OA16256A - Antipsychotic injectable depot composition. - Google Patents
Antipsychotic injectable depot composition. Download PDFInfo
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- OA16256A OA16256A OA1201200488 OA16256A OA 16256 A OA16256 A OA 16256A OA 1201200488 OA1201200488 OA 1201200488 OA 16256 A OA16256 A OA 16256A
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- Prior art keywords
- rispéridone
- drug
- polymer
- solvent
- composition
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- 201000000980 schizophrenia Diseases 0.000 claims description 5
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- RAPZEAPATHNIPO-UHFFFAOYSA-N Risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 abstract description 25
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 60
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 57
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- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
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- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
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- KTZQTRPPVKQPFO-UHFFFAOYSA-N Benzisoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention is directed to a composition that can be used to deliver an antipsychotic drug such as risperidone as an injectable in-situ forming biodegradable implant for extended release providing therapeutic plasma levels from the first day. The composition is in the form of drug suspension on a biodegradable and biocompatible copolymer or copolymers solution using water miscible solvents that is administered in liquid form. Once the composition contacts the body fluids, the polymer matrix hardens retaining the drug, forming a solid or semisolid implant that releases the drug in a continuous manner. Therapeutic plasma levels of the drug can be achieved since the first day up to at least 14 days or more.
Description
ANTIPSYCHOTIC INJECTABLE DEPOT COMPOSITION
TECHNICAL F1ELD
The présent invention is related to implantable compositions for extended drug-delivery devîces comprising certain atypical antipsychotic drugs, particularly rispéridone. Spccifïcally, the présent invention is related to compositions for injectable in-sîtu forming biodégradable implants comprising rispéridone.
BACKGROUND ART
Rispéridone is an atypical antipsychotic drug with benzisoxazole and piperidine fonctional groups, which acts as strong dopaminergic antagonist and sélective serotonin receptor antagonist. Rispéridone is FDA approved for the treatment of schizophrenia since 1993. It is the only drug presently approved for the treatment of schizophrenia in young people under 18 years, and together with lithium, for the treatment of bipolar disorders in chîldrcn/youth âges between 10-18 years old. Convcntional rispéridone therapy of schizophrenia involves daily oral tablets, although it is also available as a solution and orally disintegrating tablets.
In fact, one of the intrinsic problems that risperidone-targeted patients usually face is the dissociation of some schizophrénie patients from the treatment, moreover when it consiste of a daily médication, leading to irregular or inconstant treatments and favouring the appearance of psychotic crisis. Moreover, this kind of therapy gives rise to high différences in the plasma leve'ls (measured as the différence between Cmax and Cmin) in patients, thcrcforc usually affecting the patient’s mood.
Rispéridone is therefore a good drug candidate for incorporation into sustained delîvery devices, where the patients would be covered or treated for long time periods with just one dose and without the need of caregivers to pay attention to a daily médication, and where more homogeneous plasma Ievels in the patient are désirable.
-2One of the most usual ways to administer rispéridone présently is through the use of depot injections. Depot injections allow carefül control of drug usage (as opposed to orally administered drugs) and ensure regular contact between the caregivers team and the patient, where overall treatment efficacy and/or side effects may be identified.
Furthermore, it is easy to identify defaulters and préparé interventions. However, in situ forming implants currently described in the statc of the art cannot properly control rispéridone release from the implant, and fail to allow obtaining therapeutic plasma levels in a bi-weekly administration protocol, with rcasonable différences between maximum and minimum concentrations.
Currently, the long-acting injectable rispéridone formulation, Risperdal Consta®, is the first depot atypical antipsychotic drug in the market. It is an intramuscular risperidonecontaining PLGA microparticles formulation and is intended to deliver therapeutic levels of rispéridone by bi-weekly administrations. However, due to the inhérent lag 15 phase of most microparticlc based products, the patient is required to supplément the first weeks with daily doses of oral rispéridone after first administration. Approximately three weeks after a single intramuscular injection of Risperdal Consta® and concurrent daily doses of oral rispéridone, the microspheres release sufficient rispéridone in the systemic circulation that the patient can discontinue supplémentation 20 with daily doses of the oral therapy. However, this period of oral supplémentation could be a rîsk factor of non-compliance. Also, the presence on the body of two doses at the same time could be a potential risk of adverse events, such as irregular formulation behaviour and toxicity.
The rispéridone compositiorïs of the invention, on the contrary, can evoke therapeutic drug plasma levels from the first day up to at least 14 days, avoiding the need of supplementary oral daily therapy from the administration moment. These compositions can also reduce the différences between Cmax and Cmin as observed with dailyadministered oral tablets and subsequently may reduce variations in the patient mood. In 30 addition, they can also cover a period within administrations that is at least as long as the period covered by currently marketed extended-release rispéridone formulations.
-3The compositions of the invention are based on a biodégradable copolymer poly(Llactide-co-glycolide) matrix. These polymers hâve been used for many years in medical applications like sutures described in US 3,636,956 by Schneider, surgîcal clips and staples described in US 4,523,591 by Kaplan et al., and drug delivery Systems described 5 în US 3,773,919 by Boswell et al. However, most of the existing formulations using these biodégradable polymers require manufacturing of an implantable device in solid form prior to the administration into the body, which device is then inserted through an incision or is suspended in a vehicle and then injected. In such instances, the drug is incorporated into the polymer and the mixture is shaped into a certain form such as a 10 cylinder, dise, or fibre for implantation. With such solid implants, the drug delivery
System has to be inserted into the body through an incision. These incisions are sometimes larger than desired by the medical profession and occasionally lead to a réluctance of the patients to accepts such an implant or drug delivery System.
Injectable biodégradable polymeric matrix implants based on lactic acid, glycolic acid and/or their copolymers for sustained release hâve already been described in the state of the art. For instance, US 5,620,700 issued to Berggren describes a bioerodible oligomer or polymer material contaîning drug for local application into a diseased tissue pocket such as a periodontal pocket. However, the material requires heating to high températures to become suffîciently flowable to allow the injection, so that hardening of the material after cooling to the body température conforms the implant.
US 6,673,767 issued to Brodbeck describes procedures to obtain in situ forming biodégradable implants by using biocompatible polymers and biocompatible low water25 miscible solvents. According to this document, a viscous polymeric solution contaîning the drug that upon injection releases the drug in a controlled manner can be obtained through the use of low water-soluble solvents. In this document, low water-soluble solvents (less than 7% miscibility in water) are used as a method to reduce the release of the drug in aqueous médiums, allowing initial drug releases of 10% or lower during the 30 first 24 hours. However, in our expérience, the use of water-immiscible and/or low water-miscible solvents cannot satisfactorily control the initial in vivo release of
-4risperidone during the first 24 hours. For example, the use ofbenzyl alcohol, a solvent specifically included în US 6,673,767, causes very high plasma levels of rispéridone in the first 3 days and then the plasma levels decrease to very low levels in 7 days, whereas the use of N-methyl pyrrolidone, a solvent with a much higher water solubility, provides much smaller initial plasma levels of rispéridone and therefore a better control of the release of the drug during the first 5 days after the injection. This effect on the release of rispéridone is completely unexpected from US 6,673,767.
US 6,331,311, again issued to Brodbeck, also discloses injectable depot compositions comprising a biocompatible polymer such as PLGA, a solvent such as N-methyl-2pyrrolidone and a bénéficiai agent such as a drug, further comprising an emulsifying agent such as polyols. However, ihe compositions disclosed do not perform satisfactorily when the bénéficiai agent is rispéridone because the use of a two-phase composition with emulsifying agents accelerates implant hydration and increases effective releasing surface area, impairuig the control on the initial burst release and originating a fast decrease in drug release from the first days to the following ones.
US 4,938,763, issued to Durai et al., discloses a method for an injectable in situ forming implant. A biodégradable polymer or copolymer dissolved in a water-miscible solvent with a biologically active agent either is dissolved or dispersed within the polymeric solution. Once the polymeric solution is exposed to body fluids, the solvent diffuses and polymer solidifies entrappîng the drug within the polymer matrix. Even though patent 4,938,763 discloses the use of water miscible solvents for obtaining in situ forming polymeric implants, however this document discloses a number of polymers and solvents and even proportions between the different ingrédients that do not produce a satisfactory implant with the appropriate release characteristics, particularly when the implant contains rispéridone as active principle.
Another way to avoid surgery to administer these drugs is the injection of small-sized polymeric particles, microspheres or microparticles containing the respective drug. For instance, US 4,389,330 and US 4,530,840 describe a method for the préparation of
-5biodegradable mîcroparticles. US 5,688,801 and US 6,803,055 are related to the microencapsulation of 1,2-benzazoles into polymeric particles to achieve a drug release over extended periods of time in the treatment of mental disorders. These mîcroparticles require re-suspension into aqueous solvents prîor to the injection. On the contrary, the 5 compositions of the invention are injected as a liquid or semisolîd formulations that precipitate by solvent diffusion after the injection and forms a single (not multiparticulate) solid implant.
Based on these previous patents, US 5,770,231 describes a method for producing 10 rispéridone and 9-hydroxy-risperidone biodégradable mîcroparticles for sustained release by dissolving the drug within an organic phase. However, the use of organic solvents that are able to dissolve the rispéridone mostly or completely gives rise to very high initial plasma levels of rispéridone due to the diffusion of the drug along with the diffusion of the solvent.
US 7,118,763 describes two methods of making multi-phase sustaîned-release microparticle formulations based on the combination of different particle sizes or mîcroparticles exhibiting different release profiles. The combination of two different release profiles allows the release of the drug for periods longer than two weeks. 20 However, in practice this combination requires a mixture of particles from at least two different batches, involving the multiplication of end product spécifications and increasing batch-to-batch variability. On the contrary, the compositions of the invention provide an easier method for the production of a single unit implantable device allowîng constant and effective plasma levels during a period comprising from the first day up to 25 at least 14 days.
Finally, WO 2008/153611 A2 discloses a rather large amount of sustained delivery Systems of rispéridone compounds. However, the authors of this document failed to obtain the conclusions reached during the présent work, so that the influence in the 30 initial rispéridone burst of certain parameters or ratios as presently disclosed was ignored. In particular, none of the formulations in this document contained a
Ο
-6risperidone/polymer mass ratio between 25 and 35%, as in the presently claîmed formulations.Moreover, ail the tests discloscd in DI were carried out using a spécifie solvent, namely N-methyl-2-pyrrolîdone (NMP),
In addition, although mîcroparticle formulations can be administered by injection, they cannot always satisfy the demand for a biodégradable implant because they sometimes présent difficulties in the large-scale production. Moreover, in case of any medical complication after injection, they are more problematic to be removed from the body than implantable compositions such as those of the invention.
SUMMARY OF THE INVENTION
Therefore, the compositions already described in the state of the art do not cover the existing needs in rispéridone compositions, kits and treatments for psychiatrie disorders, and there still exists a need of compositions and devices to allow a controlled, constant 15 release of the drug during prolonged periods of time.
The solution is based on the fact that the présent inventors hâve identîfîed that the initial burst release of the drug can be satisfactorily controlled during at least 2 weeks by controlling at least one ofthe following factors, either alone or in combination:
the viscosity of the polymeric solution. Throughout the présent spécification, by “polymeric solution” it is understood the combination of the polymer and the solvent where it is dissolved;
the risperidone/polymer mass ratio,
I the rispéridone particle size, the polymeric solution/drug mass ratio, and the solvent/risperidone mass ratio
By adcquatcly controlling at least some of these factors, the release from the implant during at least the first two weeks can be precisely controlled, allow ng satisfactory
-7release profiles from the very first day until at Ieast 14 days, and achieving in some cases more than 30 days and up to 40 days following a single administration.
ïn the implantable compositions ofthe invention, compositions and kits are provided in which a solid polymer or copolymer is dissolved in a solvent, which is non-toxic and water miscible, to form a liquid solution, to which the rispéridone is provided. When these compositions are cxposcd to body fluids or water, the solvent diffuses away from the polymer-drug mixture and water diffuses into the mixture where it coagulâtes the polymer thereby trapping or encapsulating the drug within the polymeric matrix as the implant solidifies. The release ofthe drug then follows the general rules for diffusion or dissolution of a drug from within a polymeric matrix. The rispéridone compositions of the invention can therefore form a suspension or a dispersion within a biodégradable and biocompatible polymeric solution that can be administered by means of a syringe and a needle and which solidifies înside the body by solvent diffusion, thereby forming the implant.
The compositions of the invention comprise at Ieast a polymer matrix, a solvent and a drug having certain selected ranges and ratios of at Ieast one of the following parameters, either atone or in combination:
the viscosity of the polymeric solution (polymer + solvent);
the risperidone/polymer mass ratio, the rispéridone particle sîze.
Additional parameters such as the mass ratio between the amounts of polymeric solution (polymer + solvent) and drug, and the solvent/drug mass ratio, can atso be useful to control the initial release of the compositions of the invention.
Some of the key points where the compositions of the invention show improvements over the state ofthe art are:
- Stability, by using a solid product for reconstitution previous to injection;
- Pharmacokinetic profile:
Onset: The compositions of the invention show plasma therapeutic levels since the fîrst day, avoiding the 2-3 weeks lag time that the currently marketed long-term rispéridone product shows.
Duration: The compositions of the invention may allow an increase in the interval between administrations as compared to currently marketed longtcrm rispéridone product.
- Levels: The compositions of the invention in duce more sustained plasma levels, and with lower différences between Cmax and Cmin than the currently marketed long-term rispéridone product.
Accordingly, a first aspect of the invention is directed to an injectable depot composition, comprising:
a drug which is rispéridone and/or its métabolites or prodrugs in any combination thereof;
at least a biocompatible polymer which is a copolymcr based on lactic and glycolic acid having a mono mer ratio of lactic to glycolic acid in the range from 50:50 to 75:25, and
- at least a water-miscible solvent with a dîpole moment about 3.9-4.3 D, wherein the viscosity of the solution comprising the polymer and the solvent is between 0.5 and 3.0 Pa.s and the solvent/drug mass ratio is between 10 and 4, characterised in that the drug/polymer mass ratio is between 25 and 35% expressed as the weight percentage of the drug with respect of the drug plus polymer.
A second aspect of the invention is directed to the use of such compositions for the treatment of schizophrenia or bipolar dîsorders in the human body.
And a third aspect of the invention is directed to a pharmaceutical kit suitable for the in situ formation of a biodégradable implant in a body comprising the said compositions, wherein the rispéridone drug and the biocompatible polymer are contained in a first container, and the water-miscible solvent is contained in a second, separate container. These containers may be syringes and the mixing of the contents of the first and second
-9containers may be performed by direct or indirect connection followed by moving forwards and backwards the plungers of the syrînges.
DETAILED DESCRIPTION OF THE INVENTION
The compositions of the invention comprise at least a polymer or polymer matrix, a solvent and a drug.
The polymer or polymer matrix is preferably a biocompatible and biodégradable polymer matrix. In order not to cause any severe damage to the body following 10 administration, the preferred polymers are biocompatible, non-toxic for the human body, not carcinogcnic, and do not inducc significant tissue inflammation. The polymers are preferably biodégradable in order to allow natural dégradation by body processes, so that they are readily disposable and do not accumulate in the body. The preferred polymeric matrices in the practice in this invention are selected from end15 capped terminal carboxylic poly-lactide and poly-glycolic acid copolymers mixed in a ratio from 50:50 to 75:25, with intrinsic inhérent viscosity preferably in the range of 0.16-0.60 dl/g, and more preferably between 0.25-0.48 dl/g, measured in chloroform at 25°C and a 0.1% concentration. The concentration of the polymeric component in the compositions of the invention is preferably comprised în the range of 25-50%, 20 (exprcsscd as the pcrccntagc of polymer weight based on total polymeric solution component) and more preferably between 30-40%.
For the purpose of the présent invention, throughout the présent spécification the term intrinsic or inhérent viscosity (η^ύι) of the polymer is defined as the ratio of the natural 25 logarithm of the relative viscosity, ηΓ, to the mass concentration of the polymer, c, i.e.:
pinh= (ln ηΓ)/ο and the relative viscosity (ηΓ) is the ratio of the viscosity of the solution η to the 30 viscosity of the solvent η8, i.e.:
- ιοηΓ= η/ η»
If not otherwîse specified, the intrinsic viscosity values throughout the présent spécification are to be understood as measured at 25°C in chloroform at a concentration of 0.1%. The value of intrinsic viscosity is considered în the présent spécification, as commonly accepted in the art, as an indirect indicator of the polymer molecular weight. In this way, a réduction in the intrinsic viscosity of a polymer, measured at a gîven concentration in a certain solvent, with same mono mer composition and terminal end groups, îs an indication of a réduction in the polymer molecular weight (IUPAC. Basic définitions of terms relating to polymers 1974. Pure Appl. Chem. 40, 477-491 (1974),
The preferred solvents are non-toxic, biocompatible and appropriate for parentéral injection. Solvents susceptible of causing toxicity should not be used for the injection of any material into any livîng body. More preferably, selected solvents are biocompatible in order not to cause any severe tissue irritation or necrosis at the injection site. Therefore, the solvent is preferably classified as class II or III, and more preferably class 111, according to 1CH Guidelines. For the formation of the in-situ implant, the solvent should preferably diffuse quickly from the polymeric solution towards surrounding tissues when is exposed to physiological fluids. Consequently, the solvent is preferably water miscible and more preferably with a dipole moment about 3.9-4.3 D at 25°C. The most preferred solvents are DMSO, N-methyl-pyrrolîdone and PEG.
The drug is preferably rispéridone and/or a métabolite or a prodrug thereof. This drug is preferably at least partly suspended in the solvent. The solubility of the drug in the solvent is preferably lower than 90 mg/ml, more preferably lower than 65 mg/mt, and most preferably below 10 mg/ml. The advantage of this low solubility is that the initial burst of the drug when the solvent diffuses to the extemal aqueous medium is greatly reduced. In addition, in the final compositions of the invention the drug is provided in a preferred concentration between 4 and 16 wt%, expressed as the percentage of the drug in respect of the total composition weight. More preferably, the drug content is between 7 and 15%, and most preferably about 13% in respect of the total composition weight.
One of the factors contributing to control the initial release of the composition of the invention is the viscosity of the polymeric solution. The “polymètre solution”, which is defined as the combination of the polymer matrix and the solvent where it is dissolved, has a preferred viscosity in the range of 0.5-7.0 Pa.s, more preferably between 0.5-3.0 Pa.s, and most preferably about 0.7-3.0 Pa.s.
A second factor contributing to control the initial release of the compositions of the invention is the risperidone/polymer mass ratio. The préférable ranges for this mass ratio, expressed as the percentage of the drug weight in respect of the drug plus polymer weight content, should be in a range of 15-40% weight, more preferably 25-35%, and most preferably about 33%.
A third factor contributing to control the initial release of the compositions of the invention is the drug’s particle size. Large particles provide a smallcr surface area per weight thereby reducing the initial release (burst) but the release may be then delayed until the beginning of the dégradation of the polymeric matrix. On the other hand, small particles evoke higher burst levels due to an easier drug diffusion from small particles during implant hardening, followed by continuous drug release levels due to the combination ofthe processes of drug diffusion and implant érosion. Consequently, in a preferred embodiment of the invention a wide particle size distribution, combining large and small particle sizes in different ratios, is used in order to reduce the initial burst and maintain a constant drug release by diffusion of smaller particles on first phase and gradually releasing bigger particles while the polymer dégradés. For instance, a preferred particle size distribution is as follows: not more than 10% ofthe total volume of particles in particles having a less than 10 microns size and not more of 10% of the total volume of particles in particles having a higher than 225 microns size. In addition, the d0.5 value is preferably in the range of 60-130 microns.
In addition to the above factors, the following ratios between the components of the compositions according to the invention can also contribute to control the initial release:
- 12The mass ratio between the amounts of polymeric solution (polymer + solvent) and rispéridone in the compositions of the invention is preferably between 15 to 5, more preferably between 12 to 5 and most preferably between 7 and 6.5. In most preferred embodiments this mass ratio is about 6.66, as shown in the Examples below (see Example 12).
The mass ratio between the amounts of solvent and rispéridone (mg solvent/mg rispéridone) in the compositions of the invention is preferably between 12 to 4, more preferably between 10 to 4 and most preferably between 5 and 4. In most preferred embodiments this mass ratio is about 4.66 (see Example 13 below). Thîs ratio defines the rate of hardening of the implant by solvent diffusion and conséquently the précipitation of the polymer. Hence, this parametcr is also related to the proportion of drug dissolved/dispersed in the polymeric solution and therefore it controls whether further drug is difïuscd from the implant or not.
Optionally, an alkaline agent with low water solubility such as lower than 0.02 mgzml can be included within the polymer matrix, preferably in a molar relation >2/5 (drug/alkaline agent). Preferred alkalînîsing agents are alkaline or alkaline-earth hydroxidcs such as magnésium hydroxide. Preferably, the particle size of the magnésium hydroxide is below 10 microns.
Another aspect of the invention is directed to a kit comprising a first container, »
preferably syringes, vials, devices or cartridges, ail of them either being disposable or not, containing a polymer in solid form, preferably freeze-dried, such as PLGA and rispéridone (either or not additionally containing Mg(OH)z) in the appropriate amounts and a second container, likewise preferably syringes, vials, devices or cartridges, ail of them being either disposable or not, containing the water-miscible solvent. When required, the contents of both containers are combined, for example through a connector or by using male-female syringes, and mixed each other so that the compositions according to the invention are reconstituted, for example by moving forwards and
- Bbackwards the plungers of the syringes. Illustrative preferred embodiments are shown in Figure 35 (syringes connected through a connector device) and in Figure 36 (syringes connected through a direct thread).
In a preferred embodiment, the injectable depot compositions of the invention further comprise Mg(OH)2 at a molar ratio between 2/3 and 2/5, expressed as the molar ratio of drug to Mg(OH)2In an additional preferred embodiment, the injectable depot composition is stérile as a finished product. In other preferred embodiment, the biocompatible polymer is sterilized previously to its aseptie filling process, preferably by an aseptie filling process by irradation in the range 5-25 KGy. In yet another embodiment, the biocompatible polymer is sterilized previously dissolved in a solvent by a filtration process in a filter with a 0.22 μτη pore size.
In another preferred embodiment, in the injectable depot composition at least the drug and/or the biocompatible polymer of the composition hâve been submitted to terminal sterilization processes, preferably by irradiation ΐη the range 5-25 KGy,
BRIEF DESCRIPTION OF THE FIGURES
Fig I: In vitro release profile of rispéridone for the composition of Comparative Example l (rispéridone, polymer and a water-insoluble solvent).
Fig. 2: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the composition of Comparative Example l (rispéridone, polymer and a water-insolubie solvent) in rabbits.
Fig. 3: In vitro release profile of rispéridone for the composition of Example 1 (rispéridone, polymer and water-solubie solvents having different dipole moment).
Fig. 4: In vitro release profile of rispéridone for the composition of Example 2 (rispéridone, polymer and a water-soluble solvent having a high solubilîty for rispéridone).
- 14Fig. 5: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the composition of Example 2 (rispéridone, polymer and a water-soluble solvent having a high solubility for rispéridone) in rabbits.
Fig. 6: In vitro release profile of rispéridone for the composition of Example 3 (rispéridone, polymer and water-soluble solvents having moderate to low solubility for rispéridone).
Fig. 7: In vitro release profile of rispéridone for the compositions of Example 4 (different polymer concentrations with respect to solvent).
Fig. 8: In vitro release profile of rispéridone for the compositions of Example 5 (low polymer concentration of a solvent having a high solubility for rispéridone).
Fig. 9: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the composition of Example 5 (low polymer concentration of a solvent having a high solubility for rispéridone) in rabbits.
Fîg. 10: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the composition of Example 6 (intermediate polymer concentration with respect to solvent) in rabbits.
Fig. 11: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 7 (different drug loadings) in rabbits.
Fig. 12: In vitro release profile of rispéridone for Composition B of Example 8 (different particle sizes).
Fig. 13: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of Composition A of Example 8 (different particle sizes) in rabbits.
Fig. 14: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of Composition B of Example 8 (different particle sizes) in rabbits.
Fig. 15: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of Composition B of Example 8 (different particle sizes) in dogs.
Fig. 16: In vitro release profile of rispéridone for the compositions of Example 9 (different viscosities of the polymeric solution).
- 15Fig. 17: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 9 (different viscosities of the polymeric solution) in rabbits.
Fig. 18: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 9 (different viscosities of the polymeric solution) in rabbits.
Fig. 19: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 9 (different viscosities of the polymeric solution) in rabbits.
Fig 20: In vitro release profile of rispéridone for the compositions of Example 10 (different drug/polymer mass ratios in DMSO as solvent).
Fig. 21: In vivo plasma levels of rispéridone plus 9-OH-risperidonc following injection of the compositions Example 10 (different drug/polymer mass ratios) in rabbits.
Fig. 22: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions Example 10 (different drug/polymer mass ratios) in rabbits.
Fig. 23: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions Example 10 (different drug/polymer mass ratios) in dogs.
Fig. 24: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions Example 11 (different polymeric solution/drug mass ratios) in rabbits.
Fig. 25: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions Example 12 (different solvent/drug mass ratios) in rabbits.
Fig. 26: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions Example 13 (optional addition of Mg/OHja) in rabbits.
Fig 27: In vitro release profile of rispéridone for the compositions of Example 14 (different reconstitution methods).
Fig. 28: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 14 (different reconstitution methods) in rabbits.
- 16Fig. 29: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 14 (different reconstitution methods) in dogs.
Fig 30: In vitro release profile of rispéridone for the compositions of Example 15 (sterilization by irradiation).
Fig 31: In vitro release profile of rispéridone for the compositions of Example 15 (sterilization by irradiation).
Fig. 32: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Example 15 (sterilization by irradiation) in rabbits.
Fig. 33: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection 10 of the compositions of Example 15 (sterilization by irradiation) in rabbits.
Fig. 34: In vivo plasma levels of rispéridone plus 9-OH-risperidone following injection of the compositions of Comparative Example 2 (compositions obtained through the procedures of the prior art) in dogs.
EXAMPLES
The following examples illustrate the invention and should not be considered in a limitative sense thereof.
In the sense of the présent invention, without limitation and in connection with the in vivo examples, for “Initial Burst” or initial release it is meant the addition of the plasma 20 levels of rispéridone plus those of 9-OH-risperidone, which addition is also called “the active moietÿ” throughout the présent spécification, from the moment of the injection until the third day after the administration. Also in the sense of this invention, without limitation and in connection with the exâmples, acceptable plasma levels of active moiety during the initial burst phase are below 100 ng/ml in Beagle dogs and New 25 Zealand White Rabbits when doses administered are 2,5 mg''kg rispéridone in dogs and mg/kg rispéridone in rabbits.
- 17Comparative Example 1: Implantable composition including a water-insoluble solvent (example not according to the invention).
In the présent example, the composition of the implantable formulation was as follows:
| Ingrédient | Amount (mg) |
| Resomer®RG752S (polymer) | 100 |
| Rispéridone | 25 |
| Benzyl benzoate (solvent) | 233.3 |
RG752S, 75:25 lactic/glycolic acid polymer (Boehnnger Ingelheim)
The rispéridone implantable formulation was prepared by completely dissolving the polymer in the solvent and subsequently suspending the drug in said polymeric solution. In vitro release profile:
The rispéridone release from the formulation of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks having a pre-warmed release medium by using a 21G needle. The release medium was 250 ml phosphate buffer pH=
7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At prevîously scheduled time points (2h, ld, 3d, 6d, 8d, lOd, 13d, 17d, 21d, 23d, 28d, 31d, 35d, 42d), 5 ml of release medium was collected and replaccd with fresh buffer and the amount of rispéridone présent in the sample was determined by UV spectrophotometry. The profile of rispéridone released from the implants of this example is shown in Figure 1. The results are expressed as % Rispéridone released from implants as a function of time.
As it can be observed in this Figure 1, the release of rispéridone during the first 24 hours is close to 20% of the injected amount and close to 50% in the first 48 hours. This fïnding is not in accordance writh previous teachings such as US 6,673,767, since this low water-miscible solvent îs clearly unable to control the initial diffusion of 25 rispéridone from the polymer matrix.
-18In vivo plasma leveis after intramuscular administration to New Zealand rabbit:
The rispéridone composition of this example was intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. After injection, plasma leveis were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d and 28d.
The kinetics of the plasma leveis corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active metabolîte 9-OH-rîsperidone in the plasma samples. The profile of the plasma leveis of the rispéridone active moiety is shown in Figure 2. The results are expressed as the addition of rispéridone plus 9-OHrîsperidone concentrations (ng/ml) as the function of time, since the therapeutîc activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be observed in this Figure, the injection of an amount of composition équivalent to 15 mg rispéridone to New Zealand White rabbits resulted in very high initial plasma leveis followed by a rapid decrease, with no signifïcant plasma leveis from day 3 onwards. Ail 3 animais exhibited severe adverse effects related to the very high plasma leveis of rispéridone active moiety 15 min after the injection, which demonstrates the rather poor control on the initial drug release achieved with this composition.
Example 1: Study of different water-soluble solvents with different dipole moment.
In the présent example, the composition of the implantable formulation was as follows:
| Ingrédient | Composition 1 Composition 2 | Solvent dipole moment (D) | |
| Amount (mg) | |||
| RcsomcriRG503 (polymer) | 100 | 100 | |
| Rispéridone | 25 | 25 | |
| Dimethyl sulfoxide (solvent) | 233.3 | — | 3.96 |
| 1,4 -dioxane (solvent) | - | 233.3 | 0.45 |
RG503,50:50 lactic/glycolic acid polymer (Boehringer Ingelheim)
The risperidone-impIantable formulation was prepared by completcly dissolving the polymer in either of the cited water-miscible solvents having different dipole moment (DMSO or 1,4-dioxane) and subsequently suspending the drug in said polymeric 5 solution.
In vitro release profile:
The rispéridone release from the formulations of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of 10 rispéridone was injected from prefilled syringes into flasks by using a 21G needle followed by careful addition of a pre-warmcd release medium. The release medium wras 250 ml phosphate buffer pH= 7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, ld, 3d, 6d, 8d, lOd, 13d, 17d, 21d, 23d, 28d, 31d, 35d, 42d), 5 ml of release medium was 15 collccted and replaced with fresh buffer, and the amount of rispéridone amount présent în the sample was determined by UV spectrophotometry.
The profile of the rispéridone released from the formulations is shown in Figure 3, The results are expressed as %Risperidone released from the implants as a function of time. 20 As ît can be observed in this Figure 3, and în comparison with Figure 1 (corresponding to Comparative Example 1), the use of water miscible solvents versus water-inmiscible solvents in the implantable compositions of the invention allows a more précisé control of the initial rispéridone diffusion from the polymer matrix. The présent example also shows the influence of’the dipole moment of the solvent in the release of rispéridone 25 from the implantable compositions of the invention: The use of solvents with lower dipole moment (dioxane) causes a higher rispéridone diffusion than solvents having higher dipolemoment solvents (DMSO) about 3.9-4.3 D, which solvents notably reduce the drug diffusion during 2 weeks.
-20Example 2: Study of solvents with a high solubility for rispéridone:
In the présent example, the composition of the implantable formulation was as folio ws;
| Ingrédient | Amount (mg) |
| Resomer®RG752S (polymer) | 100 |
| Rispéridone | 25 |
| Benzyl alcohol (solvent) | 233.3 |
RG752S, 75:25 lactic/glycolic acid polymer (Bochringer Ingelheim)
The rispéridone-implantable formulation of this example was prepared by completely dissolving the polymer in the water-misciblc solvent having a high solubility for rispéridone (benzyl alcohol) and subsequently suspending the drug in said polymeric solution.
In vitro release profile:
The rispéridone release from the formulation of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks having a pre-warmed release medium by using a 21G needle. The release medium was 250 mi phosphate buffer pH=
7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, Id, 3d, 6d, 8d, lOd, 13d, 17d, 21 d, 23d, 28d, 31d, 35d, 42d), 5 ml of release medium was collected and replaced with fresh buffer, and the amount of rispéridone présent in the sample was determined by UV spectrophotometry.
The profile of rispéridone released from the formulation is shown in Figure 4. The results are expressed as %Risperidone released from the implants as a fonction oftime. As it can be observed in Figure 4, the use of solvents having a high solubility for rispéridone as in the présent cxample results in a high initial rispéridone diffusion and a
-21 drug release from the polymer matrix close to 30% in the first 3 days and along the first week.
In vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone composition of this example was intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corrcsponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. After injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d and 28d.
The kînetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 5. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as the function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be observed in the cited Figure, the injection of the tested composition in an amount équivalent to 15 mg rispéridone to New Zealand White rabbits resulted in very high initial plasma levels followed by a rapid decrease, with no significant plasma levels from day 5 onwards. Ail 3 animais exhibited adverse effects related to the very high plasma levels of rispéridone active moiety 15 min after the injection, which demonstrates the very poor control on the initial drug release achieved with this composition, which comprises a solvent having a high solubility for rispéridone.
Example 3: Study of solvents with different solubility for rispéridone:
In the présent case, the rispéridone implantable formulation was prepared by completely dissolving polymer Resomer®RG503 (RG5O3, 50:50 lactic/glycolic acid, Boehringer Ingelheîm) in different solvents (NMP, PEG and DMSO) having intermediate to low
C
-22solubility (in ali cases below 65 mg/ml) for rispéridone and subsequently suspending the rispéridone in the respective solvent.
In vitro release profile:
The rispéridone release from the formulations of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks by using a 2IG needle followed by the carefol addition of a pre-warmed release medium. The release medium was 250 ml phosphate buffer pH= 7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, ld, 3d, 6d, 8d, lOd, 13d, 17d, 21d, 23d, 28d, 3 Id, 35d, 42d), 5 ml of release medium was collected and replaced with fresh buffer, and the amount of rispéridone présent in the sample was determined by UV spectrophotometry.
The profile of rispéridone released from the formulations is shown in Figure 6. The results are expressed as %Risperidone released from the formulations as a fonction of time. As it can be observed in Figure 6, the use of a solvent having a lower rispéridone solubility (in comparison to high solubility as in Figure 4 from Example 2) offers initial controlled rispéridone diffusion from the polymer matrix and a controlled release up to at least 28 days. Hence, the use of solvents having a low solubility for rispéridone, such as DMSO, as in the présent example, allows a more précisé control of the drug released during the solvent diffusion and the polymer précipitation.
*
Example 4; Study of different polymer concentrations with respect to the solvent
In the présent example, the compositions of the implantable formulations were as follows:
Q
| Composition 1 | Composition 2 | Composition 3 | Composition 4 | |
| Ingrédient | Amount (%) | |||
| Resomer®RG503 (polymer) | 10 | 20 | 30 | 40 |
| Dimethyl sulfoxide (solvent) | 90 | 80 | 70 | 60 |
RG503,50:50 lactic/glycolic acid (Bochringer Ingclheîm)
The rispéridone-implantable formulations were prepared by completely dissolving the polymer in the solvent in different proportions and subsequcntly suspending the drug in said polymeric solution.
In vitro release profile:
The rispéridone release from the formulations of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefîlled syringes into flasks by using a 21G needle followed by the carefiil addition of a pre-warmed release medium. The release medium was 250 ml phosphate buffer at pH= 7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At prcviously schedulcd time points (2h, 1d, 3d, 6d, 8d, lOd, 13d, 17d, 21d, 23d, 28d, 31d, 35d, 42d), 5 ml of release medium was collected and replaced with fresh buffer, and the amount of rispéridone présent in the sample was determined by UV spectrophotometry.
«
The profile of rispéridone released from the formulations of this example is shown in
Figure 7. The results are expressed as %Risperidone released from the formulations as a function of time. As it can be observed in Figure 7, the use of polymer matrix solutions having a low polymer concentration (10% w/w), produces an extremely high initial risperidone release, so that the control of rispéridone diffusion îs very difficult. Although an increase in the polymer concentration to 20% (w/w) notably improves the
-24capacity to control the rispéridone released from the polymer matrix, it is still not enough to completely control the initial rispéridone diffusion release, which is close to 15% during first 24 hours. Polymer concentrations at 30 and 40% (w/w) lead to an efficient initial drug release control, achieving controlled release profiles up to 35-42 days.
Example 5: Study of a low (10%) polymer concentration with respect of the solvent, where the solvent has a very high solubility for rispéridone.
In the présent example, the composition of the implantable formulation was as follows:
| Ingrédient | Amount (mg) |
| Resomer'E’RG752S (polymer) | 100 |
| Rispéridone | 25 |
| Benzyl alcohol (solvent) | 900 |
RG752S, 75:25 lactic/glycolic acid polymer (Bœhringer Ingelheim)
The rispéridone-implantable formulation was prepared by completely dissolvîng the polymer in a solvent having a very high solubility for rispéridone (benzyl alcohol) and subsequently suspendîng the drug in said polymeric solution. The concentration of the polymer with respect to the solvent was low (10%).
In vitro release profile:
The rispéridone release from the formulation of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks having a pre-warmed release medium by using a 21G needle. The release medium was 250 ml phosphate buffer pH=
7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm, At previously scheduled time points (2h, ld, 3d, 6d, 8d, 10d, 13d, 17d, 21d, 23d, 28d, 31 d, 35d, 42d), 5 ml of release medium was collectcd and rcplaccd with fresh
-25buffer, and the amount of rispéridone présent in the sample was determined by UV spectrophotometry.
The profile of rispéridone released from the implants is shown în Figure 8. The results are expressed as %Rîsperidone released from the formulation as a fonction oftîme. As it can bc obscrvcd in Figure 8, and in line with the results shown in Figure 7 from Example 4, a concentration of the polymer of 10% (w/w) in the polymeric solution is not enough to retain the rispéridone in the implantable formulations, therefore inducing a too high initial rispéridone diffusion during the first days.
/n vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone composition was intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rîsperidone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G necdle. Total number of rabbits was 3. After injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d and 28d.
The kinetics of the plasma levels corresponding to the rispéridone active moîety was evaluated by measuring both rispéridone and its active métabolite 9-OH-rîsperidone in the plasma samples. The profile of the rispéridone active moîety plasma levels is shown in Figure 9. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a fonction of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be observed in said Figure, the injection of an amount of formulation équivalent to 15 mg rîsperidone to New Zealand White rabbits resulted in very high initial plasma levels released, foliowed by a rapid decrease, with no significant plasma levels from day 5 onwards. AU 3 animais exhibited adverse effects related to the very high plasma levels of rîsperidone active moiety 15 min after the injection, which shows a very poor control
-26on the initial drug release achieved with this composition comprising low polymer concentration in the polymer matrix.
Example 6: Study of inter médiate (25%) polymer concentrations with respect of solvent.
In the présent ex ample, the compositions of the implantable formulation were as follows:
| Ingrédient | Amount (mg) |
| Resomer^RGiOS (polymer) | 41.7 |
| Rispéridone | 25 |
| Polyethylene glycol 300 (solvent) | 125 |
RG503, 50:50 laclic/glycolic acid polymer (Boehringer Ingelheim)
The risperidone-implantable formulations were prepared by completely dissolving the polymer in the solvent and subsequently suspending the drug in said polymeric solution. The concentration of the polymer with respect to the solvent was intermediate (25%).
In vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone composition was intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. After injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d, 28d, 3ld, 35d, 38d and42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma sampîcs. The profile of the rispéridone active moiety plasma levels is shown
-27in Figure 10. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be observed from the cited Figure, the injection of an amount of formulation équivalent to 15 mg rispéridone to New Zealand Whîte rabbits resulted in moderate initial plasma levels followed by a dccrcase until day 2 and sustained plasma levels at least up to 24 days. The results obtained in this example are in accordance with those from Example 4, where polymer concentrations of 20% (w/w) or hîgher with respect to the polymeric solution are able to control the initial rispéridone diffusion and achieve prolonged release over time.
Example 7: Study of different drug loadings
The rispéridone implantable formulation of this example was prepared by completely dissolving polymer Resomer®RG503 (R.G503, 50:50 lactîc/glycolic acid, Boehringer Ingclhcim) in DMSO and subsequently dispersing the drug in the appropriatc amount to obtain a final drug loading between 7-13% (w/w) (weight of rispéridone in respect of the total composition weight).
In vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone formulation of this example was intramuscularly mjected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. Afïer injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, I4d, 17d, 21d, 24d, 28df 31d, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measurîng both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 11. The results are expressed as the addition of the rispéridone plus 9-OH-
-28rispéridone concentrations (ng/ml) as a fonction of time, since the therapeutic activity of 9-OH-rîsperidone is substantially équivalent to that of rispéridone. As it can be observed in said Figure, the injection of an amount of composition équivalent to 15 mg rispéridone to New Zealand White rabbits resulted in moderate and controlled initial plasma levels. An increase in the drug loading is related to a lower initial drug diffusion and release, producing as a resuit a dccrcase in the initial plasma levels. Thcreforc, a high drug loading îs préférable for the case of long-term formulations, in order to achîeve better balanced plasma levels in the whoie drug release period. In general tenais, a preferred range for the drug loading is between 4 and 16%, and a more preferred range is between 7 and 13%, expressed as the weight percent of drug with respect to the total composition.
Example 8: Study of different particle sizes.
In the présent example, the following compositions of implantable formulations according to the invention were tested:
Composition A:
| Ingrédient | Amount (mg) |
| Resomer®RG503 (polymer) | 100 |
| Rispéridone | 25 |
| Dimcthyl sulfoxide (solvent) | 233.3 |
Composition B:
| Ingrédient | Amount (mg) |
| Rcsomcr®RG503 (polymer) | 50 |
| Rispéridone | 25 |
| Dimcthyl sulfoxide (solvent) ----------------— | 166.7 |
RG503,50:50 lactic/glycolic acid polymer (Boehringer Ingelheim)
The risperidone-implantable formulations were prepared by completely dissolving the polymer in the solvent and subsequently suspending the drug in said polymeric solution.
-29The following different rispéridone particle size distributions were evaluated for the same formulation:
- 25-350 microns: dO.l, 25 microns and d0.9, 350 microns (not more than 10% of drug particles with a particle size smaller than 25 microns, and not more than 10% particles larger than 350 microns).
25-225 microns: dO.l of 25 microns and d0.9 of 225 microns (not more than 10% of drug particles with a particle size smaller than 25 microns, and not more than 10% particles larger than 225 microns).
- 90-150 microns: sîeved between 90-150 microns
- 45-90 microns: sieved between 45-90 microns milled, <10 microns: drug milled to d0.9 10 microns (not more than 10% particles larger than 10 microns).
In vitro release profile:
The rispéridone release from the formulations corresponding to Composition B was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks by using a 21G needle followed by the careful addition of a pre-warmed release medium. The release medium was 250 ml phosphate buffer pH= 7.4, The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, Id, and periodically up to a maximum of 35d), 5 ml of release medium was collected and replaced with fresh buffer, and the amount of rispéridone présent in the sample was determined by UV spectrophotometry.
The profile of rispéridone released from the implants of this example is shown in Figure 12. Results are expressed as %Risperidone released from the implants as a fonction of time. As it can be observed in Figure 12, the small drug particles (less than 10 microns) favoured the in vitro drug diffusion during first days following administration of the
-30implantable formulation, whereas the use of a mixture of particle sizes, comprising larger and smaller particles, reduced the initial diffusion.
In vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone formulations corresponding to Compositions A and B of this example were intramuscularly înjcctcd to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. After injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d, 28d, 31d, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figures 13 and 14 for Compositions A and B, respectively. The results are expressed as the addition of the rispéridone plus 9-OH-risperidone concentrations (ng/ml) as a fimction of time, since the therapeutic activity of 9-OH-risperidone is substantîally équivalent to that of rispéridone. As it can be observed in said Figures, the injection of an amount of formulation of the Compositions A and B corresponding to an équivalent to 15 mg rispéridone to New Zealand White rabbits resulted in moderate and controlled initial plasma levels followed by significant plasma levels up to at least 21 days. The smaller particle sizes produce an initial raise in the plasma levels and shortens the therapeutic plasma levels window. The use of higher particle sizes, thus avoiding smaller ones, resulted în a dramatic réduction of the initial burst effect by decreasing drug diffusion, and the consequently delay on drug release until the polymer matrix dégradés. As it is shown in Figure 14, the use of a controlled mixture of drug particle sizes induced a more controlled initial release during the diffusion phase, followed by an increase in plasma levels once the polymer dégradation begins.
In vivo plasma levels after intramuscular administration to Beagle dog
-3l The rispéridone formulations of Composition B of this example were mtramuscularly injected to Beagle dogs weighing an average of 10 kg. The amount înjected corresponded to a dose of 25 mg rispéridone and the composition was mtramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of dogs was 3. After injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d, 28d, 3ld, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 15. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone.
The injection of rispéridone formulations corresponding to Composition B of this example in an amount équivalent to 25 mg rispéridone to Beagle dogs resulted in controlled initial plasma levels followed by significant plasma levels up to at least 28 days as it can be observed in Figure 15. As previousty noted in relation to the intramuscular administration of Composition B to rabbîts (Figures 13 and 14), the administration of the same composition to dogs revealed the same variable effect depending on drug particle size: Small particles (<10 microns) induced higher initial plasma levels and a relatively fast decrease in comparison with mixtures of particles sizes comprising both small and large particles (25-225 microns), which combination is able to reduce the initial plasma levels and favours a more sustained plasma level along time.
Example 9: Study of the viscosity of the polymeric solution:
The rispéridone-implantable formulations ofthis example were prepared by completely dissolving the polymer in DMSO or NMP as the solvent and subsequently suspending
-32the drug in said polymeric solution. The formulations were the following in order to achteve polymeric solutions having different viscosities;
| Polymer Type | Polymer (%) | Viscosity of the polymeric solution (Pa.s) |
| Resomer®RG503 | 10 | 0.03 |
| Resomer®RG752S “ ” | 30 | 0.10 |
| Resomer®RG503 | 20 | 0.18 |
| Resomer®RG752S | 40 | 0.43 |
| Resomer®RG753S | 30 | 0.66 |
| Resomer®RG503 | 30 | 1.12 |
| Resomer®RG503 | 35 | 2.73 |
| Resomer®RG504 | 30 | 6.12 |
| Resomer®RG503 | 40 | 6.77 |
RG752S, and RG753S, 75:25 lactic/glycolic acid polymer (Boehringer Ingelheim) RG5O3 and RG 504, 50:50 lactic/glycolic acid polymer (Boehringer Ingelheim)
In vitro release profile:
The rispéridone release from the formulations was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks by using a 21G needle followed by the carefol addition of a pre-warmed release medium. The release medium was 250 ml phosphate buffer pH= 7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, Id, and periodically up to a maximum of 42d), 5 ml of release medium was collected and replaced with fresh buffer, and the amount of rispéridone présent in the sample was determined by UV spectrophotometry.
The profile of rispéridone released from the implants of this example is shown in Figure 16. Results are expressed as %Risperidone released from the implants as a fonction of time. As it can be observed in Figure 16, the low polymer solution viscosities lead to completeiy uncontrollable (0.03 Pa.s) and fast and high initial diffusion (0.18 Pa.s) of
-33rispéridone. On the other hand, polymer solution viscosities in the range l.l2-6.77 Pa.s resulted in well-controlled in vitro drug diffusion during first days following administration of the implantable formulation, followed by moderate drug release rates up to 35-42 days.
In vivo plasma levels after intramuscular administration to New Zealand rabbît
The rispéridone compositions of this example were intramuscularly înjected to New Zealand White rabbits weighing an average of 3 kg. The amount înjected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the 10 left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. After injection, plasma levels were obtained at 0, 4h, Id, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d, 28d.
The kinetîcs of the plasma levels corresponding to the rispéridone active moiety was 15 evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figures 17, 18 and 19. The results are expressed as the addition of the rispéridone plus 9-OH-risperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of 20 rispéridone. As it can be observed in said Figures, the injection of an amount of formulation corresponding to 15 mg rispéridone to New Zealand White rabbits with compositions having a low viscosity (0.1 Pa.s) of the polymeric solution resulted in high initial plasma levels but a fast decrease of said levels. An intermediate polymer solution viscosity (0.43 Pa.s).still evokes high initial plasma levels, although their decrease is 25 more moderate than at lower viscosity. On the contrary, higher viscosity of the polymeric solutions resulted in controlled initial plasma levels followed by signîficant plasma levels up at least 21 days when viscosity is over 0.5 Pa.s. In general terms, a preferred range for the viscosity of the polymer solution is between 0.5 and 7.0 Pa.s, and a more preferred range between 0.7 and 2.0 Pa.s.
-34Esample 10: Study of different drug/polymer mass ratios
Rîsperidone implantable formulations were prepared by completely dissolving polymer Resomer®RG503 in the solvent and subsequently dispersing the drug in the appropriate amounts to obtain the following drug/polymer mass ratios, expressed as the percentage of rîsperidone weight in respect of the polymer + rîsperidone weight:
| Rîsperidone/Polymer mass ratio [Rîsperidone/ (Polymer+Risperidone) (%w/w)j | |||||||
| 15.0 | 20.0 | 25.0 | 30.0 | 33.3 | 35.0 | 37.5 | 40.0 |
In vitro release profile:
The rîsperidone release from some of the formulations of this example was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rîsperidone was injected from prefilled syringes into flasks by using a 21G needle followed by the careful addition of a pre-warmed release medium. The release medium was 250 ml phosphate buffer pH= 7.4. The flasks were then placed into an oven at 37“C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, ld, and periodîcally up to a maximum of 42d), 5 ml of release medium was collected and replaced with fresh buffer, and the amount of rîsperidone présent in the sample was determined by UV spectrophotometry.
The profile of rîsperidone released from the formulations is shown in Figure 20. The résulte are expressed as %Risperidone released from the formulation as a function of time. . The range for the risperidone/polymer ratio between 15-35% presented in this example shows acceptable in vitro initial rîsperidone diffusion and a release time longer than 28 days. On the other hand, ratios of the order of 40% showed an inadéquate control of the in vitro drug release, probably because the amount of polymer présent in the composition was not cnough for the proper rîsperidone entrapment into the matrix.
In vivo plasma levels after intramuscular administration to New Zealand rabbit ή16256
-35Some of the rispéridone compositions of this example were intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 3. After injection, plasma Ievels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 2 ld, 24d, 28d, 31d, 35d, 38d and 42d.
The kinetics of the plasma Ievels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma Ievels is shown in Figures 21 and 22. The results are expressed as the addition of the rispéridone plus 9OH-risperidone concentrations (ng/ml) as a fonction of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be observed in the cited Figures, the injection of an amount of formulation corresponding to 15 mg rispéridone to New Zealand White rabbits resultcd in ail the cases presented in this example to show plasma Ievels from the first day until at least day 24. However, in some cases, compositions resulted in moderate and well controlled initial plasma followed by sustained Ievels during 24 days, there being no high différence between that initial plasma Ievels (first day) and the ones found on the next days. Whereas in other cases, the compositions resulted in inadequately controlled initial plasma Ievels, showing high plasma Ievels during first day followed by a notably decrease during next days until plasma Ievels were stabilized and maintained until drug it îs completely released. These fînding resulted highly surprisîng, since what it could anticipated is that the lower drug/polymer mass ratio, the better control of the initial release due to a higher presence of polymer to entrap and retain the drug. However, what we found here, is that ratios lower than 25% could not elicit an appropriaie rispéridone release and showed a high diffusion from the compositions during the initial term following administration. On the other hand, ratios in the interval 25-35% were capable to evoke more sustained plasma Ievels since the very beginning with lower différences between initial Ievels (first day) and following ones (next daysj.FînalIy, an increase in the ratio over 35% resulted in higher initial plasma Ievels compared to ones obtained during the next days, so that a value of 35% in thîs ratio is considered to
-36represent a lîmit for the minimum amount of polymer which. is necessary to provide a good rispéridone entrapment into the composition matrix. In general terms, a preferred range for the risperidone/polymer mass ratio is between 25 and 35%. A most preferred value is around 33%.
In vivo plasma levels after intramuscular administration to Beagle dog
The rispéridone formulations of this example corresponding to drug/polymer mass ratios of 20 and 33.3% were intramuscularly injected to Beagle dogs weighing an average of 10 kg. The amount injected corresponded to a dose of 25 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of dogs was 3. After injection, plasma levels were obtained at
0,4h, Id, 2d, 3d, 5d,7d, lOd, 14d, 17d,21d, 24d, 28d, 31d,35d, 38dand42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 23. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, sincethe therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be seen ïn the cited Figure, the injection of an amount of formulation corresponding to 25 mg rispéridone to Beagle dogs resulted in well-controiled initial plasma levels with sustained levels up to at least 35 days. And as previously described for rabbits, a higher drug/polymer mass ratio, between 25-35%, resulted in a surprisingly better control of the drug release than lower ones (below 25%), thus providing a controlled initial diffusion followed by a more constant release, so that more balanced plasma levels are obtained.
Example 11; Study of different polymeric solution/drug mass ratios
The rispéridone implantable formulations of this cxample were prepared by completely dissolving polymer Resomer®RG503 (RG503, 50:50 lactîc/glycolic acid, Boehringer
-37Ingelheim) in dimethyl sulfoxide and subsequently dispersing the drug in the mentioned polymeric solution adjusted to different polymeric solution/risperidone mass ratios (w/w): 6.7, 10, 11.4, 14 and 19, expressed as the weight percent of polymer solution with respect to drug.
In vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone composition of this example was mtramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 2. After injection, plasma levels were obtained at 0, 4h, Id, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21 d, 24d, 28d, 31d, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moîety plasma levels is shown în Figure 24. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As shown in the cited Figure, the injection of an amount of formulation corresponding to 15 mg rîsperidone to New Zealand White rabbits resulted in well-controlled initial plasma levels 4h post-administration, which plasma levels were maintained up to 28 days in ail polymeric solution/risperidone cases, although the lower the polymeric solution/risperidone ratio, the more constant levels were achieved. However the value of 19 is not considered adéquate due to being capable to control the very initial release (and plasma levels) approximately during the first 24h, but not during the following days (from day 2nd to 5Λ). Therefore, an appropriate composition should présent a polymer solution/drug mass ratio below 15 and at least until the last value tested (4).
-38Example 12: Study of different solvent/drug ratios.
Rispéridone implantable formulations were prepared by completely dissolving polymer Resomer®RG503 (RG5O3, 50:50 lactic/glycolic acid, Boehringer Ingelheim) in dimethyl sulfoxide and subsequently dispersing the drug in the mentioned polymeric solution adjusted to different solvcnt/rispcridonc ratios between 4.7 and 11.4 (w/w), expressed as weight percent of solvent with respect to drug.
In vivo plasma levels after intramuscular administration to New Zealand rabbit
The rispéridone compositions of this example were intramuscularly injected to New· Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 2. After injection, plasma levels were obtaîned at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d, 28d, 31d, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 25. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As shown in the cited figure, the injection of an amount of formulation corresponding to 15 mg rispéridone to New Zealand White rabbits resulted in initial plasma levels 4h postadministration, which plasma levels were sustained up to 28 days in ail solvent/risperidone ratios, although the lower the solvent/risperidone ratio, the more constant levels were achieved. Ail ratios studied showed an adéquate control of the initial plasma levels during first 24h, however, the ratio 11.4 îs not considered adéquate because it exhibits a later uncontrolled drug diffusion/release during the following days
Ο
-39(days 2nd to 5111). Therefore it is consider that an appropriate solvent/risperidone ratio should be lower than 10 and until at Ieast the lowest value tested (4).
Example 13: Study of the addition of a pH modifier.
The same rispéridone implantable formulations were prepared by completely dissolvîng the polymer in the solvent (DMSO) and subsequcntly dîspcrsing the drug in the mentioned polymeric solution with the optional addition of an alkaline agent such magnésium hydroxide.
| Ingrédient | Amount (mg) | |
| No Alkaline agent | Alkaline agent | |
| Resomer®RG503 (polymer) | 100 | 100 |
| Rispéridone | 25 | 25 |
| Dimethyl sulfoxide (solvent) | 233.3 | 233.3 |
| Magnésium Hydroxide | — | 8.3 |
RG503, 50:50 lactic/glycolic acid polymer (Boehringer Ingelheim)
In vivo plasma leveis after intramuscular administration to New Zealand rabbit
The rispéridone compositions of this example were intramuscularly injected to New
Zealand White rabbits weighîng an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits was 2. After injection, plasma leveis were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21d, 24d, 28d, 31 d, 35d, 38d and 42d.
The kinetics of the plasma leveis corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma leveis îs shown in Figure 26. The results are expressed as the addition of the rispéridone plus 9-OH-
-40rispéridone concentrations (ng/ml) as a fonction of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As shown in the cited figure, the injection of an amount of formulation corresponding to 15 mg rispéridone to New Zealand White rabbits resulted in initial plasma levels since 4h postadministration up to at least 23 days. However, by the use of an alkaline agent within the polymer matrix, a more sustaincd plasma levels starting from 4h post-administration and an enlargement of the time showing therapeutic rispéridone plasma levels up to at least 32 days is achieved.
Example 14: Study of reconstitution of the formulations.
Rispéridone implantable formulations were prepared with the following composition:
| Ingrédient | Amount (mg) |
| Resomer®RG503 (polymer) | 50 |
| Rispéridone | 25 |
| Dimethyl sulfoxide (solvent) | 166.7 |
RG503, 50:50 lactic/glycolic açid polymer (Bochringcr Ingclhcim)
The rispéridone selected for the compositions of this example showed a usual particle size distribution between 25-225 microns (not more than 10% of drug particles with a particle size smaller than 25 microns, and not more than 10% larger than 225 microns). Three different methods were applied to reconstitute the composition:
A) Vial. The polymeric solution was prepared by weighing the appropriate amounts of polymer and solvent and mixing them by vortexing until the polymer had completely dissolved in the solvent. Then, the appropriate rispéridone amount was added to the polymeric solution and a homogeneous suspension was obtained by vortexing.
B) Syringes. The rispéridone, the polymer and the solvent were weighed independently in syringes. The polymeric solution was then prepared by connecting the respective syringes by a fluid connecter so that the solvent was moved from the syringe containing it to the syringe containing the polymer and then making several forwardbackward cycles from one syringe to the other by pushing the respective plungers. Once
the polymer is completely dissolved in the solvent, the third syringe containing the rispéridone was connected and a homogeneous suspension was then obtained by doîng several additional cycles.
C) Freeze-drying. Polymer and rispéridone were freeze-dried in a prefilled syringe and the solvent was placed in a second syringe. The syringes were connected by a fluid conncctor and then the solvent was movcd to the syringe containing the freezedried polymer-risperidone mixture and finally several forward-backward cycles were repeated until a homogeneous suspension was achieved.
Préparation methods B and C can also be carried out by direct connection of syringes using female-male luer syringes.
In vitro release profile:
The rispéridone release from formulations corresponding to the three different methods was evaluated according to the following procedure: the amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks by using a 21G needle followed by the careful addition of a pre-warmed release medium. The release medium was 250 ml phosphate buffer pH= 7.4. The flasks were then placed into an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time (2h, 1 d, 3d, 7d, lOd, 14d, 17d, 21d, 24d, 28d, 3 ld and 35d), 5 ml of release medium was collectcd and replaced with fresh buffer, and the amount of rispéridone amount présent in the sample was determined by UV spectrophotometry.
The profile of rispéridone released from the implants is shown in Figure 27. The results are expressed as %Risperidone released from the formulation as a function oftime. As it can be observed in Figure 27, the release profile of the implantable formulations prepared by the three different methods was the same during first 2 weeks. However, after 14 days the préparation method A (vial) resulted in a slightly slower release rate, probably due the higher porosity of the implants formed by the other 2 methods because of the air introduced to the formulation during the reconstitution process.
-42In vivo plasma levels after intramuscular administration to New Zealand rabbît
The rispéridone compositions of this example were intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G nccdle. Total number of rabbits was 2. After injection, plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, 14d, 17d, 21 d, 24d, 28d, 31 d, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 28. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-rispcridonc is substantially équivalent to that of rispéridone. As it can be seen in the cited Figure, the injection of an amount of formulation corresponding to 15 mg rispéridone to New Zealand White rabbits resulted in initial plasma levels starting from 4h post-administration up to at least 28 days. The methods consisting on reconstitution of a formulation pre-filled in different containers by their mîxing (Methods B and C) evoked slightly higher initial plasma levels. This could be due to the higher porosity, and consequently higher initial diffusion, of the implantable formulations prepared by these two methods in comparison with Method A (préparation inside a vial). This fact could be also the reason for their higher plasma levels during the first week after administration.
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In vivo plasma levels after intramuscular administration to Beagle dog
The rispéridone formulations of this example were also intramuscularly injected to Beagle dogs weighing an average of 10 kg. The amount injected corresponded to a dose of 25 mg rispéridone and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of dogs was 3. After injection,
-43plasma levels were obtained at 0, 4h, ld, 2d, 3d, 5d, 7d, lOd, I4d, I7d, 2ld, 24d, 28d, 31d, 35d, 38d and 42d.
The kinetics of the plasma levels corresponding to the rîsperidone active moîety was evaluated by measuring both rîsperidone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rîsperidone active moîety plasma levels is shown in Figure 29. The results are expressed as the addition of the rîsperidone plus 9-OHrisperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rîsperidone. As it can be seen in 10 the cited Figure, the injection of an amount of formulation corresponding to 25 mg rîsperidone to Beagle dogs resulted in well-controlled initial plasma levels with sustained levels up to at least 35 days using different préparation methods such as prîor élaboration of polymeric solution followed by drug addition (vial, method A) or by direct reconstitution starting from solid components (syringes, method B).
Example 15: Study of the effect of stérilisation by irradiation process.
In the présent example, the composition of the rîsperidone implantable formulations was as follows maintaining always the same amounts of drug, polymer and solvent::
| Composition | Irradiation (KGy) | Polymer lactic/ glycolic ratio | Polymer End Terminal group | Mean Molecular weight (g/mol) | Polymer Solution Viscosity (Pa.s) | Solvent |
| A | 0 | 50:50 | capped | 27,020 | 1.62 | DMSO |
| B | 10 | 50:50 | capped | 23,189 | 1.30 | DMSO |
| C | 15 | 50:50 | capped | 22,182 | 1.00 . | DMSO |
| D | 25 | 50:50 | capped | 20,991 | 0.81 | DMSO |
| E | 0 | 50:50 | capped | 39,708 | 5.97 | DMSO |
| F | 25 | 50:50 | capped | 27,891 | 1.78 | DMSO |
-44The implantable formulations were prepared by direct reconstitution of 2 prefilled syringes, first one with polymer and rispéridone mixture, and second one with the solvent. Syringes were connected.
Syringes containing polymer plus rispéridone mixtures were sterilized by β-irradiation in the range 10-25 KGy. As indicatcd in the table, two different polymer were tested, one is an end capped 50:50 polymer with mean Mw 27,020 g/mol, non irradiated or irradiated at 10, 15 or 25 KGy, and the other an end capped 50:50 polymer with mean Mw 39,708 g/mol, non irradiated or irradiated at 25 KGy.
Formulations A and E received sterilization irradiations that gave rise to different compositions due to different polymer molecular weight losses during the process; however, the inhérent viscosity did not resuit below 0.25 dL/g in any case, and the viscosity of the polymer solution is maintaîned between the range 0.5-7 Pa.s previously studied as being adéquate for this kind of long lasting implantable formulations (Example 9).
In vitro release profile:
The rispéridone release from compositions of this ex ample was evaluated according to the following procedure. The amount of formulation corresponding to 25 mg of rispéridone was injected from prefilled syringes into flasks having a pre-warmed release medium by using a 21G needle. The release medium was 250 ml phosphate buffer pH= 7.4. The flasks were then placed înto an oven at 37°C and kept under horizontal shaking at 50 rpm. At previously scheduled time points (2h, Id, and periodically up to 28 days) 5 ml of release medium was collected and replaced with fresh buffer and the amount of rispéridone présent in the sample was determined by UV spectrophotometry. The profile of rispéridone reieased from the implants of this example is shown in Figure 30 and Figure 31. The results arc expressed as % drug reieased from implants as a function oftime.
As it can be observed in the Figure 30, the release of rispéridone from the same formulation either non irradiated (composition A) or irradiated at different levels
-45 (compositions B, C and D) in the range 10-25 KGy resulted in very similar profiles because polymer solution viscosîties were still within the preferred established range 0.7 to 2.0 Pa.s. Figure 31 shows how the other polymer with a higher Mw (39,708 g/mol) (composition E) which présents an slighlty slower release profile, once it is irradîated (composition F) présents a release profile doser to the non-irradîated lower Mw polymer (composition A), duc to the loss of molecular weight during sterilization process, which leads to a composition with polymer solution viscosity key parameter within preferred ranges 0.7-2.0 Pa.s.
In vivo plasma levels after intramuscular administration to New Zealand rabbit:
The rispéridone compositions A, B, C, D and G of this example were intramuscularly injected to New Zealand White rabbits weighing an average of 3 kg. The amount injected corresponded to a dose of 15 mg rispéridone, and the composition was intramuscularly placed in the left hind leg using a syringe with a 20G needle. Total number of rabbits per composition was 3. After injection, plasma levels were obtained at 0,4h, Id, 2d, 5d, 7d, lOd and periodically up to 28 days.
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma sampies. The profile of the rispéridone active moiety plasma levels is shown in Figure 32 and Figure 33. The results are expressed as the addition of the rispéridone plus 9-OH-risperidone concentrations (ng/ml) as a function of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be observed in these Figures, the injection of an amount of composition équivalent to 15 mg rispéridone to New Zealand White rabbits resulted in very similar plasma levels as could be predicted since in vitro behaviour was very similar after irradiation. Figure 32 revealed not extraordinary changes in the rispéridone active moiety plasma levels when a formulation comprising a 27,020 g/mol mean molecular weight polymer (composition A), was irradîated at 10, 15 or 25 KGy (composition B, C and D, respectively) since key parameter such as polymer solution viscosity is still insîde the prevîously préférable determined range of 0.7 to 2.0 Pa.s.
-46A higher molecular weight polymer (39,708 g/mol), with polymer solution viscosity out of the préférable range (5.97 Pa.s, composition E), upon irradiation at 25 KGy (since higher molecular weight polymers suffer proportîonally higher molecular weight losses during irradiation) teads to a polymer with lower inhérent viscosity and consequently lower but still adéquate polymer solution viscosity of 1.78 Pa.s (composition F). That higher molecular weight polymer, after 25 KGy irradiation, resulted extrcmcly close to the lower one without any irradiation (compostion A) in both molecular weight and polymer solution viscosity, therefore fulfilling in this manner the polymer solution viscosity parameter leading to adéquate long lasting implantable Systems in line with the présent invention, and experimenting a very sîmîlar in vivo behaviour (plasma levels profile) as shows Figure 33.
Comparative Example 2 (not according to the invention)
Rispéridone implantable formulations were prepared according to procedures described in US 5,688,801.
In vivo plasma levels after intramuscular administration to Beugle dog
The rispéridone formulations of this example were intramuscularly înjected to Beagle dogs weighing an average of 10 kg after resuspension of microparticles in 2 ml of a 2.5% (in weight) carboxymethyl cellulose solution in water. The amount înjected corresponded to a dose of 25 mg rispéridone and the composition was intramuscularly placed in the left hind leg. Total number of dogs was 6. After injection, plasma levels were obtained at 0, ld, 2d, 6d, 9d, 13d, 15d, 17d, 19d, 21 d, 23d, 26d, 29d, 33d, 35d, 42d and 56d.
*
The kinetics of the plasma levels corresponding to the rispéridone active moiety was evaluated by measuring both rispéridone and its active métabolite 9-OH-risperidone in the plasma samples. The profile of the rispéridone active moiety plasma levels is shown in Figure 34. The results are expressed as the addition of the rispéridone plus 9-OHrisperidone concentrations (ng/ml) as a functîon of time, since the therapeutic activity of 9-OH-risperidone is substantially équivalent to that of rispéridone. As it can be seen in
-47the cited Figure, the results of this test showed that the administration of rispéridone in preformed microparticles, according to procedures described in the prior art, fails to provide significant plasma levels of rispéridone active moiety in dogs until the third week following administration. The plasma levels observed among the 6 animais also showed a poor reproducibility, and the rise was typicalîy observed from approximately day 2ΙΛ until approximately day 28tb following administration, to then diminish at a similar rate, thereby providing a peak of plasma level with an approximate extension of 2 weeks. These profiles are completely different to the profiles observed in the examples according to the invention and clearly demonstrates the différence between the plasma levels obtained with the composition according to the invention compared to those obtained according to the prior art.
From the above experiments ît can be concluded that the viscosity of the polymeric solution (polymer + solvent), surprisingly shows a stronger influence on the controi of the drug release than other various factors that could conccivably be considcred as having a stronger effect, such as the nature of the polymer or its concentration. This resuit is unexpected and surprisîng in the light of the prior art.
It can also be concluded that, when a certain portion of the polymer is removed at a constant rispéridone amount, -or, in other words, that the drug/polymer mass ratio is increased-, the initial release is lower and consequently the plasma level profiles are flattened. This effect is likewise surprisîng, since the presence of a lower amount of polymer could be a priori related to a lower capacity to retain the drug and providing a
Claims (17)
1. An injectable depot composition, comprising:
a drug which is rispéridone and/or its métabolites or prodrugs in any combination thereof;
at least a biocompatible polymer which is a copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid in the range from 50:50 to 75:25, and
- at least a water-miscible solvent with a dipole moment about 3.9-4.3 D, wherein the viscosity of the solution comprising the polymer and the solvent is between 0.5 and 3.0 Pa.s and the solvent/drug mass ratio is between 10 and 4, characterised in that the drug/polymer mass ratio is between 25 and 35% expressed as the weight percentage of the drug with respect of the drug plus polymer.
2. The composition according to claim 1, wherein the solvent is dimethylsulfoxide (DMSO).
3. The composition according to claims 1 or 2, wherein the drug/polymer mass ratio is about 33%,
4. The composition according to any one of claims 1 to 3, wherein the solvent/drug mass ratio is between 5 and 4.
5. The composition according to claim 4, wherein the solvent/drug mass ratio is about
4.66.
6. The composition of any one of previous claims 1-5, whcrcin the particle size distribution of the drug is:
less than 10% particles smaller than 10 microns;
- less than 10% particles larger than 225 microns, and a d0.5 value in the range of60-130 microns.
7. The composition according to any one of the prevîous claims wherein the mass ratio between the weight of the solution comprising the polymer and the solvent and the drug îs between 15 and 5.
5
8. The composition according to claim 7, wherein the mass ratio between the weight of the solution comprising the polymer and the solvent and the drug îs between 12 and 5.
9. The composition according to claim 8, wherein the mass ratio between the weight of the solution comprising the polymer and the solvent and the drug is between 7 and 6,5.
10. The composition according to claim 9, wherein the mass ratio between the weight of the solution comprising the polymer and the solvent and the drug is about 6,66.
11. The composition according to any of the prevîous claims further comprising 15 Mg(OH)2 in a molar ratio between 2/3 and 2/5, expressed as the molar ratio of drug to
Mg(OH)2.
12. The composition of any one of the prevîous claims which is a stérile composition.
20
13. The composition of any one of prevîous claims for the treatment of schizophrenia or bipolar disorders in the human body.
14. A pharmaceutical kit suitable for the ΐη situ formation of a biodégradable implant in a body comprising the composition of any one of claims 1-13, wherein the drug and the
25 biocompatible polymer are contained in a first container, and the solvent is contained în a second, separate container.
15. The pharmaceutical kit according to claim 14, wherein at least one of the first and second containers is a syringe, a vial, a device or a cartridge, either disposable or not.
C
16. The pharmaceutical kit according to claim 15, wherein both the first and the second containers are disposable syringes.
17. The pharmaceutical kit according to claim 16, wherein the syringes are connectable 5 through a connector device or a direct thread.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ESEP10382154.2 | 2010-05-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16256A true OA16256A (en) | 2015-04-10 |
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