Source: http://www.patentgenius.com/patent/8709482.html
Timestamp: 2018-11-16 05:37:11
Document Index: 18882190

Matched Legal Cases: ['Application No. 2005268645', 'Application No. 2005268645', 'Application No. 2575933', 'Application No. 2005800261903', 'Application No. 2005800261903', 'Application No. 2005800261903', 'Application No. 2005800261903', 'Application No. 05763115', 'Application No. 05763115', 'Application No. 697', 'Application No. 552756']

Stabilised prostaglandin composition - Patent # 8709482 - PatentGenius
8709482 Stabilised prostaglandin composition
Foreign Patent Documents: 19842636; 19742217; 335669; 424164; 450176; 401990; 1063942; 2557576; 2705567; 2047094; 2047093; 2244920; 5600253; 1135488; 1150610; 0670952; 200502691; 2002515069; 2001513550; 2011507405; WO8001984; WO8905319; WO8907117; WO9102763; WO9403510; WO9413724; WO9422934; WO9606875; WO9615171; WO9621427; WO9631551; WO9638153; WO9717386; WO9724109; WO9856323; WO9909964; WO9947073; WO9956731; WO9956731; WO0000222; WO0040222; WO0203896; WO0209631; WO03011301; WO03087183; WO2004029125; WO2004084872; WO2005063145; WO2005068533; WO2005089778; WO2005116100; WO2006013335; WO2006048639; WO2008007098; WO2009094573; WO2010035837; WO2010119029; WO2011011099; WO2011039418
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Abstract: A pharmaceutical delivery device, such as a suppository or pessary, comprises a synthetic prostaglandin PGE.sub.1 analogue (e.g. misoprostol) in a solid polyurethane hydrogel.
1. A pharmaceutical delivery device, comprising: a formulation comprising misoprostol in a polyurethane hydrogel, wherein the hydrogel has a water content of less than0.2% by weight.
10. The delivery device of claim 1, wherein the misoprostol is present in the formulation in an amount ranging between 25 and 400 .mu.g.
11. The delivery device of claim 10, wherein the misoprostol is present in the formulation in an amount of 100 .mu.g.
12. The delivery device of claim 10, wherein the misoprostol is present in the formulation in an amount of 200 .mu.g.
17. A method for inducing labor, comprising: contacting the delivery device of claim 1 with a body cavity.
19. An article, comprising: the pharmaceutical delivery device of claim 1, and a desiccant.
20. The delivery device of claim 1, wherein the misoprostol is present in the formulation in an amount ranging between 100 and 400 .mu.g.
21. The delivery device of claim 1, wherein the misoprostol is present in the formulation in an amount ranging between 100 and 200 .mu.g.
The present invention provides a pharmaceutical delivery device comprising a synthetic prostaglandin PGE.sub.1 analogue, such as misoprostol or analogues or derivatives thereof and a polyurethane hydrogel; and also uses and methods ofpreparation of such a device.
Prostaglandins are a group of lipids, which are modified fatty acids attached to a 5-membered ring and with biological/pharmaceutical activities suitable for a variety of therapeutic uses. Such uses include reproductive health disorders anddisorders linked to inflammatory response. However, prostaglandins are often unstable under ambient conditions and have sometimes proved difficult to store and produce in a form suitable for pharmaceutical/therapeutic use.
A prostaglandin formulation, which allows controlled release of the active compound for therapeutic use is described in patent specifications GB 2047093 and GB 2047094. Such formulations use hydrogels, which are known sustained release deliveryvehicles; and in particular, "solid" cross-linked polyurethane materials having the ability to swell and absorb several times their own weight of water whilst retaining their physical integrity. The formulations have been provided as pessaries todeliver dinoprostone (a PGE.sub.2 prostaglandin) to the cervix to ripen it prior to the induction of labour, and is available under the trademarks Propess.RTM. and Cervidil.RTM.. The pessary is enclosed in a net pouch and usually remains in place inthe cervix for up to 24 hours. However, this prostaglandin, even when loaded into such hydrogels, is somewhat unstable at room temperature and therefore the pessary is generally stored at temperatures of around -20.degree. C.
Various attempts have been made to provide stabilised formulations of prostaglandins in general. PGE.sub.2 prostaglandins tend to be more unstable than PGE.sub.1 prostaglandins.
Misoprostol is a synthetic prostaglandin analogue; in particular, a cytoprotective prostaglandin PGE.sub.1 analogue. Misoprostol is a compound represented by the following stereoisomeric formulae:
Misoprostol in its physical state is an oil, which is difficult to formulate and unstable at room temperature. Misoprostol possesses mucosal protective properties and is an inhibitor of gastric acid secretion. Misoprostol has been usedpreviously in the treatment and prevention of gastric ulcers, in particular NSAID-induced ulcers.
U.S. Pat. No. 6,642,274 discloses use of a large number of prostaglandins, including misoprostol. However, there is no focus on the problems of formulating misoprostol. Hydrogels are mentioned but these are semi-liquid compositions or lowmelting compositions suitable for suppositories.
US Patent Publication 2003/0050620 discloses prostaglandins in general but not PGE.sub.1 analogues. Hydrogels are mentioned but the problems of formulating PGE.sub.1 analogues are not addressed.
It is an object of the present invention to provide a PGE.sub.1 formulation showing increased stability properties compared with unformulated misoprostol; and in particular to provide a solid state misoprostol formulation which has increasedstorage stability at room temperature.
The present invention is based on the unexpected observation that the stability of a synthetic prostaglandin PGE.sub.1 analogue, misoprostol, at room temperature is increased when formulated in a polyurethane hydrogel. This increased stabilityis surprising and is not exhibited by other prostaglandins, such as dinoprostone, when formulated in this way.
In a first aspect of the present invention there is provided a pharmaceutical delivery device comprising a synthetic prostaglandin PGE.sub.1 analogue or derivative thereof in a polyurethane hydrogel.
The pharmaceutical delivery device allows the effective sustained delivery of the pharmaceutical, a synthetic prostaglandin PGE.sub.1 analogue, such as misoprostol, from the solid state hydrogel. Typically, the pharmaceutical is intended to bedelivered to a patient (human or animal).
Generally, the synthetic prostaglandin PGE.sub.1 analogue is dispersed throughout the polyurethane hydrogel matrix.
The polyurethane hydrogel of the pharmaceutical delivery device of the present invention extends to polyurethane hydrogels well known to the man skilled in the art. Without wishing to be bound by theory, said polyurethane hydrogels whenhydrated form a gel but do not dissolve. They are solid in the sense that, whilst being swellable, they retain their physical integrity without becoming a liquid or semi-liquid gel. The polyurethane hydrogels are capable of being loaded with thesynthetic prostaglandin PGE.sub.1 analogue, such as misoprostol. The polyurethane hydrogels may be cross-linked or linear polymers. Furthermore, the polyurethane hydrogels may be swollen in a "wet state" or unswollen in a "dry" or "desiccated" state inthe device of the invention. These states will be described further below.
Alternatively, the delivery device of the present invention may include a polyurethane hydrogel, as described in patent specification WO 2004/029125. This patent specification discloses linear polyurethane hydrogels. Such linear polyurethanehydrogels may be obtained by reacting a polyethylene glycol and a diol or other difunctional compound with a difunctional isocyanate.
Without wishing to be bound by theory and unless otherwise stated herein, it should be understood that the properties and variables of the hydrogels as described in GB 2047093, GB 2047094 and WO 2004/029125 are applicable to the presentinvention.
Typically, the cross-linked polyurethane hydrogel (as described in GB 2047093 and GB 2047094) is prepared from a long chain polyethylene glycol (e.g. PEG 2000, 4000, 6000 and 8000, which has been extensively dried), a triol (for example,hexanetriol) as cross-linking agent and a diisocyanate (such as dicyclohexyl methane diisocyanate). The mixture is cured at elevated temperatures in a mould.
Typically, the linear polyurethane hydrogel is prepared from a) a polyethylene oxide, b) a difunctional compound and c) a difunctional isocyanate (as described in WO 2004/029125). Advantageously, the linear polyurethane hydrogel is swellable inwater and suitable as a carrier for the synthetic prostaglandin PGE.sub.1 analogue in the delivery device of the present invention. Furthermore, the linear polyurethane hydrogel of the delivery device of the present invention may be loaded with poorlywater-soluble pharmaceutical agents, such as a synthetic prostaglandin PGE.sub.1 analogue, including misoprostol, for example when such agents are dissolved in a common solvent with the polymer. An example of a solvent is ethanol. The resultantsolution may then be cast into any desired solid forms.
The polyurethane hydrogels for use in the present invention provide water-swellable polyurethane polymers having swellabilities, for example up to 500%, up to 800% or even about 1,000%. Percent (%) swelling, is understood to mean the increasein weight of the swollen polymer divided by the weight of the dry polymer. Usually, the polymer is swellable in the range 200% to 2000%, for example 250 to 1700%. The linear polyurethane hydrogels are also soluble in certain organic solvents, such asdichloromethane, which allows the hydrogel to be dissolved and cast into films or coatings. Therefore, as mentioned above, it also allows active agents of poor water solubility but which are soluble in organic solvents, such as misoprostol, to be loadedinto the polymer.
Polyethylene oxides contain the repeat unit (CH.sub.2CH.sub.2O) and are conveniently prepared by the stepwise addition of ethylene oxide to a compound containing a reactive hydrogen atom. Polyethylene glycols are prepared by the addition ofethylene oxide to ethylene glycol to produce a difunctional polyethylene glycol structure HO(CH.sub.2CH.sub.2O).sub.nH wherein n is an integer of varying size depending on the molecular weight of polyethylene oxide. For example, polyethylene oxides usedin the linear polyurethane hydrogels of the present invention are generally linear polyethylene glycols i.e. diols having a equivalent weight of 1500 to 20,000, particularly 3000 to 10,000 and especially 4000 to 8000. Molecular weights are usually inthe region 4000 to 35,000.
In this description the term "equivalent weight" is used as meaning the number average molecular weight divided by the functionality of the compound.
The difunctional compound is reactive with the difunctional isocyanate, and is typically a difunctional amine or diol. Diols in the range C.sub.5 to C.sub.20, preferably C.sub.8 to C.sub.15 are preferred. Thus, decane diol has been found toproduce particularly good results. The diol may be a saturated or unsaturated diol. Branched diols may be used but straight chain diols are preferred. The two hydroxy groups are generally on terminal carbon atoms. Thus, preferred diols include1,6-hexanediol, 1,10-decanediol, 1,12-dodecanediol and 1,16-hexadecanediol.
The ratio of the components (a) to (b) to (c) of the linear polymer described above (in terms of equivalent weights) is generally in the range 0.1-1.5 to 1 to 1.1-2.5, particularly 0.2-0.9 to 1 to 1.2-1.9. A preferred range is 0.5-0.9 to 1 to1.5-1.9. Of course, the skilled man through reasonable experimentation would determine the best ratio of ingredients to give the desired properties. The amount of component (c) is generally equal to the combined amounts of (a) and (b) to provide thecorrect stoichiometry.
Linear polyurethane hydrogels produced at extreme ends of the ranges may not necessarily give optimal properties. For example, high amounts of (a) polyethylene oxide may undesirably lead to the polymer being water-soluble. Small amounts mayreduce the percentage swelling. Generally, the ratio of (a) polyethylene oxide to (b) difunctional compound is preferable 0.1-1.5 to one, preferably 0.2-0.9 to one.
The linear polyurethane hydrogels are generally produced by melting the previously dried polyethylene glycol together with the difunctional compound (e.g. diol) at a temperature of around 85.degree. C. A catalyst such as ferric chloride isincorporated. The molten mixture is dried under vacuum to remove excess moisture and the diisocyanate added thereto. The reaction mixture is then poured into billet moulds and cured for a specified time. Thus, the linear polyurethane hydrogel isinitially formed as a moulded solid. However, the linear polyurethane hydrogels of the delivery device of the present invention are soluble in certain organic solvents. This allows the polymer to be dissolved and the resultant solution cast to formfilms. The solution may also be employed for coating granules, tablets etc., in order to modify their release properties. Alternatively, the solution can be poured into a non-solvent so as to precipitate polymer/active microparticles.
Generally, the polyurethane hydrogel is washed in water, followed by washing in an ethanol:water mixture before being loaded with a synthetic prostaglandin PGE.sub.1 analogue by soaking the hydrogel in an aqueous solution of a syntheticprostaglandin PGE.sub.1 analogue of required concentration for a time sufficient for uptake of the synthetic prostaglandin PGE.sub.1 analogue to occur, followed by drying the hydrogel down to the required water content. Typically, the syntheticprostaglandin PGE.sub.1 analogue is dissolved in organic solvent, such as an ethanol:water solvent, before being loaded into the polyurethane hydrogel.
The term "synthetic prostaglandin PGE.sub.1 analogue" as used herein is understood to cover the compound generally known as misoprostol and any analogues or derivatives thereof. Analogues or derivatives thereof are intended to encompassstructural analogues or derivatives of the synthetic prostaglandin PGE.sub.1 analogue which maintain the essential pharmaceutical activity of the synthetic prostaglandin PGE.sub.1 analogue, including misoprostol; for example, prostaglandins of differentchain length, or different salts or esters which maintain pharmacological activity. These may also encompass stereoisomers of the synthetic prostaglandin PGE.sub.1 analogue, such as misoprostol. It will be understood that the term syntheticprostaglandin PGE.sub.1 analogue (or misoprostol) is not intended to encompass naturally occurring PGE.sub.1. Synthetic PGE.sub.1 analogues or derivatives may be in the form of an ester; such as a methyl ester: whereas said naturally occurring PGE.sub.1is normally in the acid form. One or more C.sub.1-6 alkyl groups (particularly methyl) may be attached to the prostanoic acid carbon chain, especially at the 15-position. Typically, misoprostol PGE.sub.1 analogue or derivative in its physical state isan oil, whereas naturally occurring PGE.sub.1 is in a crystalline form.
Misoprostol should be understood to mean (11.alpha.,13E)-(.+-.)-11,16-Dihydroxy-16-methyl-9-oxoprost-13-en-1-oic acid methyl ester or analogue(s) or derivative(s) thereof, as described herein. Preferably, misoprostol has the formulaC.sub.22H.sub.33O.sub.5 or the general structure as hereinbefore described.
The delivery device of the present invention may be in the form of a suppository, a pessary for vaginal use, a buccal insert for oral administration, an implant etc. Preferably, the device is in the form of a comfortable unit, which is flexibleenough (particularly when swollen) to be accommodated within a body cavity: for example, buccal cavity in intimate contact with the mucosal membrane. Preferred shapes include sheets, discs, ovals, kidney shapes, strips and cylinders. Generally, thesmallest dimension is in the range 5-15 mm and the longest dimension in the range 10-25 mm. Preferred thicknesses are in the range 0.5-5 mm, especially 0.5-2.5 mm, particularly 1-2.5 mm and more particularly 0.8-1.5 mm. It will be understood, however,that length and thickness of said delivery device may be altered and designed to preferred sizes per individual patient.
The delivery device of the present invention has a number of applications including the treatment of schizophrenia, prevention of gastric ulcers, mucositis and orthodontic applications. Typically, the device is used for its action upon thefemale reproductive system of both human and non-human animals. Preferably, the device of the present invention is used in the induction of labour. The device may also be used for first and second trimester abortion and the prevention of postpartumhaemorrhage (PPH).
The pharmaceutical delivery device of the present invention is intended to administer a synthetic prostaglandin PGE.sub.1 analogue to a patient, remaining in place until partial or complete delivery of the synthetic prostaglandin PGE.sub.1analogue has occurred. The spent delivery device may then be removed from the patient. Advantageously, the delivery device may further comprise means for removal of the device from a patient. For example, using means well known to the person skilledin the art, such as removal means used for conventional tampons for vaginal use.
An objective of the present invention is the stabilisation of a synthetic prostaglandin PGE.sub.1 analogue in the delivery device of the present invention, especially at temperature above +4.degree. C., particularly at room temperature ofaround +20.degree. C. The synthetic prostaglandin PGE.sub.1 analogue-containing delivery device of the present invention allows the controlled release of a synthetic prostaglandin PGE.sub.1 analogue into a patient. At low water contents, the deliverydevice may adhere to the mucosal membrane of a patient. The synthetic prostaglandin PGE.sub.1 analogue may be absorbed systemically or may exert a local action on adjacent tissue structures. Typical autoadhesive properties for improved means ofdelivery of said synthetic prostaglandin PGE.sub.1 analogue to a patient are described in WO 00/32171.
Typically, stabilisation of synthetic prostaglandin PGE.sub.1 analogue is understood to mean the increased stability or, conversely, the decreased degradation of this prostaglandin at temperatures above 4.degree. C. within the delivery deviceof the present invention. For example, wherein the percent dose of the synthetic prostaglandin PGE.sub.1 analogue present within the delivery device of the present invention after storage at temperatures above 4.degree. C. (preferably room temperatureof around 20.degree. C.) is within a range of 90-100% of initial dose of the synthetic prostaglandin PGE.sub.1 analogue added to the delivery device of the present invention. The stability also depends on the water content of the hydrogel.
If necessary, penetration enhancers, as known in the art, may be employed to assist the rate of transmucosal delivery, depending on the nature of the synthetic prostaglandin PGE.sub.1 analogue, for example, its lipophilic or hydrophiliccharacteristics, size and molecular weight. Generally, the more lipophilic the compound, the better the absorption. The nonionized form of a synthetic prostaglandin PGE.sub.1 analogue appears to be best for absorption. In view of the rapid andeffective delivery through mucosal tissues, penetration enhancers may not be required. Such penetration enhancers are known from topical application to skin tissue, which constitutes a more significant barrier to absorption. Weak acids and somedetergents have been used as penetration enhancers.
The release properties of the polyurethane hydrogel of the delivery device of the present invention may be modified by applying a coating thereto. The synthetic prostaglandin PGE.sub.1 analogue may be included in a coating as well as in thehydrogel matrix in order to provide a desired delivery profile.
The polyurethane hydrogel of the delivery device of the present invention in use may be in a swollen or "wet" state or unswollen in a "dry" or "desiccated" state as hereinbefore described. For example, in swollen state water content may be30-40% by weight. Preferably, 25% by weight or less. More preferably, 5-10% by weight. Alternatively, in unswollen or dry state the polyurethane hydrogel usually contains little or no water. For example, about 1-2 wt %. Preferably, the water contentof the hydrogel is about or less than 1%. More preferably, the water content is around 0.5% to around 0.8%. Even more preferably the water content of the polyurethane hydrogel is about or less than 0.1%.
Advantageously, the delivery device of the present invention in its "dry" state lends to easier storage before use, including at temperatures above 4.degree. C., such as room temperature of 20.degree. C., without loss of or reduced syntheticprostaglandin PGE.sub.1 analogue activity. Indeed, as hereinbefore described, the synthetic prostaglandin PGE.sub.1 analogue displays increased stability when formulated in the polyurethane hydrogel delivery devices of the present invention. Typically,said dry state may contain a water content of around 0.5% to around 0.8% and be stored with a desiccant to further reduce the water content of the delivery device.
Typically, the water content of the hydrogel is less than or about 0.1% when said hydrogel is desiccated or in "dry" state. Generally, the desiccated hydrogel may absorb water from the surroundings after administration.
Typically, the delivery device of the present invention comprises: synthetic prostaglandin PGE.sub.1 analogue in a dose of about 25 to 400 micrograms (.mu.g); has a thickness of around 0.4 to 1.5 mm; and has a weight of around 120 to 500milligrams (mg). Typically, a dose of synthetic prostaglandin PGE.sub.1 analogue of around 100 .mu.g is contained within a polyurethane hydrogel of around 241 mg weight and of around 0.8 mm thickness.
a) contacting a polyurethane hydrogel with an aqueous solution of synthetic prostaglandin PGE.sub.1 analogue such as to swell the hydrogel;
In a yet further aspect of the present invention there is provided use of the pharmaceutical delivery device of the present invention for controlled administration of a synthetic prostaglandin PGE.sub.1 analogue to a human or animal.
FIG. 1--shows a graph displaying the results of enhanced stability of polyurethane hydrogel containing 100 .mu.g misoprostol (desiccated and undesiccated batches) at 25.degree. C. The results are compared against the stability of MisoprostolOil standard (in the absence of polyurethane hydrogel) which degrades with time at 25.degree. C.
FIG. 2 (Comparison)--shows a graph of the stability of bulk drug crystal of dinoprostone (a PGE.sub.2 prostaglandin), and dinoprostone loaded into polyurethane hydrogel at 25.degree. C. The dinoprostone is less stable when contained in thehydrogel; and both the hydrogel and non-hydrogel samples show considerable degradation over time.
0.8 mm Polymer slices are purified by submerging in an excess of water for a first and second wash for a number of hours. The water is decanted after each wash and then the units are finally washed in an ethanol (25%):water mixture for afurther few hours. This solution is again discarded.
The correct amount of misoprostol is weighed to achieve the desired final potency and dissolved in ethanol (25%): water along with the Butylated Hydroxy Anisole (BHA) used to stabilise the polymer. Sufficient of this solution is made tosubmerge the previously washed units and the units left to rotate in a closed vessel for a period at 4.degree. C. The excess loading solution is decanted off and the units shaken dry.
Loaded inserts are placed in a tablet coating pan and rotated at ambient temperature and air and finally dehumidified air. Units may then be inserted into a retrieval tape and packaged appropriately. The solvent remaining in the units (water)is typically less than 1% at this stage (about 0.5-0.8%). The addition of a desiccated label inside the packaging reduces this down to 0.1-0.2%.
100-400 .mu.g Doses
The series of concentrations required for misoprostol standard preparation is described below. However, prior to the dilution to the mark of the misoprostol standard, pipette a volume of BHA stock solutions ca 40 .mu.g/ml and 70 .mu.g/mlprepared in mobile phase that would represent 10% of the total volume of the flask, i.e., 20 ml in 200 ml and 50 ml in 500 ml for respective extraction volume scenarios.
A level one standard of approximately 8 mg and a level two standard of approximately 12 mg of misoprostol reference standard was accurately weighed and added each to separate 100 ml volumetric flask containing approximately 50 ml of 70% methanolmobile phase. Flasks were placed in an ultrasonic bath for 5 minutes and agitated on a flat bed shaker for no less than one hour. Standard flasks were diluted to volume with 70% methanol mobile phase. Depending on the target potency of the particularbatch, the two standard solutions were diluted with 70% mobile phase using the guidelines outlined in table 1 below.
TABLE-US-00001 TABLE 1 Standard Dilution Guidelines for Misoprostol Analysis Batch Target Potency Standard Dilution (.mu.g/unit) Potency Determination 100 1 in 20 200 1 in 10 300 1 in 15 400 1 in 10
Sample Preparation--for 100-400 .mu.g Doses
10 pessary units were swollen in 40 ml of mobile phase. The units were then transferred to a Waring blender, macerated and quantitatively transferred to the appropriate volumetric flask through washing with mobile phase. The beaker used toswell the units was washed with mobile phase into the volumetric flask (see table 2). The flask and its contents were then shaken on a flat bed shaker for 2 hours, after 1 hour the neck of the flask was washed down with mobile phase. The flask was thendiluted to the mark with mobile phase and contents allowed to settle and equilibrate for 20 minutes prior to sampling into HPLC vials.
TABLE-US-00002 TABLE 2 Extracting Volumes for Misoprostol Analysis Batch Target Potency Extraction Volume (.mu.g/unit) (ml) 100 200 200 200 300 500 400 500
Misoprostol potency, together with the related impurities 8-iso misoprostol, dehydroxy misoprostol type A and unidentified impurity peaks were quantified with reference to the area response factor from the prepared misoprostol standard solutionsusing the following expression.
Note Standard Concentrations for Calibration are Expressed in Terms of .mu.g Misoprostol Per ml
.times..times..times..times..times..times..times..times..times..times..ti- mes..times..times..times..times..times..times..times. ##EQU00001## .times..times..times..times..times..times..times..times..times..times..ti-mes..times..times..times..times..times. ##EQU00001.2##
Stability Study of Misoprostol Oil at 25.degree. C.
Misoprostol stability was tested over a period of 6 months. The misoprostol tested was the commercially available misoprostol in the form of an oil. Misoprostol was stored at a temperature of 25.degree. C., and misoprostol content measuredusing HPLC at 0, 2, 4, 8 weeks and 3 and 6 months.
TABLE-US-00003 TABLE 1 Attribute Specification 0 2 w 4 w 8 w 3 m 6 m Physical Clear Colourless Colourless Colourless Clear Straw Yellow form colourless to oil oil oil colourless yellow oil yellow oil oil oil Misoprostol 97.0-102.0% 101.59 99.6198.59 96.87 93.63 57.07 content w/w
Stability Study of Desiccated and Undesiccated Polyurethane Polymers loaded with Misoprostol (Misoprostol Batches of Dose 100 .mu.g, 200 .mu.g, and 400 .mu.g)
A stability study was carried out on batches of dose 100 .mu.g, 200 .mu.g, and 400 .mu.g of misoprostol. Desiccated and undesiccated packaged pessaries were stored at -20.degree. C., 4.degree. C., 25.degree. C. and 40.degree. C./75%relative humidity, to study the effect of these conditions on the formulation over a 12 month period.
The main focus of the study was misoprostol potency and levels of degradation products/impurities. BHA levels, release rate testing, loss on drying and % swelling testing were also carried out. Results are shown below for desiccated andundesiccated misoprostol containing hydrogels stored at 25.degree. C.
2.1-25.degree. C. Data for Undesiccated Batches
2.1.1 100 .mu.g Misoprostol Dose Batch
Shown in Table 4 are the misoprostol potencies and the levels of degradation product/impurities found for the undesiccated 100 .mu.g batch, over 12 months at 25.degree. C. Results are also displayed in FIG. 1.
TABLE-US-00004 TABLE 4 Misoprostol potency degradation product/impurities levels of undesiccated 100 .mu.g batch, over 12 months at 25.degree. C. 8-iso Misoprostol Misoprostol misoprostol A Time Point .mu.g/unit % Label % Initial % Label %Label Initial 103.9 103.9 100.0 0.7 0.1 4 weeks 102.1 102.1 98.3 0.9 0.3 4 months 98.8 98.8 95.1 1.0 0.5 7 months 94.0 94.0 90.5 0.8 1.4 12 months 97.9 97.9 94.2 1.0 2.5
Misoprostol potency for this batch falls over the 12 month duration of the study at 25.degree. C. The potency value has dropped to 94.2% of the initial value. Levels of 8-iso misoprostol, over the study period at 25.degree. C. reach a maximumof 1.0% label. Misoprostol A levels increase over the 12 month period, reaching a maximum of 2.5% label.
2.1.2 200 .mu.g Dose Batch
Shown in Table 5 are the misoprostol potencies and the levels of degradation product/impurities found for the undesiccated 200 .mu.g batch, over 12 months at 25.degree. C.
TABLE-US-00005 TABLE 5 Misoprostol potency degradation product/impurities levels of undesiccated 200 .mu.g batch, over 12 months at 25.degree. C. 8-iso Misoprostol Misoprostol misoprostol A Time Point .mu.g/unit % Label % Initial % Label %Label Initial 206.3 103.1 100.0 0.5 ND 4 months 202.3 101.2 98.1 0.9 0.8 12 months 192.8 96.4 93.5 1.1 1.5 ND--none detected
Misoprostol potency has fallen for this batch over the 12 month duration of the study at 25.degree. C. The potency value has dropped to 93.5% of the initial value. Levels of 8-iso misoprostol reached 1.1% label. Misoprostol A levels increaseover the 12 month period, reaching a maximum of 1.5% label.
2.1.3 400 .mu.g Dose Batch
Shown in Table 6 are the misoprostol potencies and the levels of degradation product/impurities found for the undesiccated 400 .mu.g batch, over 12 months at 25.degree. C.
TABLE-US-00006 TABLE 6 Misoprostol potency degradation product/impurities levels of undesiccated 400 .mu.g batch, over 12 months at 25.degree. C. 8-iso Misoprostol Misoprostol misoprostol A Time Point .mu.g/unit % Label % Initial % Label %Label Initial 424.3 106.1 100.0 1.0 0.5 4 weeks 416.6 104.2 98.2 1.0 0.8 4 months 404.7 101.2 95.4 1.1 1.2 7 months 389.2 97.3 91.7 1.0 1.8 12 months 382.1 95.5 90.1 1.3 2.6
Misoprostol potency has dropped for this batch over the 12-month duration of the study at 25.degree. C. The potency value has dropped to 90.1% of the initial value. Levels of 8-iso misoprostol reached 1.3% label. Misoprostol A levels increaseover the 12-month period, reaching a maximum of 2.6% label.
2.1.4 100 .mu.g-400 .mu.g Doses--Summary of Findings for Undesiccated Doses--Storage at 25.degree. C.
Misoprostol potency in all three undesiccated doses falls over the 12-month duration of the study at 25.degree. C. Potency values have dropped to between 90.1% and 94.2% of the initial values of the doses. 400 .mu.g batch, shows the largestdrop to 90.1% initial. Levels of 8-iso misoprostol do not show any marked change over the study period at 25.degree. C. with maximums of 1.3% label found. Misoprostol A levels increase over the 12-month period, reaching maximum levels of 2.6% label inthe 400 .mu.g batch, at 25.degree. C.
2.2-25.degree. C. Data for Desiccated Batches
2.2.1 100 .mu.g Dose Batch
Shown in Table 7 are the misoprostol potencies and the levels of degradation product/impurities found for the desiccated 100 .mu.g batch, over 12 months at 25.degree. C. Results are also displayed in FIG. 1.
TABLE-US-00007 TABLE 7 Misoprostol potency degradation product/impurities levels of desiccated 100 .mu.g batch, over 12 months at 25.degree. C. 8-iso Misoprostol Misoprostol misoprostol A Time Point .mu.g/unit % Label % Initial % Label % LabelInitial 103.9 103.9 100.0 0.7 0.1 4 weeks 90.1 90.1 86.7 0.2 0.4 6 months 101.6 101.6 97.8 0.5 1.4 12 months 102.4 102.4 98.6 0.7 1.9
Generally for this dose misoprostol potencies fall within 97% to 100% initial over the 12 month duration of the study at 25.degree. C. The exception is the 3-month time point. At this test point the misoprostol potency was found to be 86.7% ofthe initial value. This is out of character with the other test points at this temperature for this batch and of other batches tested at this test point for the same storage condition. For levels of 8-iso misoprostol, no change over the study period at25.degree. C. with maximums of 0.7% label found. Misoprostol A levels increase slightly over the 12-month period, reaching maximum levels of 1.9% label.
2.2.2 200 .mu.g Dose Batch
Shown in Table 8 are the misoprostol potencies and the levels of degradation product/impurities found for the desiccated 200 .mu.g batch, over 12 months at 25.degree. C.
TABLE-US-00008 TABLE 8 Misoprostol potency degradation product/impurities levels of desiccated 200 .mu.g batch, over 12 months at 25.degree. C. 8-iso Misoprostol Misoprostol misoprostol A Time Point .mu.g/unit % Label % Initial % Label % LabelInitial 209.2 104.6 100.0 1.0 0.6 12 months 202.0 101.0 96.6 1.1 2.6
Misoprostol potency drops very slightly over the 12 month duration of the study at 25.degree. C. for this dose, down to 96.6% initial. Levels of 8-iso misoprostol show no change over the study period at 25.degree. C. with maximums of 1.1%label found. Misoprostol A levels increase slightly over the 12-month period, reaching maximum levels of 2.6% label.
2.2.3 400 .mu.g Dose Batch
Shown in Table 9 are the misoprostol potencies and the levels of degradation product/impurities found for the desiccated 400 .mu.g batch, over 12 months at 25.degree. C.
TABLE-US-00009 TABLE 9 Misoprostol potency degradation product/impurities levels of desiccated 400 .mu.g batch, over 12 months at 25.degree. C. 8-iso Misoprostol Misoprostol misoprostol A Time Point .mu.g/unit % Label % Initial % Label % LabelInitial 424.3 414.0 100.0 1.0 0.5 4 weeks 424.4 106.1 100.0 1.0 0.8 6 months 409.1 102.3 96.4 1.6 1.2 12 months 408.3 102.1 96.2 0.8 2.2
Misoprostol potency drops very slightly over the 12-month duration of the study at 25.degree. C. for this dose, down to 96.2% initial. Levels of 8-iso misoprostol show no change over the study period at 25.degree. C. although a maximum of1.6% label is found at 6 months. Misoprostol A levels increase slightly over the 12-month period, reaching maximum levels of 2.2% label
2.2.4 100 .mu.g-400 .mu.g Doses--Summary of Findings for Desiccated Doses--Storage at 25.degree. C.
For all three desiccated doses, misoprostol potency drops very slightly over the 12-month duration of the study at 25.degree. C. Generally potencies fall within 96% to 100% of the initial values. The exception being the 100 .mu.g batch after 4weeks, which has a potency of 86.7% of the initial value. This is out of character with the other test points at this temperature for this batch. Levels of 8-iso misoprostol showed no change over the study period at 25.degree. C. although a maximum of1.6% label is found. Misoprostol A levels increase slightly over the 12 month period, reaching maximum levels of 2.6% label in the 200 .mu.g batch, at 25.degree. C.
Misoprostol potency and levels of degradation products/impurities remain unchanged after 12 months/15 months storage at -20.degree. C. for both desiccated and undesiccated doses.
Desiccation appears to improve the stability of the misoprostol over 12 months at 4.degree. C. and particularly at 25.degree. C. and 40.degree. C. At 25.degree. C., after 12 months, desiccated batches have misoprostol potencies greater than95% of their initial values, whereas undesiccated batches of the same dose have potencies ranging from 90% to 94% of their initial value. At 40.degree. C., after 12 months desiccated doses have misoprostol potencies of typically 90% of their initialvalues, whereas undesiccated doses range from 83% to 88% of their initial values. Correspondingly, at 40.degree. C. levels of misoprostol A are greater in undesiccated batches than desiccated batches of the same dose.
Levels of the polymer stabilising excipient, butylated hydroxy anisole (BHA) remain fairly constant in all desiccated and undesiccated batches at 25.degree. C. over 12 months.
Loss on drying data shows no change over 12 months at 25.degree. C. for undesiccated batches (results not shown). There was a decrease in loss on drying values for desiccated batches at 25.degree. C. (results not shown).
% Swelling values remained within specification (275-3250) for all the desiccated doses at 25.degree. C. over the 12-month study period (results not shown).
Comparative Stability Results at 25.degree. C. For Polyurethane Hydrogel Loaded with Dinoprostone
The following Table 10 shows the stability of dinoprostone (a PGE.sub.2 prostaglandin) both as a bulk drug crystal and contained within a polyurethane hydrogel matrix at 25.degree. C. Measurements are taken at 0, 1, 2, 3, and 6 months. Thefollowing results are for comparative purposes only and are not intended to form part of the present invention.
TABLE-US-00010 TABLE 10 Dinoprostone Test Point Dinoprostone in the hydrogel (months) (% potency) (% potency) 0 100 103.5 1 96 90.9 2 83.0 3 89 75.3 6 75 57.1
Thus, in contrast to the misoprostol hydrogel formulation of the present invention, the formulation of dinoprostone in a hydrogel reduces its storage stability. Moreover, dinoprostone both with and without hydrogel shows marked degradation onstorage.
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