundles that constitute a textile, and the surface wetting characteristics of the fibers. Any one or combination of these factors can be controlled and adjusted to achieve a broad range of rheo-mechanical responses if so desired.
- the relative BUP release rates were compared among three types of formulations: 1) a formulation containing PLGA-encapsulated BUP in a replicate of 14C-3A from Example 12; 2) a formulation containing dispersed BUP free base powder and placebo PLGA microspheres in a replicate of 14C-3B2 from Example 12; and 3) a formulation containing a dispersed mixture of both PLGA-encapsulated BUP and BUP free base (sample 14C-3C).
- Mixtures can be augmented in other ways to include the use of other dispersed or dissolved ingredients that can have an impact on release rates, either alone or in combination with one another, or in combination with the dispersed ingredients mentioned above, and at various weight ratios.
- Other dispersed ingredients can include, for example, BUP-HCI powder which is more water soluble than BUP, PLGA-encapsulated BUP-HCI, PLGA-encapsulated mixtures of BUP free base and BUP-HCI.
- the same PLGA-encapsulated ingredients can be comprised of larger or smaller PLGA particle size distributions, or mixtures of different PLGA particle size distributions.
- this is an example of the type of formulation flexibility that can allow for the creation of formulations with the capacity to deliver higher maximum BUP dosages on a unit weight basis than those that would otherwise be possible through the use of PLGA microspheres alone, or more specifically with the 4.3 micron 20% BUP free base loaded PLGA microspheres as used in this example.
- the potential for higher maximum dosages in a formulation with more hydrophobic ingredients will generally exceed what is possible with the more hydrophilic formulation embodiments, partly because the latter require water-dilution for plasticization in order to render them as compliant and useable.
- the averages of the values calculated from the 262 nm and 270 nm wavelengths (using the calibration lines from Tables 12-3 and 13-3) are presented below, together with the weight fractions that had eluted after 8 days of soaking in pH-2 water.
- EXAMPLE 14 Suspension test for choosing liquid components suitable for use in preparing hydrophobic and hydrophilic formulations.
- hydrophobic formulations and delivery devices can be desirable from the standpoint that they can be formulated to yield dough-like materials with compliance characteristics that are conducive to end use deployment, without having to rely upon pre deployment swelling and gelation of the gelatin particulates.
- hydrophobic formulations and delivery devices are ones whereby the gelatin particulates remain intact during manufacture and during storage, and do not yield macroscopic chain-entangled gelled networks until they become exposed to the tooth extraction socket and its fluids after deployment, unless the option of pre deployment hydration is exercised.
- each of the embodiments of the formulation will eventually become hydrated with fluids from the tooth extraction socket after deployment. This is predominantly due to the presence of hygroscopic, water-absorbing network-forming polymers like gelatin or to the presence of other water-absorbing materials such as cellulose fibers.
- water was used as a plasticizer to pre-hydrate and to masticate blends of powdered ingredients to yield compliant dough-like mixtures, including water and bovine gelatin with PLGA- encapsulated BUP as described in Example 12.
- water was the primary liquid ingredient in the formulation, and the mechanical integrity of the device was achieved by virtue of gelation and network formation prior to the deployment of the device.
- the compliance and conformability of these formulations were controlled by the weight ratio of water to gelatin with consideration also given to the total weight % solids in the plasticized mixture.
- water was used as a liquid plasticizer for the gelatin polymer.
- a plasticizer is generally a liquid (sometimes a solid) that when blended with a polymer increases the fraction of free volume, which in turn lowers the polymer glass transition temperature and consequently the elastic modulus and increases the compliance. Plasticizers are known to be at least partially miscible with the polymers that they plasticize.
- the mechanical integrity of the pre-deployed device was not achieved by virtue of gelling a polymer with a plasticizer to yield a reinforcing polymer network, but instead it was achieved by virtue of fiber reinforcement by impregnating knitted or woven cellulose textiles, or non-woven fibers with non-gelled suspensions to yield fiber-reinforced composite-like structures.
- hydrophilic device is comprised of a water- miscible hygroscopic polymer network that is homogenously gelled and pre-plasticized with a polar, hydrogen bonding liquid such as water, glycerin, honey, polyethylene glycols, polypropylene glycols, etc.; while by contrast, the hydrophobic device contains inter-dispersed fibrous components and suspended particulates of water-miscible and hygroscopic network-forming polymers like gelatin that have the latent potential to form gelled networks once exposed to water (i.e., after deployment), but in their pre-deployment state, they are made to persist as morphologically discrete entities suspended within and wetted by a hydrophobic vehicle.
- a polar, hydrogen bonding liquid such as water, glycerin, honey, polyethylene glycols, polypropylene glycols, etc.
- the hydrophobic device contains inter-dispersed fibrous components and suspended particulates of water-miscible and hyg
- Monitoring times of suspensions can include various time points after the suspensions are mixed, including for example, 5 minutes after mixing, 0.5 hours after mixing, 1 hour after mixing, 5 hours after mixing, 24 hours after mixing, 48 hours after mixing, 1 week after mixing, 1 month after mixing, 6 months after mixing, 1 year after mixing, and even 2 to 5 years after mixing.
- Qualitative techniques for monitoring suspensions for time-dependent changes that pertain to gelation or the lack thereof can include, for example: 1) monitoring the suspensions for relative time-dependent changes in viscosity by means of hand-stirring the suspensions with a spatula (spatula test-1); 2) determining whether the suspensions can still be poured from their containers after various periods of aging (pour test); 3) shaking the suspensions by hand to determine if they remain as liquid dispersions after various periods of aging (shake test); 4) using an optical microscope to determine if discrete particulates of gelatin remain intact and suspended within the liquid over time (microscope test); or 5) qualitatively viewing the elastic recovery response of the suspension when it is perturbed by hand using either a spatula or a similar object to see if a plasticized and gelled polymer network begins to develop, as evidenced by being able to lift the plasticized polymer from its container with a spatula (spatula test 2).
- the particulates of a water-miscible and hygroscopic network-forming polymer do not gel for at least a time period of 24 hours after being separately suspended within one or more hydrophobic components, or more preferably for at least a time period of less than 3 to 12 months after being separately suspended within one or more hydrophobic components, then the one or more hydrophobic components are deemed suitable for preparation of a hydrophobic sustained release system or formulation. Conversely, if the particulates of a water-miscible and hygroscopic network forming polymer form a gel within a time period of 24 hours after being separately suspended within one or more of the components, then the one or more components are deemed suitable for preparation of a hydrophilic sustained release system or formulation.
- liquid carrier liquids with other dispersed ingredients, including for example, microspheres of PLGA-encapsulated BUP, freely dispersed BUP, freely dispersed BUP-HCI, citric acid, ascorbic acid, citrates, etc.
- the liquid carrier can also be modified in advance of the test via incorporation of optional waxes or surfactants if so desired.
- the suspension test is not necessarily limited to gelatin protein. Instead, it can be used to test the suitability of a liquid for use in preparing hydrophobic or hydrophilic formulations wherein the formulation comprises other, alternative water-miscible and hygroscopic network forming polymer components besides gelatin.
- suspension tests were conducted using candidate liquid carriers as described in Table 14-1.
- 0.50 g aliquots of GLBG with general information provided in Table 14-2 were weighed into 11 ml glass vials with lids.
- a 1 g aliquot of a candidate test liquid was weighed into an individual vial containing the GLBG to achieve a 2/1 liquid/GLBG weight ratio.
- a spatula was used to stir the ingredients to create a suspension.
- the degree of hydrophilicity and hydrophobicity of a liquid can also be gauged by parameters that pertain to molecular-level properties such as polarity (e.g., dipole moment forces from permanent dipoles), dispersion forces (e.g., non-permanent dipoles or van der Waals forces), and hydrogen bonding forces.
- polarity e.g., dipole moment forces from permanent dipoles
- dispersion forces e.g., non-permanent dipoles or van der Waals forces
- hydrogen bonding forces e.g., hydrogen bonding forces.
- HSP Hildebrand Solubility Parameter
- HAN Hansen Solubility Parameter
- the most hydrophobic liquids can be defined as those with either a small or no permanent dipole moment, and with a low capacity to participate in hydrogen bonding.
- These types of liquids have been observed to be the least compatible with highly polar and water-soluble protein-based polymers like gelatin, which explains why the gelatin particulates remain dispersed and stable over time when suspended (i.e., not gelled) in formulations comprising such liquid carriers.
- These types of liquids would also be expected to have limited compatibility with other polar molecules such as water and BUP-HCI, thus rendering them as relative deterrents to both molecular-level and macro-level diffusion during the end use application as has been illustrated in Example 12. This behavior renders such liquids as useful levers in quests aimed at achieving specific control over time-release profiles.
- An example of an extreme version of this type of liquid is represented by a paraffinic hydrocarbon like mineral oil.
- liquids with permanent dipoles and with higher capacities for hydrogen bonding can be classified as being less hydrophobic and more hydrophilic.
- HSP approximately 48 MPa 1/2
- these types of liquids are highly compatible with hygroscopic polymers like gelatin, which explains why the dispersed gelatin particulates do not persist in formulations containing water, but instead become swollen through diffusion and plasticization, leading to the coalescence of the particulates through polymer chain entanglement and leading ultimately to gelation and to solid network formation prior to deployment of the device.
- the mechanical integrity of the more hydrophobic formulation is predominantly derived from its reinforcement with cellulose fibers.
- the morphology of the hydrophobic formulation has been designed to adsorb polar liquids like water as demonstrated in Examples 5 and 7.
- a polar liquid such as water, glycerin, polyethylene glycol, mixtures thereof, or fluids from the tooth extraction socket, etc.
- hydrophilic liquids like water and glycerin are more compatible and more miscible with polar molecules like BUP-HCI, a fact which is consistent with the observation of faster diffusion rates exhibited by formulations that are pre-plasticized with water as opposed to those prepared with mineral oil as the liquid vehicle carrier as in Example 12.
- end-product objective is to maximize the release rates of water-soluble active-ingredients while simultaneously achieving mechanical compliance characteristics that are desirable for deployment, then pre-gelation of gelatin or other hygroscopic components with hydrophilic liquids like water and glycerin could be a desirable approach wherein gelation is made to occur before deployment of the device.
- the formulation of a more hydrophilic formulation represents a method of approach towards achieving this objective, but only if the resulting dilution of active ingredients can be tolerated in the end use application.
- the more hydrophobic formulas achieve their initial mechanical cohesive integrity through a mechanism that is independent of gelled network formation.
- the formulation is formulated to have the compliance characteristics of a cream, it can then be used to disperse active ingredients, and it can then be impregnated into a fibrous textile which serves as a reinforcing scaffold for the formulation before its deployment.
- the reinforced delivery device is therefore made to have cohesive integrity and compliance which renders it as sufficiently acceptable for use by the clinician during its deployment.
- the gelatin particulates dispersed within the formulation and cellulose fibers begin to swell with liquids from the tooth extraction socket, leading to their chain entanglement and ultimately to their network formation and to an accompanying change in morphology.
- the gelled network then becomes a type of reinforcing scaffold for the device in vivo, serving to enhance its cohesive strength which enhances its mechanical integrity after deployment and not before.
- liquids besides mineral oil such as caprylic triglyceride and isopropyl palmitate as demonstrated in Example 10
- mineral oil such as caprylic triglyceride and isopropyl palmitate as demonstrated in Example 10
- their polarity and H-bonding characteristics are insufficient to cause gelation of the gelatin particulates that are suspended within them.
- these types of liquids have permanent dipoles and therefore have some capacity for hydrogen bonding, they are poor plasticizers for gelatin.
- formulations comprised of such liquids are also classified as more hydrophobic formulations and delivery devices. These more hydrophobic formulations and the delivery devices containing them have a
- liquid carriers that serve to suspend and bind the ingredients within the vehicle do not promote the gelation of the gelatin particulates, and they are either immiscible with gelatin or have limited miscibility under ambient conditions. Consequently, macromolecular chain entanglement and gelation do not occur when the particulates are suspended in such liquids.
- Liquids that are deemed as being suitable for use in a more hydrophobic formulation via the suspension test can also perform other functions when included in the formulation.
- the HAN of isopropyl palmitate is reported as 15.3 MPa 1/2 .
- these types of liquids are recognized as being more polar than mineral oil, for the purposes of the present description they are still classified as being relatively hydrophobic in that they do not diffuse and swell gelatin particulates in the way that water does. Instead, the gelatin protein particulates persist in such formulations until they are subjected to hydration during end use. Nevertheless, the permanent dipole moments of these liquids would be anticipated to render them as more amenable to facilitating molecular-scale diffusion of small polar molecules than would mineral oil.
- EXAMPLE 15 Preparation of a fibrous reinforced delivery device with glycerin as the liquid component.
- a formulation comprising a hydrophilic liquid
- a formulation that is pre-mixed with water can be useful in achieving relatively fast time-release profiles of water-soluble ingredients as demonstrated in Example 12.
- the present description provides for creating a formulation that is first premixed and pre-plasticized with water, glycerin, polyethylene glycols, other polyhydric alcohols, or mixtures thereof.
- These types of formulations are analogous to the more hydrophobic formulations , but they are made with a polar H-bonding liquid as the primary liquid ingredient instead of oils and waxes, and they are designed to gel prior to deployment instead of afterwards.
- these types of formulations can be used for controlled-release delivery on their own without fiber reinforcement.
- they can also be optionally reinforced with a fibrous cellulose hemostat to form a composite structure.
- the purpose of this example is to demonstrate this aspect of the formulation.
- diffusion and erosion are interactive processes, and that diffusion involves not just the egress of active ingredients from a delivery device , but ingress of water and fluids from the chemical environment where the device is deployed.
- the matrix polymer can become more susceptible to erosion, either through dissolution of volume elements from the exposed surfaces of the delivery device, from the macro separation of particulates near the surfaces of the device, or through a combination of the two.
- one advantage of using fibrous reinforcement for a delivery device is that it can improve the cohesive integrity of the device, and thereby render it to be more erosion resistant.
- internal cohesive failures of the matrix can cause particulates of the device to become macroscopically separated from the original structure.
- fluids can permeate into the matrix phase of the device through a combination of macroscopic and microscopic diffusion mechanisms. Macroscopic diffusion can occur through permeable boundaries that are present from defects like void elements arising from entrapped air between partially bonded matrix polymer particulates, such as gelatin particulates, or from matrix polymer that is partially delaminated from the surfaces of weakly bonded elements or components that are dispersed within the matrix.
- the matrix contains a polymer that is hygroscopic, as it is in a more hydrophilic formulation, molecular level diffusion of hydrous liquids can occur along every frontal boundary that becomes available to the fluid.
- the fluid macroscopically diffuses into the matrix along a frontal boundary, it also can begin to permeate into the matrix polymer through a process of molecular-level diffusion.
- a volume element of a matrix polymer begins to expand from the ingress of lower molecular weight fluids, it can become plasticized by the fluid, leading to an increase in the fraction of free volume within the matrix polymer phase and to a subsequent further increase in the rate of molecular level diffusion, both into and out of the matrix polymer network.
- An increase in free volume at the molecular level also leads to a number of additional physical changes in the matrix polymer phase, including a decrease in the glass transition temperature, an accompanying decrease in modulus, a decrease in ultimate stress to failure resulting in lower strength, and to an accompanying acceleration in the rate of molecular level diffusion of molecules both into and out of the matrix polymer phase.
- the macro volume expansion of the liquid-occupied volume element that is the polymer volume element that has become diffusion-permeated and plasticized by fluids, leads to the development of localized stresses that tend to accumulate at weak boundaries, such as at frontal boundaries that separate swollen volume elements from other volume elements that have not yet been permeated and are not yet swollen.
- Defects sites near these boundary regions become particularly susceptible to localized stress- induced tensile and shear types of failures.
- the ensuing number of internal cohesive failure events can begin to increase and even to accelerate from excessive strains at weak junctures at cell walls of macroscopic voids, at the interfaces of weakly bonded particulates, etc.
- the cycle continues as more macroscopic pathways develop for the macroscopic ingress of even more fluids, leading to a further increase in the number of pathways for molecular level diffusion, which then leads to an increase in the number of swollen volume elements, which then leads to the further development of more localized stresses.
- the cascade continues, culminating in an acceleration in the rate of occurrence of ultimate failure events.
- This process will not only impact the molecular level diffusion rates through the matrix polymer, it can impact the molecular level diffusion rates through other types of secondary diffusion barriers that have been purposely put into place, the diffusion barrier created by a PLGA polymer which serves to impede the molecular-level diffusion rate of its encapsulated active ingredients like BUP or BUP-HCI.
- PLGA can hydrolyze.
- the hydrolysis process leads to a decrease in molecular weight, to the production of more chain ends, and thus to a further increase in free volume which further enhances the rate of diffusion.
- a gelatin matrix polymer with polypeptide sequences will also be susceptible to the same type of hydrolysis-initiated acceleration of free volume.
- each molecular level diffusion barrier that is purposely set in place to control the release of drugs and the like can become altered and affected by a cascade of macroscopic and molecular-level events. These events will collectively affect the global time release profile of the device.
- the matrix can be reinforced with fibers or with particulates, which serve as scaffolds that can help to hold a mechanically weaker matrix phase in place by reducing the probability of crack growth and propagation along any one single boundary via distributing stresses from swelling over larger volume elements and hence over multiple boundaries within the structure, thereby reducing the magnitudes of localized stresses and strains, and hence reducing the number and frequency of catastrophic failure events.
- Lower levels of localized stresses will translate to lower localized strains, which in turn, depending on the geometric structure of the defect site, can lead to sustained mechanical and cohesive integrity of the delivery device over longer periods of time.
- hydrophobic formulations lend themselves well to the creation of fiber-reinforced composites primarily because, by design, the formulations that are used to impregnate the fibers are not pre-gelled into macro polymeric networks. Instead, these formulations, with their hydrophobic liquid carriers, remain compliant and moldable for long periods of time. The gelatin particulates suspended therein do not begin to gel and swell until they are exposed to fluids within the tooth extraction socket. Even then, the rate of water ingress is diminished owing to the hydrophobic nature of the formulation. All of this translates to an extended work-time for accomplishing the manufacturing steps that are required to make a composite device, including the time needed to complete multiple process steps, such as mixing, metering, impregnating, conveying, cutting, and packaging.
- the work time window prior to gelation is significantly shortened for formulations comprising hydrophilic liquids.
- hydrophilic liquids For example, when water is mixed with GLBG at a 2/1 (w/w) ratio, gelation and elastic network formation was observed to begin almost immediately.
- the work time window prior to the onset of gelation was observed to be significantly longer, thereby making glycerin a more practical choice as a liquid for creating more hydrophilic hemostatic fiber-reinforced delivery devices.
- the time-period preceding gelation defines the window of time that enables the product to be made through the process of impregnating a fibrous substrate.
- the viscosity and elasticity of the vehicle will be low enough to enable facile impregnation of fibrous substrates with high expediency.
- the gelation process be made to occur after the fibrous textile is impregnated with the formulation, and not before.
- the liquid component be miscible enough with the hygroscopic network-forming component, including gums like gelatin, gum arabic, ghatti, karaya, tragacanth, agar, Irish moss, carrageenin, alginates, seed extracts of which include locust bean, locust kernel, and quince seed gums as examples, manufactured and modified dextrins and British gums, water-dispersible or soluble derivatives of cellulose, etc., to lead to gelation and to the formation of a plasticized polymer network.
- gums like gelatin, gum arabic, ghatti, karaya, tragacanth, agar, Irish moss, carrageenin, alginates, seed extracts of which include locust bean, locust kernel, and quince seed gums as examples, manufactured and modified dextrins and British gums, water-dispersible or soluble derivatives of cellulose, etc.
- the work-time prior to gelation be long enough to facilitate all of the process steps that are required for product formation, such as vehicle mixing, metering, conveying, wetting, pressing, etc.
- the work-time window for textile impregnation can be determined from the suspension test as defined in Example 14. If a continuous or semi-continuous process is used to meter and convey the formulation onto a web of fibrous material, then the web could be optionally conveyed through a forced air or infrared heated oven to facilitate faster gelation.
- the resulting impregnated composite can be cut to achieve the desired geometric size for the application, and then the resulting delivery device can be packaged for storage prior to deployment.
- the liquid be biostable, either on its own, or through the incorporation of preservatives that guard against bacterial growth during periods of product manufacturing, packaging and storage. It is also desirable that the liquid lead to formation of a gelled polymer network after textile impregnation and not before.
- a liquid that meets both criteria is glycerin.
- Other liquids can be used, including for example, propylene glycol, polyethylene glycols and polypropylene glycols of various molecular weights, water-based natural products like honey, polyhydric alcohols and derivatives of the same, as well as mixtures of any of these types.
- the resistance of the fibrous material to water dissolution or to degradation can be an important and desirable attribute, particularly after deployment of the delivery device.
- the fibrous material eventually degrade and become bio-absorbed, it is still desirable that the fibrous material maintain integrity for a period of time during the post-deployment lifetime of the device, mainly because the retention of a composite structure with fibrous reinforcement is conducive to maximizing macroscopic erosion resistance, which is another desirable attribute for longer-term durability if the delivery device is deployed in an oral tooth socket application.
- Step-1 a segment of Surgicel Original (SO) oxidized cellulose textile was cut (1.8 x 3.8 cm) and weighed at 0.0475g;
- Step-3 a premixed suspension of Great Lakes bovine gelatin (GLBG) and glycerin was prepared using 1.8 g GLBG + 3.6 g glycerin, and the mix was allowed to set for 10 minutes;
- GLBG Great Lakes bovine gelatin
- Step-4 0.4317 g of the premixed suspension from step 3 was added to the beaker with the pre weighed PLGA-encapsulated microspheres, and the resulting vehicle was mixed by hand for approximately 5 minutes with a spatula until it formed a homogeneous cream;
- Step-5 using a spatula, 0.6189 g of the cream from step-5 was coated and spread over the entire length of a single pre-weighed textile from step-1, and then the textile was folded once in its center, over and onto itself before being subjected to light pressing with the spatula to achieve
- Step-7 the delivery device was then allowed to set and gel under ambient conditions ( ⁇ 20 degrees C), and then was qualitatively monitored over time.
- step-4 the more hydrophilic 15A formulation as prepared in step-4 was noted to be qualitatively similar in viscosity and in compliance to the comparable, but more hydrophobic formulation of 14C-3A that was prepared in Example 12.
- step-6 the device was also noted to be qualitatively similar in stiffness and in compliance to the analogous delivery device that was prepared in Example 12.
- the delivery device was still cohesively intact, but it had become noticeably more stiff owing to the onset of gelation.
- the 2/1 glycerin/GLBG (w/w) mixture that was retained from step-3 had become waxy and higher in viscosity at this stage.
- the 2/1 glycerin/GLBG (w/w) mixture that was retained from step-3 had become a solid elastic network.
- the device itself exhibited internal cohesive failure as it had opened along its fold to reveal a powdery and friable surface of cohesively failed formulation.
- the stress of the fold in the textile coupled with swelling stresses from the glycerin-infused gelatin particles was substantial enough to cause cohesive failure of the gelled mixture.
- the more hydrophilic delivery device of sample 15A was unable to retain enough cohesive strength after gelation to resist swelling stresses and to remain cohesively intact, thereby illustrating one of the difficulties in manufacturing a more hydrophilic composite reinforced delivery device which is gelled prior to deployment.
- This result serves to demonstrate one of the limitations of a more hydrophilic delivery device that does not occur with comparable hydrophobic devices. Specifically, higher total binder levels (e.g., water ⁇ GLBG or glycerin ⁇ GLBG) are required for devices where the binder is designed to be gelled prior to deployment.
- sample 15B was prepared using a 3.92/1 w/w ratio of glycerin to GLBG instead of 2/1 w/w, and a total vehicle binder level (glycerin + gelatin) of 62% by weight instead of 58.51 % by weight.
- the steps used in preparing 15B are provided below.
- Step-1 a segment of Surgicel Original (SO) oxidized cellulose textile was cut (1.8 x 3.8 cm) and weighed at 0.0489g;
- Step-3 a premixed suspension of Great Lakes bovine gelatin (GLBG) and glycerin was prepared using 1.0 g GLBG + 3.92 g glycerin, and then the mix was allowed to set for approximately 20 minutes;
- Step-4 0.5 g of the premixed suspension from step 3 was added to the beaker with the pre-weighed PLGA-encapsulated microspheres, and the resulting vehicle was mixed by hand with a spatula for approximately 10 minutes until it formed a homogeneous cream;
- Step-5 using a spatula, 0.6119 g of the vehicle cream from step-5 was coated and spread over the entire length of a single pre-weighed textile from step-1, and then the textile was folded once in its center, over and onto itself before being subjected to light pressing with the spatula to achieve impregnation;
- Step-7 the delivery device was then allowed to set and gel under ambient conditions ( ⁇ 20 degrees C), and it was qualitatively monitored over time.
- the 15B formulation as prepared in step-4 was noted to be qualitatively similar in viscosity to sample 15A at the same stage of the process.
- the delivery device was also noted to be qualitatively similar in stiffness and in compliance to 15A, and to the analogous more hydrophobic delivery device that was prepared in Example 12.
- the delivery device of 15B was still cohesively intact, but unlike 15A, there was no noticeable qualitative change in the compliance of the device. Also, unlike the 15A premix of glycerin and gelatin that had become waxy at this stage, the 3.92/1 (w/w) premix for 15B was still a pourable liquid.
- the 15B device did not exhibit a noticeable change, and it was still cohesively intact.
- the 3.92/1 (w/w) premix from 15B had become noticeably more elastic.
- the 15B delivery device continued to remain mechanically stable and unchanged throughout the duration of the experiment of 48 hours.
- compositions of the 15A and 15B vehicles are provided in Table 15-1, and the final device compositions are provided in Table 15-2. Note that the level of dispersed solids is expressed for two different physical states of the formulations- before gelation, while glycerin is the continuous phase for dispersed particulates of gelatin and PLGA), and after gelation when plasticized gelatin becomes the continuous phase for the dispersion of PLGA.
- Table 15-2 Weight % compositions of hydrophilic textile-impregnated devices made with glycerin as the liquid carrier for the vehicle.
- the vehicle compositions as reported in Table 15-1 were separately impregnated into individual SO textiles.
- the calculations for compositions also include the weight % concentration of BUP, and the effective available BUP concentration for release on a unit weight of device basis (mg/g).
- EXAMPLE 16 Preparation of a temperature activated hydrophobic device with coconut oil as the liquid component.
- a delivery device analogous to 14C-3A from Example 12 was prepared using coconut oil (CO) as the liquid carrier in place of mineral oil.
- CO coconut oil
- the CO as discussed in Example 14 was deemed to be suitable for use as a liquid carrier in preparing a more hydrophobic device.
- the compositions of the vehicle and the device are provided in Tables 16-1 and 16-2.
- the formulation and textile impregnated delivery devices were prepared using procedures outlined in Examples 9, 12 and 13. However, while preparing both the premix of gelatin with CO and the formulation with added PLGA, the temperature was maintained at 27 degrees C, which is above the melt point of the CO. The CO/gelatin premix was observed to solidify upon cooling to 20 degrees C.
- CO is a complex mixture of symmetric and asymmetric triglycerides. Some of the components within the CO have melt points that render the mixture as having the capability of exhibiting solid-like characteristics at 20 degrees C and liquid characteristics at 27 degrees C.
- a delivery device can be made to soften at or above 37 degrees C (body temperature) and to freeze or harden when it becomes cooled.
- body temperature 37 degrees C
- the advantage is that through pre-heating the device, it can be made conformable for optimal placement into the tooth extraction socket. Upon cooling to body temperature, the delivery device can then be made to harden via recrystallization of components that have been formulated into the vehicle.
- a delivery device can be made to soften upon deployment. This can be accomplished by tuning the melt point of the vehicle to be near or below body temperature.
- a softer and more compliant delivery device is easier to conform to the geometric shape of a cavity.
- a delivery device with higher modulus can exhibit better resistance to erosion.
- a delivery device that remains soft and conformable after deployment could be made to temporarily harden if the patient consumes a cold liquid. This can result in improved erosion resistance on-demand upon exposure to the cooler liquid as it flows across an exposed surface of the delivery device. Release rates and fluid influx rates will also be affected by the compliance of the delivery device, with diffusion being slower through a more rigid matrix medium than through a softer medium.
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Abstract
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PCT/US2019/048846 WO2020047277A1 (fr) | 2018-08-31 | 2019-08-29 | Formulation pharmaceutique et système et procédé d'administration |
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