Sustained release small molecule drug formulation

[0001] The invention relates generally to the delivery of small molecule drugs.

[0002] The term "small molecule drug" as used herein refers to preferred low molecular weight agents. Beneficial agents are usually synthesized by organic chemistry but can also be isolated from natural sources such as plants, fungi and microbes. Typical delivery routes for small molecule drugs are oral, pulmonary, transdermal, and injection.

[0003] Many psychotherapeutic drugs are small molecules and are usually administered in the form of oral pills or bolus injections that can be administered one or more times a day. However, oral pills and bolus injections may not be optimal routes for administering low molecular weight psychotherapeutic drugs due to the maxima and minima observed in their plasma concentrations after dosing. Adverse reactions and loss of therapeutic effect, respectively, have been associated with maxima and minima of plasma drug concentrations.

[0004] In view of the above, psychotherapy, as well as other forms of treatment currently based on small molecule drugs administered in the form of oral pills and bolus injections, may benefit from sustained release dosage forms designed to minimize fluctuations in their concentration in plasma after dosing. The administration of psychotherapeutic agents in the form of sustained-release preparations will also improve patient compliance.

International Patent Application No. WO 2005/048989 describes injectable sustained release gel compositions and excipient delivery kits for modulating the release rate and stabilizing beneficial agents. International Patent Application No. WO 00/24374 describes a controlled polymer composition comprising a polymer or copolymer, an organic solvent, a polymer release control additive and a biologically active agent released from the polymer composition when it solidifies into a solid implant. The release controlling additive is preferably a poly (lactide-co-glycolide) / polyethylene glycol block copolymer.

SUMMARY OF THE INVENTION [0005] The present invention relates to an extended release injection formulation comprising:

biocompatible polylactide being a lactic acid polymer or a copolymer based on lactic acid and glycolic acid, in which the ratio of lactic acid to glycolic acid monomers in polylactide is from 100: 0 to 15:85 and in which the polylactide has a weight average molecular weight from 1000 to 30,000; an organic solvent combined with a biocompatible polymer to give a sticky gel; and, introduced into the viscous gel, risperidone (risperidone, riseperidon) in the form of a base or salt.

[0006] The present invention also relates to an extended release injection formulation according to the present invention for use in a method of treatment of the human or animal body by administering risperidone to a patient in a controlled manner.

[0007] Other features and advantages of the invention will become apparent from the following description.

BRIEF DESCRIPTION OF THE FIGURES

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PZ / 2073 / AGR [0008] FIG. 1 depicts the effect of the salt drug on the in vivo release profile of the formulations according to an embodiment of the invention.

[0009] FIG. 2 illustrates the effect of the type of solvent on the in vivo release profile of formulations according to an embodiment of the invention.

[0010] FIG. 3 illustrates the effect of the type of polymer on the release profile of formulations in vivo according to an embodiment of the invention.

[0011] FIG. 4 depicts formulations with near-zero-order release kinetics according to an embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION [0012] The invention will now be described in detail with reference to preferred solutions as illustrated in the accompanying drawing. The following description provides many specific details to enable a thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention may be practiced without considering some or all of these specific details. In other cases, well-known features and / or process steps were not described in detail to avoid describing the invention in an incomprehensible manner. The features and advantages of the invention can be better understood by referring to the figures and the following discussion.

[0013] The invention is based in part on the finding that the incorporation of a sparingly soluble small molecule drug into a sustained release gel carrier results in a small molecule drug preparation with near zero order kinetics in vivo. The release profile indicates the minimum delayed absorption and the minimum rapid burst of the active substance. In the case of a sustained release formulation, this release profile is unexpected because in the art there is a prevailing view that small rapid bursts of active substance and close to zero order release kinetics are virtually impossible to achieve without specific steps such as drug coating and microencapsulation. . In this invention, several small molecule drug formulations with in vivo release profiles with a C ratio have been identified_max to C._min of less than 200 and absorption delay time, Tlag, of less than 0.2.

[0014] The variable "C_min"Is the minimum concentration of the drug in the plasma or serum. The variable 'C_max"Is the maximum concentration of the drug in plasma or serum. The variable "Tlag" is the ratio of Tvalley to T, with the value of Tvalley lower than the value of T_total. The "Tvalley" variable is the time it takes to reach Cvalley. The variable "Cvalley" is the first minimum drug or plasma concentration during release. The variable 'T_total"Is the total release time.

[0015] The small molecule drug formulations of the present invention are prepared in the form of delayed release injections. The application environment is a fluid environment and may include the subcutaneous, intramuscular, adventitial, intracerebral or intracerebral part, myocardium, wound site or tight joint spaces or human or animal body cavity. The patient may be given multiple or repeated injections, e.g., when the therapeutic effect of the drug has ceased or the period during which the drug was to have a therapeutic effect has expired or when the patient for any reason requires further drug administration. The preparation serves as an implanted extended-release system that provides the drug after injection into a patient. Such controlled release can last for

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PZ / 2073 / AGR a week, over a week, a month or more than a month. Preferably, controlled release lasts for at least a week, more preferably for at least a month.

[0016] The small molecule drug formulation according to embodiments of the invention comprises a sustained release gel carrier. The sustained release gel carrier contains a biocompatible polymer, i.e., a polymer that will not cause irritation or necrosis in the application environment. Biocompatible polymers that may be useful in the present invention may be susceptible to biological erosion, i.e., gradually decompose, dissolve, hydrolyze and / or erode in situ. The polymer is typically present in the sustained release gel carrier in an amount ranging from 5 to 80% by weight, preferably from 20 to 70% by weight, often from 40 to 60% by weight.

[0017] The polymer is a polylactide polymer, i.e. a polymer based on lactic acid, or a copolymer based on lactic acid and glycolic acid. The polylactide polymer may contain small amounts of other comonomers that do not significantly affect the beneficial results that can be obtained according to the invention. The term "lactic acid" includes L, D, DL isomers of lactic acid and lactide. The term "glycolic acid" includes glycolide. The proportion of lactic acid to glycolic acid monomers in the polymer is from 100: 0 to 15:85, preferably from 60:40 to 75:25, often around 50:50. The polylactide polymer has a weight average molecular weight in the range from 1000 to 30,000, preferably from 5000 to 30,000, as determined by gel permeation chromatography. Suitable polylactide polymers are commercially available.

[0018] The sustained release gel carrier further comprises a biocompatible solvent which, when combined with the polymer, forms a viscous gel, typically having a viscosity in the range from 500 poise to 200,000 poise, preferably from 1000 poise to 50,000 poise. The solvent used in the sustained release gel carrier is typically an organic solvent and may be a single solvent or a mixture of solvents. To limit the absorption of water by the sustained release gel carrier in the application environment, the solvent, or at least one of the solvent components in the case of a multi-component solvent, is preferably mixed with water to a limited extent, e.g. with water below 7% by weight, preferably below 5% by weight, more preferably below 3% by weight. Examples of suitable solvents include, but are not limited to, benzyl benzoate (BB), benzyl alcohol (BA), ethyl benzoate (EB), triacetin and N-methyl-2-pyrrolidone (NMP). The solvent is typically present in the sustained release gel carrier in an amount in the range of 20 to 95% by weight, preferably in an amount in the range of 30 to 80% by weight, often in an amount in the range of 40 to 60% by weight.

[0019] The formulation according to an embodiment of the invention comprises a small molecule drug dispersed or dissolved in a sustained release gel carrier as described above. The term "dispersed or dissolved" is intended to include all methods for obtaining a low molecular weight drug in a viscous gel and includes dissolving, dispersing, suspending, etc. The low molecular weight drugs used in the formulations of the invention are sparingly soluble in water. In a preferred embodiment, the water solubility of the small molecule drugs used in the formulations of the invention is below 1 mg / ml. In one embodiment, the low molecular weight drugs used in the formulations of the invention have a molecular weight ranging from 200 to 2000 Daltons. The small molecule drugs used in the formulations of the invention may have a narrow or wide window

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PZ / 2073 / AGR therapeutic. Nevertheless, the invention generally provides health benefits in a sense

C_max and control the toxicity of small molecule drugs characterized by a narrow therapeutic window. The small molecule drug is typically present in the formulation in an amount in the range of 1 to 50% by weight, more preferably in an amount in the range of 5 to 40% by weight, often in an amount in the range of 10 to 30% by weight.

[0020] In general, the small molecule drug formulation may contain a small molecule psychotherapeutic drug such as a small molecule antipsychotic agent, dopamine receptor agonist, dopamine receptor antagonist, serotonin receptor agonist, serotonin receptor antagonist and a drug that inhibits serotonin uptake. Table 1 below presents the physicochemical properties of some small molecule psychotherapeutic drugs. The R209130 base has the molecular formula C₁₉H₂₀FNO. The mandelic acid salt R209130 (R209130) has a molecular formula

Cl9H20FNO C8 ^ ^ O3. The tartaric acid salt R209130 (R167154) has a molecular formula

Cl9H20FNO ^ C4H6O6. R209130 and its analogues have putative atypical antipsychotic properties and have shown anxiolytic, antidepressant and socializing effects in animal models. These properties can be attributed to the dual antagonistic effect of R209130 on dopamine D receptors₂ and 5-HT serotonin receptors_2A and 5-HT_2C in the central nervous system and inhibiting the uptake of adrenaline. However, the present invention is limited to risperidone in the form of a base and salt. The risperidone base has the molecular formula C₂₃H₂₇FN₄ABOUT₂. Risperidone pamoate has the molecular formula C23H27FN4O2 ^ C23H16O6. Risperidone is a combined serotonin receptor (5-HT) antagonist₂) and dopamine (D2).

TABLE 1

<td>Property</td><td>R209130</td><td>R167154</td><td>Principle R209130</td><td>Principle risperidone</td><td>pamoate risperidone</td>

<td>pK</td><td> 9,2</td><td> 9,2</td><td> 9,2</td><td> 8,2/3,1</td><td> 8,2/3,1</td>

<td>Solubility in H2O (mg / ml)</td><td>0.32 (pH 4.9)</td><td>41.84 (pH 3.4)</td><td>0,008 (pH 9.5)</td><td>0.09 (pH 8.8)</td><td>0.2 (pH 7.2)</td>

<td>Solubility at pH 7 (Mg / ml)</td><td> 0,35</td><td>6.1 (pH 6.5)</td><td> 2</td><td> 1</td><td>0.2 (pH 7.2)</td>

<td>Solubility in BB ^ g / ml)</td><td>58.6 in temperature 40 ° C</td><td>10.3 in temperature 40 ° C</td><td> &gt; 200 000</td><td> 32 000</td><td> 50</td>

<td>Solubility in BA (mg / ml)</td><td>7.3 in temperature 40 ° C</td><td>41.3 in temperature 40 ° C</td><td> &gt; 200 000</td><td> 407</td><td> 2,97</td>

<td>Specific dissolution rate (mg / cm²^ Min)</td><td> 0,054</td><td> 3,7</td><td> 0,7</td><td> 0,0025</td><td>Not applicable</td>

<td>LoP (buffer C₈OH / pH 7)</td><td> 3,9</td><td> 4,0</td><td>Not applicable</td><td> 3,04</td><td>Not applicable</td>

<td>Molecular weight</td><td> 449,5</td><td> 447,5</td><td> 297,4</td><td> 410,5</td><td> 798,5</td>

[0021] A study was conducted to determine the pharmacokinetic (PK) profile of a small molecule drug delivered from a sustained release gel carrier according to the invention and the effect of drug salt form, type of solvent , type of polymer, polymer molecular weight, polymer: solvent ratio, drug load, and particle size, per PK profile.

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PZ / 2073 / AGR [0022] The following examples are provided for illustrative purposes and are not intended to limit the invention in another manner described herein.

EXAMPLE 1 [0023] A sustained release gel carrier was prepared as follows: the HDPE container was tared on a Mettler PJ3000 top loading balance. Poly (D, L-lactide-ciclycolide) (PLGA) (L / G ratio 50/50), available under the name RESOMER® RG 502 (PLGA502), was weighed into the container. The container containing PLGA-502 was tared and the appropriate solvent was added to it. The amounts expressed as a percentage for various combinations of PLGA-502 and solvent are shown in Table 2 below. A hybrid mixer was used to mix PLGA-502 and the solvent mixture, resulting in a clear, gel-like polymer solution in a solvent.

TABLE 2

<td>Preparation</td><td>PLGA-502 (weight%, g)</td><td>Benzyl benzoate (% by weight, g)</td><td>Benzyl alcohol (% by weight, g)</td>

<td>AND</td><td> 50,067</td><td> 50,044</td><td></td>

<td>B</td><td> 50,023</td><td> 24,988</td><td> 24,988</td>

<td>C</td><td> 50,365</td><td> 45,093</td><td> 5,1780</td>

<td>D</td><td> 50,139</td><td> 37,553</td><td> 12,560</td>

<td>E</td><td> 50,350</td><td> 45,193</td><td></td>

[0024] Additional sustained release gel carriers were prepared using solvents selected from benzyl benzoate (BB), benzyl alcohol (BA), ethyl benzoate (EB), ethyl hydroxide (EtOH), triacetin and N-methyl-2-pyrrolidone (NMP), and mixtures thereof, and polymers selected from poly (D, L-lactide) available under the name RESOMER® L 104, RESOMER® R 104, RESOMER® 202, RESOMER® 203, RESOMER® 206, RESOMER® 207 , RESOMER® 208; PLGA with a L / G ratio of 50/50, under the name RESOMER® RG 502H; PLGA with a L / G ratio of 50/50, under the name RESOMER® RG 503; PLGA with a L / G ratio of 50/50, under the name RESOMER® RG 755; poly (L-lactide) with a molecular weight of 2000, under the name RESOMER® L 206, RESOMER® L 207, RESOMER® L 209, RESOMER® L 214; poly (L-lactide-coD, L-lactide) with an L / G ratio of 90/10, under the name RESOMER® LR 209; PLGA with a L / G ratio of 75/25, under the name RESOMER® RG 752, RESOMER® RG 756, PLGA with a L / G ratio of 85/15, under the name RESOMER® RG 858; poly (L-lactide-trimethylene carbonate), with a L / G ratio of 70/30, under the name RESOMER® LT 706 and poly (dioxanone), under the name RESOMER® X210 (Boehringer Ingelheim Chemicals, Inc. Petersburg, VA); DL-lactide / glycolide (DL) with an L / G ratio of 100/0, under the name MEDISORB® Polymer 100 DL High, MEDISORB® Polymer 100 DL Low; DL-lactide / glycolide (DL) with an L / G ratio of 85/15, under the name MEDISORB® Polymer 8515 DL High, MEDISORB® Polymer 8515 DL Low; DL-lactide / glycolide (DL) with a L / G ratio of 75/25, under the name MEDISORB® Polymer 7525 DL High, MEDISORB® Polymer 7525 DL Low; DL-lactide / glycolide (DL) with a L / G ratio of 65/35, under the name MEDISORB® Polymer 6535 DL High, MEDISORB® Polymer 6535 DL Low; DL-lactide / glycolide (DL), with a L / G ratio of 54/46, under the name MEDISORB® Polymer 5050 DL High, MEDISORB® Polymer 5050 DL Low, MEDISORB® 5050 Polymer DL 2A (3), MEDISORB® 5050 Polymer DL 3A (3), MEDISORB® 5050 Polymer DL 4A (3) (MEDISORB Technologies International LP, Cincinnati, OH); and PLGA (L / G ratio 50/50), PLGA (L / G ratio 65/35), PLGA (L / G ratio 75/25), PLGA (L / G ratio 85/15), poly (D, L-lactide), poly (L-lactide), poly (glycolide), poly (e-caprolactone), poly (D, L-lactide-coEP2361609B1

PZ / 2073 / AGR caprolactone) (L / K ratio 25/75) and poly (D, L-lactide-co-caprolactone) (L / K ratio 75/25), available from Birmingham Polymers, Inc., Birmingham, AL. Polycaprolactone-glycolic acid-lactic acid copolymer (PCL-GA-LA) was also used - mixed with poly (vinylpyrrolidone) (PVP) or alone. Typical molecular weights of these polymers ranged from 6,000 to 20,000.

EXAMPLE 2 [0025] Drug particles were prepared as follows: drug R209130, R167154, risperidone base or risperidone pamoate were passed through screens of various sizes to give drug particles with a certain range of particle size distribution. Particles in the range 20 to 63 μm, 63 to 125 μm, 75 to 125 μm, or less than 38 μm were obtained. The obtained micronized particles were also used as drug particles.

EXAMPLE 3 [0026] Sustained-release preparations were prepared as follows: the sieved drug particles prepared as described in Example 2 were added to the sustained-release gel carriers prepared as described in Example 1 in an amount of 0 to 50% by weight and mixed by hand until the drug particles were completely wetted. The mixture of drug particles and the sustained release gel was then thoroughly mixed in a conventional manner using a Caframo mechanical stirrer with an attached metal paddle with a square end. Final homogeneous gel preparations were transferred to₃ disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or dispensing.

EXAMPLE 4 [0027] In accordance with the above procedures, a representative number of implant gels were prepared and tested in rats in vivo to determine drug release by determining the concentration of drug in serum or plasma over time.

[0028] In general, in vivo studies in rats were conducted according to an open protocol to determine plasma drug concentration (e.g., R209130, R167154, risperidone base, risperidone pamoate) after systemic drug administration using the implant systems of the invention. The drug-containing sustained release gel formulations prepared as described in the examples above were introduced into 0.5 cm disposable syringes³. Disposable needles (size 18) were put on the syringes and heated to 37 ° C using a circulation bath. Rats were injected with sustained release gel formulations. Blood was drawn at defined intervals and analyzed for drug content. All plasma samples were stored at 4 ° C prior to analysis. EXAMPLE 5 (reference only) [0029] In this example, the effect of drug salt form on release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0030] Particles R209130 and R167154, in a suitable size range, were introduced into the sustained release gel carriers according to the procedure of Example 3. The resulting preparations are shown in Table 2 below. The final homogeneous sustained release formulations are transferred to disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or dispensing. Drug in vivo release was analyzed according to the procedure of Example 4. In vivo release profiles of formulations are shown in FIG. 1. Ratio C_max to C._minand Tlag preparations are shown in Table 2. R167154 and R209130 are different salt forms of the same drug. Formulation 7 (R209130) has a C ratio_max to C._min 19.2 and Tlag 0.61, while formulation 3 (R167154) has a ratio of C_max to C._min of 25.7 and Tlag of 0.33.

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This example indicates that the in vivo release process is affected by the salt form of the preparation. Even though Tlag for formulation 7 (R209130) has a higher value than Tlag for formulation 3 (R167154), it appears that formulation 7 has a better release rate profile and release time than formulation 3.

TABLE 2

<td>No.</td><td>PLGA (% by weight).</td><td>BA by weight).</td><td> (%</td><td>BB by weight).</td><td> (%</td><td>triacetin (wt%)</td><td>Bow (wt%)</td><td>^Cmax^{/ C}min</td><td>^Tlag</td>

<td>32, a, II, a, A</td><td> 45</td><td colspan="2"> 22,5</td><td colspan="2"> 22,5</td><td> 0</td><td> 10</td><td> 25,7</td><td> 0,33</td>

<td>7I, a, II, a, B</td><td> 45</td><td colspan="2"> 22,5</td><td colspan="2"> 22,5</td><td> 0</td><td> 10</td><td> 19,2</td><td> 0,61</td>

<td colspan="10">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate; a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55 / 5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H 1: 1); a = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

EXAMPLE 6 [0031] In this example, the effect of the type of solvent on the release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0032] Sustained-release gel carriers were prepared using PLGA-502 and the solvent was selected from BA, BB, EB, EtOH, NMP and triacetin, and combinations thereof, according to the procedure of Example 1. The sustained-release gel carriers were introduced to the appropriate extent, according to the procedure of Example 3. The resulting preparations are shown in Table 3 below. The final homogeneous sustained release formulations are transferred to disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or dispensing. In vivo release profiles of formulations from Table 3 are shown in FIG. 2. Table 3 shows the ratio C_max to C._min and Tlag preparations.

TABLE 3

<td></td><td colspan="8">Target content in the preparation (% by weight)</td><td></td><td></td>

<td>No.</td><td>PLGA</td><td>BA</td><td>BB</td><td>EtOH</td><td>Virgin Mary</td><td>triacetin</td><td>EB</td><td>Bow</td><td>^Cmax^{/ C}min</td><td>^Tlag</td>

<td>22, a, II a, A</td><td> 45</td><td> 0</td><td> 45</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 10</td><td> 59,86</td><td>NV</td>

<td>32, a, II a, A</td><td> 45</td><td> 22,5</td><td> 22,5</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 10</td><td> 25,68</td><td> 0,33</td>

<td>101, a, III, a, C</td><td> 40</td><td> 40</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 20</td><td> 4,35</td><td> 0,61</td>

<td>141, a, III, and C</td><td> 40</td><td> 20</td><td> 20</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 20</td><td> 3,15</td><td> 0,50</td>

<td>633, a, VII, and C</td><td> 43,3</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 43,3</td><td> 0</td><td> 13,4</td><td> 1364,43</td><td> 0,14</td>

<td>733, a, VII, and G</td><td> 43,3</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 43,3</td><td> 13,4</td><td> 5,20</td><td>ON</td>

<td colspan="11">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55/5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); a = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

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PZ / 2073 / AGR [0033] In Table 3 above, the ratio C_max to C._min formulation 63 (risperidone / PLGA / triacetin base, delayed release) is 1364.64. On the other hand, the ratio C_max to C._min formulation 73 (risperidone / PLGA / EB base, delayed release) is 5.20, which is much lower than the C ratio_max to C._min formulation 63. Ratio C_max to C._min Formulation 2 (R167154 / PLGA / BB, delayed release) was 59.68. On the other hand, the ratio C_max to C._min formulation 3 (R167154 / PLGA / BA / BB) was 25.68 and was below half the C ratio_max to C._minformulation 2. This indicates that the type of solvent may affect the release profile of the formulation in vivo.

EXAMPLE 7 [0034] In this example, the effect of the type of polymer on the release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0035] Sustained-release gel carriers were made using various polymers and

R209130, in the appropriate size range, according to the procedure of Example 3. The resulting preparations are illustrated in Table 4 below. Final homogeneous sustained release formulations were transferred₃ for disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or dispensing. The table shows the C ratio_max to C._min and Tlag for in vivo formulation release profiles. FIG. 3 shows the in vivo release profiles of formulations from Table 4.

TABLE 4

<td></td><td colspan="5">Target content in the preparation (% by weight)</td><td></td>

<td>No.</td><td>Polymer</td><td>BA</td><td>BB</td><td>Bow</td><td>^Cmax^Cmin</td><td>^Tlag</td>

<td>22% a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 9,86</td><td> 0,17</td>

<td>23% a, IV a, C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 6,83</td><td> 0,17</td>

<td>24% A, IV A, E</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 44,0</td><td>NV</td>

<td>25% C, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 29,49</td><td> 0,45</td>

<td>32% d, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 10,65</td><td> 0,12</td>

<td>33% f, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 6,35</td><td> 0,14</td>

<td>34% a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 8,75</td><td> 0,23</td>

<td>35% C, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 44,21</td><td>NV</td>

<td>48% C, IV, and E</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 163,12</td><td>NV</td>

<td>53% e, IV, and E</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 31,16</td><td> 0,25</td>

<td>59% d, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 6,26</td><td> 0,07</td>

<td colspan="7">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55/5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); α = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

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EXAMPLE 8 [0036] In this example, the effect of the molecular weight of polymers on the release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0037] Sustained-release gel carriers were made using polymers of different molecular weights and drug substance in the appropriate size range according to the procedure of Example 3. The resulting preparations are illustrated in Table 5 below. The final homogeneous sustained release formulations are transferred to disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or dispensing. Table 5 shows the C ratio_max to C._min and Tlag for in vivo formulation release profiles.

TABLE 5

<td></td><td colspan="5">Target content in the preparation (% by weight)</td><td></td><td></td>

<td>No.</td><td>PLGA</td><td>BA</td><td>BB</td><td>triacetin</td><td>Bow</td><td>^Cmax^{/ C}to me n</td><td>^Tlag</td>

<td>101, a, III, a, C</td><td> 40</td><td> 40</td><td> 0</td><td> 0</td><td> 20</td><td> 4,35</td><td> 0,61</td>

<td>111, a, III a, D</td><td> 40</td><td> 40</td><td> 0</td><td> 0</td><td> 20</td><td> 12,06</td><td> 0,61</td>

<td>121, a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 0</td><td> 30</td><td> 4,78</td><td> 0,14</td>

<td>131, a, IV a, D</td><td> 35</td><td> 35</td><td> 0</td><td> 0</td><td> 30</td><td> 5,29</td><td> 0,36</td>

<td>211 C, III, and C</td><td> 40</td><td> 40</td><td> 0</td><td> 0</td><td> 20</td><td> 48,55</td><td>NV</td>

<td>251 C, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 29,49</td><td> 0,45</td>

<td>261 C, IV, and D</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 41,67</td><td>NV</td>

<td>481, c, IV, and E</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 163,12</td><td>NV</td>

<td>491, c, IV, 6, E</td><td> 42</td><td> 0</td><td> 28</td><td> 0</td><td> 30</td><td> 66,31</td><td> 0,39</td>

<td>633, a, VII, and C</td><td> 43,3</td><td> 0</td><td> 0</td><td> 43,3</td><td> 13,4</td><td> 1364,43</td><td> 0,14</td>

<td>644 C, VIII, and C</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 0</td><td> 26,1</td><td> 11,66</td><td>NV</td>

<td>694 a, VIII a, E</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 0</td><td> 26,1</td><td> 14,12</td><td> 0,90</td>

<td>704 C, VIII, and C</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 0</td><td> 26,1</td><td> 22,11</td><td>NV</td>

<td>723, a, VII, and G</td><td> 43,3</td><td> 0</td><td> 43,3</td><td> 0</td><td> 13,4</td><td> 24,48</td><td>Not applicable</td>

<td colspan="8">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55/5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); a = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

EXAMPLE 9 [0038] In this example, the effect of polymer: solvent ratios on the release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0039] Sustained-release gel carriers were prepared using different polymer: solvent and drug substance ratios, in the appropriate size range, according to the procedure of Example 3. The resulting preparations are illustrated in Table 6 below. The final homogeneous sustained release formulations are transferred to disposable syringes with a capacity of 3, 10 or 30 cm³ down

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TABLE 6

<td></td><td colspan="4">Target content in the preparation (% by weight)</td><td></td><td></td>

<td>No.</td><td>PLGA</td><td>BB</td><td>EtOH</td><td>Bow</td><td>^Cmax^{/ C}min</td><td>^Tlag</td>

<td>22% a, IV a, C</td><td> 35</td><td> 0</td><td> 0</td><td> 30</td><td> 9,86</td><td> 0,17</td>

<td>23% a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 6,83</td><td> 0,17</td>

<td>24l, a, IV, and E</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 44,00</td><td>NV</td>

<td>25l, c, IV, and C</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 29,49</td><td> 0,45</td>

<td>26l, c, IV a, D</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 41,67</td><td>NV</td>

<td>27% c, IV, p, C</td><td> 28</td><td> 42</td><td> 0</td><td> 30</td><td> 54,16</td><td>NV</td>

<td>28% c, IV, p, D</td><td> 28</td><td> 42</td><td> 0</td><td> 30</td><td> 120,74</td><td>NV</td>

<td>29l, a, IV,% C</td><td> 31,5</td><td> 34,65</td><td> 3,85</td><td> 30</td><td> 1,93</td><td>NV</td>

<td>30l, a, IV,% D</td><td> 31,5</td><td> 34,65</td><td> 3,85</td><td> 30</td><td> 7,07</td><td> 0,29</td>

<td>481, c, II, a, E</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 163,12</td><td>NV</td>

<td>49I, c, IV, 6, E</td><td> 42</td><td> 28</td><td> 0</td><td> 30</td><td> 66,31</td><td> 0,39</td>

<td>52l.e, IV, p, E</td><td> 28</td><td> 42</td><td> 0</td><td> 30</td><td> 47,86</td><td>NV</td>

<td>53l, e, IV, and E</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 31,16</td><td> 0,25</td>

<td> 56¹’^BJV’^E’^F</td><td> 38,5</td><td> 31,5</td><td> 0</td><td> 30</td><td> 17,10</td><td>NV</td>

<td>654, c, VII, A, E</td><td> 36,9</td><td> 36,9</td><td> 0</td><td> 26,1</td><td> 50,87</td><td>NV</td>

<td> 66^{4, c, VIII,}e^G</td><td> 40,6</td><td> 33,2</td><td> 0</td><td> 26,1</td><td> 38,39</td><td>NV</td>

<td> 67^{4, c, VIII,}e^G</td><td> 33,2</td><td> 40,6</td><td> 0</td><td> 26,1</td><td> 43,55</td><td>NV</td>

<td colspan="7">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55/5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); α = P / S ratio is 50/50, p = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

EXAMPLE 10 [0040] In this example, the effect of drug loading on the release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0041] Sustained-release gel carriers were prepared with varying drug percentages in the appropriate size range according to the procedure of Example 3. The resulting preparations are shown in Table 7 below. The final homogeneous sustained release formulations are transferred to disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or

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PZ / 2073 / AGR dosing. Table 7 shows the C ratio_max to C._min and Tlag for in vivo formulation release profiles.

TABLE 7

<td></td><td colspan="4">Target content in the preparation (% by weight)</td><td></td><td></td>

<td>Preparation No.</td><td>PLGA</td><td>BA</td><td>BB</td><td>Bow</td><td>^Cmax^Cmin</td><td>^Tlag</td>

<td>4l, and, II, A, B</td><td> 45</td><td> 45</td><td> 0</td><td> 10</td><td> 4,37</td><td> 0,50</td>

<td>g1, and III, a, b</td><td> 40</td><td> 20</td><td> 20</td><td> 20</td><td> 10,66</td><td> 0,61</td>

<td>γΙ, α, ΙΙ, α, Β</td><td> 45</td><td> 22,5</td><td> 22,5</td><td> 10</td><td> 19,17</td><td> 0,61</td>

<td>1QL, a, III, and C</td><td> 40</td><td> 40</td><td> 0</td><td> 20</td><td> 4,35</td><td> 0,61</td>

<td>111, a, III a, D</td><td> 40</td><td> 40</td><td> 0</td><td> 20</td><td> 12,06</td><td> 0,61</td>

<td>12l, a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 4,78</td><td> 0,14</td>

<td>13l, a, IV a, D</td><td> 35</td><td> 35</td><td> 0</td><td> 30</td><td> 5,29</td><td> 0,36</td>

<td>14l, and III, a, C</td><td> 40</td><td> 20</td><td> 20</td><td> 20</td><td> 3,15</td><td> 0,50</td>

<td>1G1, a, III a, D</td><td> 40</td><td> 20</td><td> 20</td><td> 20</td><td> 9,60</td><td> 0,61</td>

<td>161, a, IV a, C</td><td> 35</td><td> 17,5</td><td> 17,5</td><td> 30</td><td> 7,16</td><td> 0,61</td>

<td>171, a, IV a, D</td><td> 35</td><td> 17,5</td><td> 17,5</td><td> 30</td><td> 17,35</td><td> 0,36</td>

<td>181, a, V, and C</td><td> 30</td><td> 30</td><td> 0</td><td> 40</td><td> 3,54</td><td> 0,39</td>

<td colspan="7">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55/5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); a = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

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EXAMPLE 11 [0042] In this example, the effect of drug particle size on the release of small molecule drugs from sustained release gel carriers in vivo was investigated.

[0043] Sustained-release gel carriers were prepared with drug particles in the appropriate size range according to the procedure of Example 3. The resulting preparations are shown in Table 8 below. The final homogeneous sustained release formulations are transferred to disposable syringes with a capacity of 3, 10 or 30 cm³ for storage or dispensing. Table 8 shows the ratio C_maxto C._min and Tlag for in vivo formulation release profiles.

TABLE 8

<td></td><td colspan="4">Target content in the preparation (% by weight)</td><td></td><td></td>

<td>Preparation No.</td><td>PLGA</td><td>BA</td><td>BB</td><td>Bow</td><td>^Cmax^{/ C}min</td><td>^Tlag</td>

<td>71, a, II, A, B</td><td> 45</td><td> 22,5</td><td> 22,5</td><td> 10</td><td> 19,17</td><td> 0,61</td>

<td>1Q1, a, III, and C</td><td> 40</td><td> 40</td><td> 0</td><td> 20</td><td> 4,35</td><td> 0,61</td>

<td>111, a, III a, D</td><td> 40</td><td> 40</td><td> 0</td><td> 20</td><td> 12,06</td><td> 0,61</td>

<td>231, a, IV a, C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 6,83</td><td> 0,17</td>

<td>241, a, IV, a, E</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 44,00</td><td>NV</td>

<td>25% C, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 29,49</td><td> 0,45</td>

<td>26% C, IV, and D</td><td> 35</td><td> 0</td><td> 35</td><td> 30</td><td> 41,67</td><td>NV</td>

<td>644 C, VIII, and C</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 26,1</td><td> 11,66</td><td>NV</td>

<td>654, c, VIII, and E</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 26,1</td><td> 50,87</td><td>NV</td>

<td> 66^{4, c, VIII,}e^G</td><td> 40,6</td><td> 0</td><td> 33,2</td><td> 26,1</td><td> 38,39</td><td>NV</td>

<td>723, a, VII, and G</td><td> 43,3</td><td> 0</td><td> 43,3</td><td> 13,4</td><td> 24,48</td><td>ON</td>

<td colspan="7">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular weight = 6400), d = 40/55/5 PCL-GA-LA (molecular weight = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); α = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = P / S ratio is 60/40, ε = P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

EXAMPLE 12 [0044] The preparation is described as a preparation with close to zero order release kinetics if the ratio C_max to C._min it is below 200, preferably below 50, more preferably below 30. The Tlag in the release of the formulation is preferably below 0.2. Preparations not showing Cvalley do not show delay. Table 9 shows a number of formulations exhibiting a zero-order release kinetics feature. FIG. 4 shows the in vivo release profiles of selected formulations from

Table 9.

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TABLE 9

<td></td><td colspan="5">Target content in the preparation (% by weight)</td><td></td><td></td>

<td>Preparation No.</td><td>Polymer</td><td>BA</td><td>BE</td><td>EtOH</td><td>particles drug</td><td>^Cmax^{/ C}m in</td><td>^Tlag</td>

<td>121, a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 0</td><td> 30</td><td> 4,78</td><td> 0,14</td>

<td>221, a, IV a, C</td><td> 35</td><td> 35</td><td> 0</td><td> 0</td><td> 30</td><td> 9,86</td><td> 0,17</td>

<td>231, a, IV a, C</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 6,83</td><td> 0,17</td>

<td>291 a, IVxC</td><td> 31,5</td><td> 0</td><td> 34,65</td><td> 3,85</td><td> 30</td><td> 1,93</td><td>NV</td>

<td>321, d, IV, and C</td><td> 35</td><td> 35</td><td> 0</td><td> 0</td><td> 30</td><td> 10,65</td><td> 0,12</td>

<td>331, f, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 6,35</td><td> 0,14</td>

<td>351, c, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 44,21</td><td>NV</td>

<td>551, e, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 6,33</td><td> 0,11</td>

<td> 56^{1, b, and}V^F</td><td> 38,5</td><td> 0</td><td> 31,5</td><td> 0</td><td> 30</td><td> 17,10</td><td>NV</td>

<td>601, c, VI a, C</td><td> 25</td><td> 0</td><td> 25</td><td> 0</td><td> 50</td><td> 12,90</td><td> 0,07</td>

<td>611, c, IV, and C</td><td> 35</td><td> 0</td><td> 35</td><td> 0</td><td> 30</td><td> 26,53</td><td> 0,11</td>

<td>644, c, VIII, and C</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 0</td><td> 26,1</td><td> 11,66</td><td>NV</td>

<td>704, c, VIII, and C</td><td> 36,9</td><td> 0</td><td> 36,9</td><td> 0</td><td> 26,1</td><td> 22,11</td><td>NV</td>

<td colspan="8">1 = R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate; a = 50/50 PLGA-502 (molecular weight = 16,000), b = 50/50 PLGA-502H (molecular weight = 11,000), c = 50/50 PLGA (molecular mass = 6400), d = 40/55/5 PCL-GA-LA (molecular mass = ~ 13,500), e = 75/25 PLGA (molecular weight = 14,300), f = 80/20 PCL-GA-LA / PVP, g = RG502: RG502H (1: 1); a = P / S ratio is 50/50, β = P / S ratio is 40/60, χ = P / S ratio is 45/55, δ = the P / S ratio is 60/40, ε = the P / S ratio is 55/45; A = 63-125 μm, B = 20-63 μm, C = 75125 μm, D = &lt;38 μm, E = micronized, F = unchanged, G = not suitable; NV = no minimum concentration</td>

[0045] Although the invention has been described with respect to a limited number of solutions, those skilled in the art using the present disclosure will be aware that other solutions that do not depart from the scope of the invention disclosed herein may be developed.

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