Patent Application
20170143695
The present invention relates to porous particles comprising a coating formed from a glassy material, and their methods of manufacture. More particularly, the invention relates to coated porous particles comprising an active ingredient, wherein the coating exhibits tuneable solubility characteristics in aqueous and alcoholic media.
The abuse or misuse of medications represents an ongoing challenge for public health authorities. Whether intentional or accidental, the improper use of prescription medicaments has the potential to cause serious harm, ranging from reduced efficacy of the drug, to an increased expression of side effects and addictions.
Drug abusers have devised a variety of ways for achieving the “high” associated with improper substance use. A primitive, yet effective, technique sees a user crush or pulverize one or more oral dosages for subsequent administration via other routes, such as snorting, smoking or injecting. More elaborate methods involve extracting active ingredients from pharmaceuticals with the aid of household solvents, and even kitchen appliances, such as microwaves.
The threat to public health posed by improper drug use has prompted numerous public health authorities to task drug manufacturers with developing improved tamper-proof technologies. One approach has been to provide analgesic compositions comprising both agonistic and antagonistic ingredients, with the antagonistic effect designed to dominate when the composition is administered by an abusive route, such as by injection.
Other tamper-proof techniques have focused around so-called aversion technologies, which aim to discourage the would-be abuser by making the process more difficult and less pleasurable. Such approaches have involved using gelling agents to prevent a user from drawing the substance into a syringe, or including additives to cause increased burning and irritation in the nasal passages when snorted.
However, with abuse rates having quadrupled in the decade from 1990 to 20001,2, there remains a constant need for improved tamper-resistant technologies.
The present invention was devised with the foregoing in mind.
According to a first aspect of the present invention there is provided a particle comprising:
According to a second aspect of the present invention there is provided a process for the preparation of a plurality of particles as claimed in any preceding claim, the process comprising the steps of:
According to a third aspect of the present invention there is provided a product (e.g. a particle) obtainable, obtained, or directly obtained, by a process defined herein.
According to a fourth aspect of the present invention there is provided tamper-proof, or abuse-deterrent, particles comprising coated particles as defined herein, the coated particles comprising at least one active ingredient.
According to a fifth aspect of the present invention there is provided a solid dosage form comprising a particle defined herein.
As described hereinbefore, the present invention provides a particle comprising:
In the particles of the present invention, the dissolution rate of the alkali phosphate or alkali silicate glassy material in aqueous media is greater than it is in alcoholic media. The dissolution rate of the alkali phosphate or alkali silicate glassy material in aqueous and alcoholic media can be determined by techniques well known in the art. In an embodiment, the dissolution rate may be determined by immersing a given quantity of the alkali phosphate or alkali silicate glassy material sample in a given quantity of an aqueous or alcoholic media for a given period of time (e.g. 5, 10, 20 or 30 minutes) and then determining the dissolution rate by either:
In an embodiment, a suspension (e.g. a 1% w/v suspension) of the alkali phosphate or alkali silicate glassy material (optionally with a particle size within the range of 30 to 250 microns) is dispersed in a given quantity of an aqueous media (e.g. phosphate buffered saline) or an alcoholic media (e.g. 40% ethanol in 0.1M HCl) for a given period of time (e.g. 5, 10, 20 or 30 minutes), and the amount of dissolution is determined by either:
It will be understood that the phrase “substantially encapsulating the core substrate” relates to either or both of the scenarios where (i) the coating covers a substantial part of the outermost surface of the core substrate, and (ii) the coating blocks, partially blocks or impregnates all or a substantial number of pores present in the core substrate in a manner which restricts the availability of the active ingredient(s) contained therein to the alcoholic medium.
The solubility characteristics of particles of the invention present a number of advantages, most notably in the field of drug delivery. Until now, drug abusers have been endowed with a variety of methods for extracting active ingredients from prescription pharmaceuticals, which may then be concentrated to higher dosages for subsequent recreational use. Perhaps the most effective technique involves the use of one or more solvents to leach out the active ingredients from high-dosage controlled-release prescription medicaments. This so-called “dose-dumping” may also occur accidentally, whereby the simultaneous consumption of particular solvents, often ethanol present in alcoholic beverages, can induce the medicament to release its load almost instantaneously. Whether intentional or accidental, dose-dumping of this type can lead to abnormal quantities of the active ingredient in the blood stream, provoking a loss of efficacy, or an increased risk of side-effects and dependencies. The present invention now provides a novel means of significantly reducing the viability of such dose-dumping techniques by using particles comprising a core having a plurality of pores (which serves to retard the release of the drug) and a coating of particular glassy material having tuneable solubility characteristics in both alcoholic and aqueous media. When compared with the drug release profile under physiological conditions, the poor dissolution rate of the glassy coating in alcohol, coupled with the slow release of drug from the porous core if/when the coating or portions of the coating has dissolved, serve to make such dose-dumping techniques impractical, if not impossible. The particles of the invention thereby present a means of realising tamper-proof and abuse-deterrent medicaments. Furthermore, by varying the porosity of the core substrate as well as the quantity of coating material, the particles of the invention allow the release profile of the active ingredient(s) to be tailored according to a patient's needs.
In an embodiment, the coating is formed from an alkali phosphate glass or an alkali silicate glass. Suitably, the alkali phosphate and alkali silicate glassy materials comprise at least one oxide selected from alkali metal oxides and alkaline earth metal oxides. In one embodiment, the alkali phosphate and alkali silicate glassy materials comprise only one oxide. Suitably, the oxide is Na2O. Such binary systems balance ease of manufacture with the ability to offer a range of solubility characteristics. In another embodiment, the alkali phosphate and alkali silicate glassy materials comprise Na2O, and optionally one or more other oxides selected from suitable glass-modifying oxides such as calcium oxide and magnesium oxide. Such ternary and quaternary systems offer a greater degree of flexibility depending on the desired solubility characteristics of the coating.
In another embodiment, the alkali silicate glassy material has a weight ratio of silica to total alkali oxide of 9:1 to 1:1. Suitably, the alkali silicate glassy material has a weight ratio of silica to total alkali oxide of 4:1 to 1:1. More suitably, the alkali silicate glassy material has a weight ratio of silica to total alkali oxide of 4:1 to 1.25:1. Within these weight ratios, the solubility of the material can be engineered to offer the desired coating characteristics.
In another embodiment, the alkali phosphate glassy material comprises 30-50 mol % phosphate. In another embodiment, the alkali phosphate glassy material is a metaphosphate or a pyrophosphate. Suitably, the alkali phosphate glassy material comprises 40-48 mol % phosphate. Suitably, the phosphate is provided as phosphorus pentoxide (P2O5).
In another embodiment, the alkali phosphate glassy material comprises 50-70 mol % oxide selected from alkali metal oxides and alkaline earth metal oxides. Suitably, the alkali phosphate glassy material comprises 52-60 mol % oxide selected from alkali metal oxides and alkaline earth metal oxides. More suitably, the alkali phosphate glassy material comprises 54 mol % oxide selected from alkali metal oxides and alkaline earth metal oxides. Suitably, the oxide is Na2O.
In another embodiment, the coating is formed from an alkali phosphate glass consisting of 46 mol % P2O5 and 54 mol % Na2O.
In another embodiment, the at least one active ingredient is a pharmaceutically active compound. Suitably, the active ingredient is present in a quantity designed for extended release dosage, which may be an opioid or a non-opioid (e.g. pseudoephedrine). More suitably, the active ingredient is an opioid, opium derivative, or an opiate drug, including their isomers, esters, ethers and any salts thereof. More suitably, the at least one active ingredient is a drug defined as a “controlled substance” in the USA Controlled Substance Act, the Single Convention on Narcotic Drugs 1961 or the Misuse of Drugs Act 1971. Even more suitably, the active ingredient comprises one or more of oxycodone, hydrocodone, oxymorphone, morphine, or codeine, or a pharmaceutically acceptable salt thereof. Most suitably, the active ingredient is oxycodone, or a pharmaceutically acceptable salt thereof. Ethanol dose-dumping is an issue for almost all extended release medicaments, whose high dosages present an attractive target for drug misusers. Although opioid painkillers, in particular oxycodone, are incredibly potent analgesics, they can also lead to devastating addictions, thereby underlining the importance of the tamper-proof particles disclosed herein.
In another embodiment, the at least one active ingredient may be a non-opioid drug, such as a stimulant (e.g. pseudoephedrine).
In another embodiment, in addition to the at least one active ingredient, the particle comprises one or more other compounds, such as, for example, pharmaceutically-acceptable excipients.
In another embodiment, the core substrate may comprise two or more active ingredients, and optionally one or more other compounds, such as, for example, pharmaceutically-acceptable excipients.
In another embodiment, the core substrate is selected from a group of inorganic materials that could be naturally occurring or synthesized via (i) ambient/moderate temperature or (ii) high temperature processing. Examples of (i) include zeolites or cylindrical clay structures such as hectorites, foamed ceramics and porous ceramics generated via sol-gel processing (the last of these either with or without sacrificial organics that are subsequently sintered out). Examples of (ii) include soluble glasses, and glasses that have undergone phase separation and chemical treatment to remove the lower durability phase. Suitably, the core substrate is an inorganic material offering either or both of (a) dissolution or (b) diffusion from a porous substrate. In an embodiment, the core substrate is an amorphous silica. More suitably, the core substrate is created via a tetraalkylorthosilicate monomer or a trialkylorthosilicate containing a single “organic” entity on the fourth bond to silicon. Most suitably, the core substrate is created via a tetraethyl orthosilicate monomer.
In another embodiment, the particle is a microparticle. Smaller particles offer enhanced tamper-proof characteristics by virtue of their reduced crushability. Suitably, the particle has a diameter of 50-350 μm. More suitably, the particle has a diameter of 125-250 μm.
In another embodiment, the particle comprises 1-10 wt % of the coating. Suitably, wherein the particle comprises 1-5 wt % of the coating. Most suitably, the particle comprises 2-5 wt % of the coating.
In another embodiment, the plurality of pores each have a diameter of 1.5-50 nm. Suitably, the plurality of pores each have a diameter of 1.5-30 nm.
In another embodiment, the core substrate has a pore volume of 1×10−3-10 cm3g−1. Suitably, the core substrate has a pore volume of 5×10−3-5 cm3g−1.
As described hereinbefore, the present invention also provides a product (e.g. a particle) obtainable, obtained, or directly obtained, by a process defined herein.
As described hereinbefore, the present invention provides a process for the preparation of a plurality of particles as defined herein, the process comprising the steps of:
In one embodiment, step b) comprises the step of fluidizing the plurality of core substrates in the presence of an alkali phosphate or an alkali silicate glassy material as claimed in any preceding claim, such that the plurality of core substrates become coated with the alkali phosphate or an alkali silicate glassy material. Suitably, the plurality of core substrates are fluidized in the presence of a sprayed solution of an alkali phosphate or an alkali silicate glassy material. In one embodiment, the solution of alkali phosphate or alkali silicate is sprayed onto the core substrates from above. In an alternative embodiment, the solution of alkali phosphate or alkali silicate is sprayed onto the core substrates from a column (e.g. a Würster column) provided within the fluidizing chamber.
The core substrates forming part of the invention can be coated via a variety of methods, some of which yield better results than others. Perhaps the crudest coating method involves mixing the plurality of core substrates with a solution of the glassy coating materials and then evaporating away the solvent. Although still a viable technique, the aforementioned process is hampered by the need to mill the resulting material back to the desired particle size, thereby running the risk of creating freshly cleaved uncoated surfaces, which may have an adverse effect on the release profile of the active ingredient(s). The coating process can be improved by employing a technique which coats the core substrates individually. The fluidisation embodiment of the present invention involves fluidising the plurality of core substrates (keeping particles in dynamic motions and so apart from each other) and then spraying a solution of the glassy coating material either on top of, or preferably within, the fluidised bed. Atomised droplets of glass solution land on individual core substrates and are instantly evaporated. The continual fluidisation and movement of the core substrates ensures no agglomeration.
In an embodiment, step a) comprises forming a plurality of core substrates each comprising a plurality of pores as defined herein, wherein the pores comprise at least one active ingredient as defined herein, and wherein the at least one active ingredient is introduced into the pores of the core substrate either during the formation of the core substrate or after the formation of the core substrate.
Suitably, the core substrates provided in step a) are prepared according to a sol-gel protocol.
In another embodiment, step a) comprises the steps of:
Suitably, step a1) comprises providing a mixture of core substrate precursors in an aqueous solution having a pH of 0-11.
Suitably, the at least one active ingredient is contacted with the liquid mixture of core substrate precursors prior to step a2). More suitably, the at least one active ingredient is in aqueous solution.
In one embodiment, the core substrate precursors are either identical or different. Suitably, the core substrate precursors are tetraethylorthosilicate (TEOS) monomers.
In another embodiment, step a2) comprises contacting the liquid mixture with the at least one active ingredient and stirring the resulting biphasic mixture. Suitably, the solution is stirred at room temperature. More suitably, the solution is stirred for 48-96 hours. Most suitably, the solution is stirred until a gel is formed.
In another embodiment, step a3) comprises drying the resulting core substrates, then milling the dried core substrates. Suitably, the core substrates resulting from step a2) are dried at a temperature of 30-90° C. for 20-100 hours. More suitably, the core substrates resulting from step a2) are dried at a temperature of 50-70° C. for 12-36 hours. Suitably, the dried core substrates are milled, and optionally sieved, to a particle size of 50-350 μm. More suitably, the dried core substrates are milled, and optionally sieved, to a particle size of 125-250 μm. Optionally, step a3) comprises one or more additional drying steps either during or after milling. Suitably, the one or more additional drying steps comprises heating the core substrates at a temperature of 30-100° C. for 12-72 hours.
In another embodiment, the alkali phosphate or alkali silicate glassy material used in step b) is provided as an aqueous solution comprising 3-25% (m/v) of the glassy material.
In another embodiment, step b) comprises introducing the solution of alkali phosphate or alkali silicate glassy material to a fluidized bed of core substrates. Suitably, the solution of alkali phosphate or alkali silicate glassy material is introduced under sufficient pressure to provide a mist, or droplets, of glassy material. More suitably, the solution of alkali phosphate or alkali silicate glassy material is introduced to the fluidized bed of core substrates at a pressure of 0.8-1.5 bar. Most suitably, the solution of alkali phosphate or alkali silicate glassy material is introduced to the fluidized bed of core substrates at a pressure of 1.1-1.3 bar.
In another embodiment, the exhaust air and plurality of core substrates are maintained at a temperature of 30-50° C. during fluidization. Suitably, the exhaust air and plurality of core substrates are maintained at a temperature of 35-47° C. during fluidization.
In another embodiment, the core substrates are maintained at a temperature of 30-50° C. during fluidization. Suitably, the core substrates are maintained at a temperature of 35-47° C. during fluidization.
In another embodiment, the aqueous solution of glassy material is sprayed into the fluidization chamber using a peristaltic pump at a rate of 2-5 rpm.
As described hereinbefore, the present invention also provides tamper-proof, or abuse-deterrent, particles comprising coated particles as defined herein, the coated particles comprising at least one active ingredient.
In an embodiment, the at least one active ingredient is a drug.
The tamper-proof or abuse-deterrent particles of the present invention present an effective means of reducing, or even eliminating, the viability of dose-dumping drug misuse techniques. The coated particles prevent a user from achieving a rapid extraction of an active ingredient, either in vitro (i.e. intentionally), or in vivo (i.e. accidentally), thereby reducing the risk of users developing health issues linked to side effects, dependencies, or reduced efficacy of drugs. The solubility characteristics of the particle's coating in aqueous media mean that the efficacy of the solid dosage under physiological conditions is not compromised.
In another embodiment, the tamper-proof/abuse-deterrent particles are provided as a solid dosage form.
As described hereinbefore, the present invention also provides a solid dosage form comprising a particle defined herein, wherein the particle comprises at least one pharmaceutically active compound.
In one embodiment, the solid dosage form is intended for oral or sublingual administration.
In another embodiment, the solid dosage form comprises a particle defined herein, wherein the particle comprises two or more pharmaceutically active compounds.
In another embodiment, the solid dosage form is an extended release dosage. Given that extended release dosage often contain high quantities of active ingredients, they pose an attractive target for drug misusers.
In another embodiment, the solid dosage form comprises at least one opioid active ingredient. Although opioids are widely used for their analgesic benefits, they are increasingly targeting by drug misusers. Suitably, the opioid is oxycodone or a pharmaceutically acceptable salt thereof.
In another embodiment, the solid dosage form is suitable for use as, or alongside, an abuse-deterrent medicaments.
Examples of the invention will now be described, for the purpose of reference and illustration only, with reference to the accompanying figures, in which:
Tetraethoxyorthosilane (TEOS) (3.50 kg, 16.80 moles) and hydrochloric acid (0.1 M solution in DI water, 840 mL, 83.95 mmoles) are added to a 10 L polypropylene beaker and stirred vigorously on a stirrer/hotplate. Oxycodone hydrochloride (252 g, 717.80 mmoles) is dissolved in deionised water (1579 mL) and then added to the TEOS/0.1 M HCl mixture. The resulting biphasic mixture is covered and left to stir at room temperature (NB. the reaction is exothermic in the initial stages and the temperature of the solution rises to ˜60-65° C. before naturally cooling to room temperature). The reaction gels after ˜72 hours, at which point the gel is transferred to HDPE trays, spread out and dried in a venting oven at 60° C. for 48 hours.
The resulting solid sol-gel glass chunks are reduced in size using a FitzMill Comminutor to give ˜500 μm sized particles of the drug-loaded sol-gel carrier. This material is then placed back in the oven and left to dry. After 40 hours the powder is removed from the oven and hand-milled using a mortar and pestle and subsequently sieved through 125 and 250 μm test sieves to give the desired particle size distribution. The hand-milled powder is then returned to the oven to dry for a further 20 hours.
The coating procedure is carried out using a Glatt GPCG 3 fluid bed-coater with a Würster insert attachment. A 40% (m/v) sodium phosphate coating solution (with a weight ratio of 1.89:1 P2O5:Na2O) is first diluted to 10% (m/v). 400 g of 125-250 μm oxycodone-loaded sol-gel powder is added to the chamber of the coating machine, to the outer zone around the Würster cylinder. Fluidisation and heating is applied to the core powder for 10-15 minutes, with the following settings:
Air flow: 40 cfm
Inlet air temperature: 65° C.
Product temperature: 45° C.
Exhaust air temperature: 45° C.
Würster cylinder height: 10
The coating solution is then transferred to the coating chamber through a spray nozzle, via rubber tubing, using a peristaltic pump set at 3 rpm. The following settings are applied:
Air flow: 40 cfm
Inlet air temperature: 60° C.
Humidity dewpoint: 8.0° C.
Atomising pressure (to break coating solution into droplets): 1.2 bar
Filter shake time: 6 s
Filter shake repeat: 30 s
Product temperature: 37° C.
Exhaust air temperature: 37° C.
The amount of coating applied to the powder is calculated by measuring the weight loss of the coating solution. Usually, a target coating weight is between 1 and 5 by weight of solid glass as a function of the original sol-gel powder.
Tetraethoxyorthosilane (TEOS) (3.50 kg, 16.80 moles) was weighed out into a 10 L polypropylene beaker. Oxycodone hydrochloride (252 g, 717.80 mmoles) is dissolved in ‘extra’ deionised water (see Table 2) using an overhead stirrer and then added to the TEOS. 0.1 M hydrochloric acid (see Table 2) is then added to the reaction flask and the resulting biphasic mixture stirred vigorously using a magnetic stirrer. A homogeneous sol is formed after approximately 25 minutes, and due to the exothermic nature of TEOS hydrolysis, coincides with a maximum temperature reached of ˜62° C. The reaction beaker is covered and left to stir. After 18 hours the beaker covering is removed and the reaction left to stir at room temperature. Gellation occurs after a further X hours (see Table 3). The contents of the beaker are transferred to polypropylene drying trays and place in a vented oven at 60° C. to remove all residual solvents for Y hours (see Table 3). The resulting sol-gel glass chunks are then milled using a Retsch DM200 disc mill using progressively narrower gap widths (for individual protocols see Table 4). The milled powders are then sieved to the necessary particle size ranges (see Table 2) using 53, 90, 125, 180 and 250 μm test sieves and put in the oven for further drying for Z hours (see Table 3).
The coating procedure is carried out using a Glatt GPCG 3 fluid bed-coater with a Würster insert attachment. A 40% (m/v) sodium phosphate coating solution is first diluted to 10% (m/v). 450 g of the oxycodone-loaded sol-gel powder is added to the chamber of the coating machine, to the outer zone around the Würster cylinder. Fluidisation and heating is applied to the core powder for 10-15 minutes, with the following settings:
Air flow: 40 cfm
Inlet air temperature: 60-65° C.
Product temperature: 37° C.
Exhaust air temperature: 37° C.
Würster cylinder height: 10
The coating solution is then transferred to the coating chamber through a spray nozzle, via rubber tubing, using a peristaltic pump set at 2-5 rpm. The following settings are applied:
Air flow: 25-60 cfm
Inlet air temperature: 60-65° C.
Humidity dewpoint: 8-11° C.
Atomising pressure (to break coating solution into droplets): 1.2 bar
Filter shake time: 3/6 s
Filter shake repeat: 15/30 s
Product temperature: 37° C.
Exhaust air temperature: 37° C.
Würster cylinder height: 0-10
The amount of coating applied to the powder is calculated by measuring the weight loss of the coating solution. Usually, a target coating weight is between 1 and 5% by weight of solid glass as a function of the original sol-gel powder (see Table 5).
Aqueous solutions of the sodium phosphate and potassium silicate water-soluble glasses are first freeze-dried for 24 hours. The resulting solids are then milled and sieved to obtain glass powders of the size range 38-250 μm.
500 mg of the glass powder is added to 50 mL of the dissolution medium (pH 6.8 phosphate buffer or 40% EtOH/0.1 M HCl) and stirred. At the following time points −5, 10, 20 and 30 minutes, a 10 mL aliquot is removed and filtered through a 0.45 μm PVDF syringe filter and analysed by ICP-OES analysis for sodium, potassium, silicon and phosphorus content as required. Simultaneously, the remaining solution (˜40 mL) is filtered through a fluted filter paper. Residual solids collected on the filter paper, and left in the reaction beaker, are dried thoroughly in the oven (typically 50-80° C. overnight) and weighed.
The results of the dissolution studies are provided in
Using the procedure detailed in paragraph [0068] and [0069] above, a 1% (w/v) potassium silicate glass suspension with a ratio of 1.43:1 was made up and stirred in the dissolution medium (pH 6.8 phosphate buffer or 40% EtOH/0.1 M HCl) for 30 minutes. Aliquots of the suspension were taken at 5, 10, 20 and 30 minutes. The suspensions from the aliquots were then filtered and the resulting solids were dried at 80-95° C. overnight before being weighed to determine the % weight loss (or % dissolution).
Standard conditions as specified by the United States Pharmacopoiea (USP) guidelines were followed, using a Distek USP I apparatus (basket dissolution tester).
900 mL of dissolution media (pH 6.8 phosphate buffer and 40% EtOH/0.1 M HCl) was first de-gassed and then equilibrated to 37° C.±0.5° C. 200 mg of the formulation with the desired particle size distribution was added to 150 mesh baskets and submerged into the dissolution media and stirred at 100 rpm. At the necessary time points (every 15 minutes up to 2 hours for EtOH/HCl media and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours for phosphate buffer) 9 mL of dissolution media was removed using a Distek autosampler and analysed for oxycodone content by UV/Vis spectroscopy. The results are provided in Tables 6-9 below, and in
In general, the range of release data shown demonstrates that by varying the sol-gel processing parameters; amount of acid catalyst and particle size distribution, elution of the encapsulated active can be controlled both in terms of its rate and extent of release.
Once coated, the rate of release of the encapsulated drug from the core particles is reduced. Typically the rate of release is reduced to a greater extent when the dissolution medium is 40% EtOH/0.1 M HCl than when the dissolution medium is pH 6.8 phosphate buffer. The results also suggest that the reduction in release rate can be correlated with the amount of glass coating present.
Table 10 below provides particle size data for formulation 2 particles having a particle size of 125-250 μm. The data show that particle size is not substantially altered by the quantity of coating applied to the core substrate.
Table 11 below shows that for the disc milling process employed, the size distributions for the products formed are consistent within the nominal size ranges desired.
While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1411704.8 | Jul 2014 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2015/051930 | 7/1/2015 | WO | 00 |
