Extended release bioabsorbable subcutaneous medicinal dosage delivery implant system

Abstract

An extended-release bio absorbable subcutaneous medicinal dosage delivery implant system includes an implant fabricated from a highly homogeneously mixed composition including a medicinal agent in combination with release controlling polymers which include poly (DL-lactide) and polycaprolactone. In one implementation for treating an opioid disease, the formulation composition includes naltrexone at 40 weight percent, poly (DL-lactide) in the range between 36 and 46.4 weight percent, and polycaprolactone in the range between 24 and 11.6 weight percent. In addition, in order to provide anti-biofouling quality and prevent foreign body adsorption/interaction with the material of the implant, polyethylene glycol is added in a preferred content of 2.0%. The manufacturing process includes hot melt extrusion and a mini jet based implant formation stage with the optimized process space were the temperature of the process ranges from 170° C.-180° C., mixing time through the HME process ranging from 8 minutes to 12 minutes, and injection time ranging from 8 seconds to 12 seconds. The resulting implants have a uniquely shaped free of defects bio absorbable solid body.

Claims

1. An extended-release sub-cutaneous medicinal dosage delivery implant system, comprising: at least one bio absorbable implant having a solid implant body, said solid implant body being formed from a material having a composition formulated with at least one medicinal agent and release controlling polymeric compounds intermixed substantially homogeneously with said at least one medicinal agent in a predetermined weight relationship to one another, said release controlling polymeric compounds control the release profile of said at least one medicinal agent, wherein said release controlling polymeric compounds include at least poly (DL-lactide) in a weight % ranging from 6% to 52.2% and polycaprolactone in a weight % ranging from 5.8% to 51%.

2. The system of claim 1, wherein said composition of the material of the implant body further includes an anti-biofouling agent containing polyethylene glycol (PEG) homogeneously intermixed with said at least one medicinal agent and said release controlling polymeric compounds.

3. The system of claim 2, wherein a weight % of said anti-fouling agent is about 2%.

4. The system of claim 1, wherein said at least one medicinal agent further includes naltrexone base anhydrous (naltrexone) having a weight % of about 40% providing an increased serum level ranging from 3 ng/ml to 6 ng/ml during a therapeutic lifespan of the implant.

5. The system of claim 4, wherein said composition of the material of the implant body includes 40% of naltrexone, 36% of poly (DL-lactide), and 24% of polycaprolactone.

6. The system of claim 4, wherein said composition of the material of the implant body includes 40% of naltrexone, 46.4% of poly (LD-lactide), 11.6% of polycaprolactone, and further includes 2% of polyethylene glycol (PEG).

7. The system of claim 1, wherein said implant further includes a radiopaque localizer embedded in said implant body.

8. The system of claim 1, wherein said at least one implant further includes an auxiliary implant containing a radiopaque localizer and fused with said implant body.

9. The system of claim 7, wherein said radiopaque localizer is fabricated from a material selected from a group consisting of iron oxide, gadolinium, barium sulfate, lohexol, bismuth sub-carbonate, bismuth oxychloride, and a combination thereof.

10. The system of claim 1, wherein said implant body is fully bioabsorbable.

11. The system of claim 1, wherein said implant body is a solid implant body having a predetermined asymmetric configuration with a smooth surface devoid of sharp areas.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A-1B are representative of the subject implant system surgically inserted under the skin of a patient's body;

(2) FIGS. 2A-2D are representative of the subject system's bioabsorbable subcutaneous implant with FIG. 2A being a planar view, FIG. 2B being a side view, FIG. 2C being a perspective view of the implant with the embedded OR localizer element, and FIG. 2D showing an alternative design of the implant in a two-piece implementation;

(3) FIGS. 3A-3B illustrate the concept of the bio-fouling property in the present implant with FIG. 3A showing the foreign body absorption-interaction with the implant surface, and FIG. 3B showing the PEG compound preventing the foreign body absorption interaction with the implant surface;

(4) FIG. 4 is representative of the subject HME manufacturing process using bench-top injection mold;

(5) FIGS. 5A-5C are representative of the alternative HME process using Thermo Fisher equipment trains, with FIG. 5A showing the removal and/or replacing of the barrel of the twin screw extruder, FIG. 5B detailing the subject process equipment, and FIG. 5C detailing the twin screw extruder design used in the subject process; and

(6) FIG. 6 is a diagram representative of the optimized manufacturing process technological parameters.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(7) The present subcutaneous implantable medicinal dosage delivery implant system for the extended release of medicinal agent is a further development for releasing of a medication over an extended period of time for the purpose of treating numerous medical conditions, where pharmacokinetics is controlled by varying the weight percentages of the release controlling polymers, which is enhanced by embedding radiopaque localizer elements in the implant, and where the implant contains an anti-fouling agent to prevent foreign-body absorption/interaction with the implant surface. The subject implant is fabricated by a combination of hot melt extrusion and injection molding where the unique process design space (temperature regime, mixing time regime, and ejection time regime) has been found to provide highly homogeneous implants which are free of defects.

(8) The present invention embraces, in its broad sense, an extended-release subcutaneous medicinal dosage delivery implant platform designed to provide therapeutic levels of numerous medications into the patient's serum and various locations of the patient's body for the purposes of treating a number of medical conditions.

(9) As an example only, but not to limit the scope of the subject invention to a particular application, the following description will address the BIOPIN, i.e., Biodegradable Polymeric Implant containing naltrexone base anhydrous (NTX) adapted for treating opioid use disorder. It is however to be understood that this is only an exemplary embodiment of the subject system, and medicinal agents other than naltrexone, and other therapy protocols for treating numerous medical conditions are contemplated.

(10) The present Biodegradable Polymeric Implant Containing naltrexone base anhydrous (BIOPIN) may be a 6-12 month (or longer) subcutaneous bio absorbable implant for the prevention of relapse to opioid dependence, following opioid detoxification and alcohol use disorder. The BIOPIN implant includes two essential components: a medicinal agent naltrexone base anhydrous (NTX) and a combination of polymer compounds. The polymer compounds are selected to regulate passive release of the medicinal agent, and are formulated using at least poly (DL-lactide) PDL 0.6 dl/g, and polycaprolactone PC 0.8 dl/g or PC 0.4 dL/g.

(11) The BIOPIN is a solid implant containing 40 wt. percent naltrexone base anhydrous (NTX) and 60 wt. percent release controlling polymers. The release-controlling polymers are comprised of poly-(DL lactide) (range 6 wt. %-52.2 wt. %) and polycaprolactone (range 5 wt. %-51 wt. %). Small amounts (2 wt. %) of the plasticizer, polyethylene glycol (PEG), can also be added to extend the duration of NTX release and to act as an anti-fouling agent.

(12) Polycaprolactone is degraded through the hydrolytic cleavage of ester groups under physiological conditions, thus it is attractive as an implantable biomaterial. Polycaprolactone undergoes a non-enzymatic hydrolysis of ester linkages, which is attributed to random chain scissions, causing a characteristic erosion, confirmed by the decrease in molecular weight.

(13) The main mechanism of poly (DL-lactide) degradation is the hydrolysis of the ester bond backbone. The amorphous character of poly (DL-lactide) suggests faster degradation than the other poly lactic acids. The degradation products are lactic acid or lactic acid oligomers. The degradation is thought to be catalyzed by the newly formed terminal carboxylic acid groups at the ends of the PLA chains which can cause the polymer to swell as degradation proceeds (Bode, et al. 2019).

(14) In the pre-clinical studies, the proposed human dose was determined based on rodent and canine PK studies. The dosages tested in the rat study were 320 mg, 640 mg, and 1280 mg NTX per 260-gram animal. The dosages tested in the canine study were 600 mg and 1200 mg per 10 kg animal. The planned dose in humans is 8 grams of NTX. The dose of NTX is not adjusted for the weight of the human subject. The implant is intended to be placed into the subcutaneous space of patients with Opioid Use Disorder (OUD) to prevent relapse following detoxification. The bio-resorbable implant does not have to be removed surgically, however, in cases of a medical emergency, removal can be effected. For this, fluoroscopic visualization of the implant is needed which can be provided by radio-opaque elements embedded in the implant. Those may be in the form of radio-opaque, bio absorbable compounds including iron oxide, gadolinium, barium sulfate, Iohexol, bismuth sub-carbonate, bismuth oxychloride, and combinations.

(15) BIOPIN is expected to release adequate levels of naltrexone for six to twelve months, which can be assessed in individual patients by measuring NTX drug levels in serum.

(16) Almost all of illegally sourced heroin contains some fentanyl. Thus, there is a need for newer XR-NTX to release higher serum NTX concentrations than the currently available XR naltrexone compositions. In order to attain potential efficacy against fentanyl, the subject BIOPIN has been designed to deliver higher serum levels of NTX (3-6 ng/ml) throughout its therapeutic lifespan. The use of the BIOPIN implant reduces the incidence of fentanyl-induced respiratory depression and death.

(17) Referring to FIGS. 1A-1B and 2A-2D, the present system 10 constitutes a platform designed to provide therapeutic levels of various medications delivered into the patient's serum, entire body, or various anatomical locations in the patient's body, for an extended period of time as required by specific therapy protocols to treat medical conditions.

(18) Referring to FIGS. 1A-1B, the subject extended release subcutaneous medicinal dosage delivery implant system 10 is implanted beneath the skin of a patient by a preferred number of surgical procedures at anatomical locations required by the treatment protocol with the intention of releasing a medication over an extended period of time (sometimes over 12 months) for the purpose of treating a number of medical conditions (diseases).

(19) As presented in FIGS. 1A-1B and 2A-2D, the subject system 10 includes at least one implant 18 for being implanted under the skin 12 of a patient 14 under treatment. The implant 18 is the drug-eluting unit which has a solid disk-shaped bio-absorbable body 16 formed from a composition which comprises one or several medicinal agent(s) 20 and a composition of polymeric compounds 22. The polymeric compounds 22 in the present composition are formulated which are homogeneously intermixed and melted together with the medicinal agent 20 to form the chemical composition of the implant body 16 to control the release of the medicinal agent 20 from the implant body 16 in a steady-state controlled manner into the patient's body.

(20) Once the implant 18 is implanted under the skin 12 of the patient 14, the medicinal agent 20 (triggered by the physiological conditions in the surrounding tissues) egresses from the implant's outermost surface 24 as a result of non-enzymatic hydrolysis of ester linkages between the medicinal agent 20 and the release controlling polymeric compounds 22 via a combination of the surface and the bulk erosion over time.

(21) After the medicinal agent 20 has been completely depleted, the remaining polymeric release compounds 22 in the implant body 16 continue to resorb through bio dissolution until they are naturally removed from the patient's body. The subject implant 18 does not have to be removed by a surgical procedure, as it is completely bio absorbable in the patient's body.

(22) Although the present system is applicable for treating various medical conditions with various medicinal agents released into the patient's body, as one of the examples (but not to limit the scope of protection for this particular application), the subject system will be further described for treatment of opioid dependency treatment. In this particular application, as an example, the medicinal agent 20 in the implant 18 may include a naltrexone base anhydrous, further referred to herein as naltrexone. The subject system will be also further referred to herein intermittently as a BIOPIN, e.g., Biodegradable Polymeric Implant containing naltrexone (NTX).

(23) Being implanted under the skin 12 of the patient body 14, the subject BIOPIN implant 18 releases the medicinal agent (naltrexone) with the rate (or the release profile), which is controlled by a specific combination of the release controlling polymers 22 and their percentages in each implant 18.

(24) A specific composition for the implant 18 has been developed to control the pharmacokinetics (PK) of the solid extended-release subcutaneous medicinal dosage implant 18. This composition may be varied to either slow down or to accelerate the PK as needed for each particular treatment protocol.

(25) The medicinal agent, i.e., naltrexone, is evenly distributed within the implant body 16 and all ingredients of the composition of the implant body 16 are highly homogeneously intermixed with one another.

(26) As presented in FIGS. 2A-2D, the implant 18 is fabricated in a somewhat asymmetric configuration of the implant body 16. The implant body 16 may have a planar disk-like configuration. The implant body 16 may have planar or somewhat slightly curved convex sides 32 and 34 joined at a periphery thereof by smooth curved edges 36 extending along the entire perimeter of the convex sides 32, 34. The curved edge 36 of the implant body 16, as well as the entire surface thereof, is devoid of sharp edges. Completely smooth outer surface of the implant body 16 devoid of sharp edges helps to minimize (or avoid) possible trauma to surrounding tissues, thus dramatically decreasing (or eliminating) an inflammation response of the patient's body to the implant 18 embedded under the skin of the patient's body.

(27) Each side 32, 34 of the implant 18 has a wider end portion 38, and a narrow end portion 40 interconnected by a central portion 42. As an example, the wide end portion 38 may have the width of about 4.55 mm. The side portions 44 and 46 of the curved edge 36 are joined at the wide end portion 38 by the end perimeter portion 48 in a smooth arcuate configuration with a radius of approximately 1.82 mm. The side perimeter portions 44 and 46 are connected at the narrow end portion 40, by a smooth arcuate portion 49. As shown in FIG. 2B, the thickness of the curved edge 36 is approximately 0.64 mm with the radius of approximately 0.32 mm.

(28) The combination of the outer surface/edges smoothness with the asymmetric configuration of the implant 18 (with the wide end portion 38 and narrow end portion 40), and the slightly convex (almost planar) shape of the sides 32 and 34 of the implant body 16 provide a convenient arrangement for maneuvering of the implant 18 into the patient's body with a minimal traumatism during the insertion surgical procedure.

(29) The unique implant configuration allows for in-vitro release data modeling and more accurate IV-IVC (in-vitro in-vivo correlation) which is helpful in prediction of the in-vivo performance of a drug based on the in-vitro drug release profiles. Various equations modeling the dissolution of the drugs are known which compute the in-vivo absorption of drugs.

(30) The present implant 18 is completely bio dissolvable at the end of the treatment period and does not need to be surgically removed. However, in the event of a medical emergency (such as, for example, intolerance to the medication or to the protocol of medicinal agent release), the implant 18 must be surgically removed. To facilitate the surgical removal of the implant, visualization of the medical implant is needed and usually provided by using fluoroscopy. In order to facilitate the visualization of the implant position under the skin of a patient, a radiopaque (RO) localizer element 50 may be embedded into the implant body 16. The RO component 50 may be fabricated using either a one-piece, integrated design (as shown in FIG. 2C), or as a two-piece design (shown in FIG. 2D) with the bio absorbable RO element(s) 50 fabricated into a separate bio absorbable auxiliary implant 52 which is fused to the main medicinal dosage delivery implant body 16. In any implementation, the RO elements 50 are bio absorbable and are selected for their safety by compatibility.

(31) Being incorporated into the solid formulation of the implant 18, the medicinal agent (for example, naltrexone) and the release controlling polymers, such as poly (DL-lactide) (PDL), and polycaprolactone (PCL), as well as the plasticizer/anti-biofouling agent polyethylene glycol (PEG), are GRAS (generally recognized as safe materials) category materials.

(32) One of the unique features of the subject formulation composition of the solid implant 18 is the combination of naltrexone and the release controlling polymers including poly (DL-lactide) (PDL) and polycaprolactone (PCL) in specific weight percentage shown in Tables 1 and 2. The poly (DL-lactide) is an ingredient which slows the release of the medicinal agent, while polycaprolactone is an ingredient which accelerates the release. The unique weight percentage of the relationship between these two polymer compounds (in relation to the medicinal agent) provides a control over the release profile for a particular treatment protocol. In Tables 1 and 2, the BIOPIN-6 compositions were formulated by increasing the polycaprolactone content, and the BIOPIN-8 compositions were formulated by increasing the poly (DL-lactide) content.

(33) The BIOPIN compositions presented in Table 1 and 2 contain about 40 wt. % of naltrexone base anhydrous, which provides delivery of an increased serum level of NTX (3-6 ng/ml) throughout the therapeutic lifespan of the BIOPIN-8 to attain efficacy against fentanyl.

(34) TABLE-US-00001 TABLE 1 BIOPIN-7 Composition B7-3 w/o Iron Composition BIOPIN-6 B7-1 B7-2 B7-3 Oxide Naltrexone  40%  40%  40%  40%  40% Poly(DL-  36%  22%  16%  6%  7% Lactide) Polycaprolactone  24%  34%  40%  50%  51% PEG —  2%  2%  2%  2% Iron Oxide —  2%  2%  2% — Total 100% 100% 100% 100% 100%

(35) TABLE-US-00002 TABLE 2 BIOPIN-6 BIOPIN-8 Composition Composition BIOPIN-6 (with PEG) B8-1 B8-2 B8-3 Naltrexone  40%  40%   40%   40%   40% Poly(DL-  36%  35% 40.6% 46.4% 52.2% Lactide) Polycaprolactone  24%  23% 17.4% 11.6%  5.8% PEG —  2%  2%  2%  2% Total 100% —  100%  100%  100%

(36) As shown in Tables 1 and 2, the BIOPIN formulation may include 2 wt. % of PEG to study the effect of the PEG ingredient on the drug release. Table 1 summarizes the composition of BIOPIN-6 and different BIOPIN-7 formulations. Table 2 summarizes the composition of BIOPIN-6 and different BIOPIN-8 formulations. Among different exemplary embodiments of the compositions, BIOPIN-6 and BIOPIN-8(2) may be preferred embodiments for the system of the present invention.

(37) The unique implant composition has been optimized by using the polymers poly (LD-lactide) and polycaprolactone which are biodegradable. In addition, the implant composition includes the polymer PEG (numbered by the numeral 54 in FIGS. 1B and 3B) which is a plasticizer and anti-biofouling agent capable of reducing possible foreign absorption-interaction at the implant surface. In FIG. 3A, the blood plasma proteins 56 including immunoglobulin and complement proteins can interact with the implant surface 24, thus undermining the correct treatment protocol and possibly causing inflammation reaction of the patient to the foreign accumulations on the implant surface. Shown in FIG. 3B, when the implant composition includes PEG, this compound protects the implant surface 24 from interaction with blood clots, proteins, immunoglobulin, and complement proteins, and thus prevents possible foreign-body adsorption/interaction with the material of the implant 18.

(38) The combination of polymers poly (LD-lactide) and polycaprolactone with naltrexone base anhydrous in predetermined weight percentages is not believed to have been formulated prior to the subject implant composition to provide the controlled dispersion of the medicinal composition based upon the ratio of the polymers poly (LD-lactide) to polycaprolactone dependent upon a selected treatment. Poly (LD-lactide) extends the dispersion time whereas polycaprolactone shortens the dispersion time. The ratio of poly (LD-lactide) polycaprolactone provides for the controlled dispersion of the subject application system. Thus, for the purposes and objectives of the subject application, the ratio by weight percentage of the polymers poly (LD-lactide) and polycaprolactone becomes a critical factor in controlling the medicinal composition release for a selected treatment protocol.

(39) With use of the naltrexone, it has been found that for selected treatment protocols in combatting OUD, that the polymer poly (LD-lactide) in the weight range of 6% to 52.2% and the polycaprolactone in the weight range of 5.8% to 51% of the entire poly (LD-lactide), polycaprolactone, and naltrexone composition provides for a highly controllable releasable composition for a selected protocol in combatting OUD. The combination of poly (LD-lactide)/polycaprolactone/naltrexone has been found to provide extremely high capabilities of controlling the dispersion of the medicine as opposed to the use of the medicine with only polymers poly (LD-lactide) or polycaprolactone by themselves.

(40) Clinical studies were conducted on the subject system 10 both in vivo experiments (animal-canine) and in vitro (dissolution). Due to optimized controllability of the medicinal agent release profile through formulation of the subject composition (both ingredients and their relative wt. % content) as well as due to the optimized process of manufacturing the solid highly homogeneous defect-free implant 18, the clinical studies confirmed successful treatment using the subject system 10. The fabrication process regime (process design space) has been optimized with regard to the temperature of the process and mixing time of the ingredients, as well as the injection time.

(41) The present subcutaneous implantable medicinal dosage delivery implant system for the extended release of the medicinal agent is uniquely equipped for releasing of a medication over an extended period of time (for 12 month and over treatment duration, if needed) for the purpose of treating numerous medical conditions, where pharmacokinetics is controlled by varying the percentages of each of the various polymers, which is enhanced by embedding radiopaque localizer elements in the implant, here the implant contains an anti-fouling agent polyethylene glycol (PEG) to prevent any possible foreign-body absorption/interaction with the implant surface, and where the delivery of an increased serum level of naltrexone base anhydrous (NTX) is attained to mitigate effects of fentanyl consumed with heroin. The subject implant may be fabricated by a combination of hot melt extrusion and injection molding where the unique process design space (temperature regime, mixing time regime, and ejection time regime) is optimized to produce highly homogeneous and free of defects implants.

(42) As shown in FIGS. 4 and 5A-5C, the present system is fabricated by a combination of processes of hot melt extrusion (HME) and injection molding using a custom-made mold. The subject process method is intended for obtaining at the final stage a highly homogeneous defect-free solid implant 18 having a unique product composition formulated for a highly controlled prolonged release profile, unique implant design. The subject manufacturing process has been optimized to provide a combination of the process temperature, mixing time, and injection time.

(43) Referring to FIG. 4, in one implementation, the present hot melt extrusion (HME) process uses bench-top injection mold. At Step 1, the ingredients (the medicinal agent, such as naltrexone base anhydrous, polymers poly (LD-lactide) compound, polycaprolactone compound, and PEG compound) are weighted and added in the injection tube 60. From Step 1, the procedure follows to Step 2 which uses a mixing device 62. Upon weighting and adding the polymers and the medicinal agent in the injection tube 60 in Step 1, in the subsequent Step 2, a controller in the mixing device 62 is turned on to establish the temperature of about 176° C., and the solid dispersion of polymers (polymers poly (LD-lactide), polycaprolactone, and PEG) and naltrexone in the injection tube is added in the mixing device 62. The solid dispersion is kept at 176° C. and mixed for about 10 minutes.

(44) Subsequently, in Step 3, an injection device 64 is used. A blank mold is inserted in (or attached at) the blank mold portion 66 at the bottom of the injection device 64, and the injection tube 60 from the mixing device 62 is transferred to the injection device 64 and inserted in the injection tube section 68. The transfer of the mixture of the injection tube 60 to the injection device 64 is to be performed as quickly as possible in order to keep the temperature of the mixture in the injection tube 60 at the predetermined level of 176° C., which corresponds to the temperature of the injection device 64.

(45) In order to inject the molten mixture from the injection tube 60 into the blank mold at the section 66, the handle 70 is lowered in the injecting device 64 and the molten mixture from the injection tube 60 is injected into the blank mold at the blank mold section 66 where it is formed into the resulting implant 18, and subsequently is output when cooled.

(46) Alternatively, the HME process may use Thermo Fisher equipment shown in FIGS. 5A-5C accompanied by a mini jet implant formatting unit. This equipment provides the hot melt extrusion processing of polymeric materials above their glass transition temperature in order to affect a molecular level mixing of thermoplastic polymers and the medicinal agent. The HME in this process is a combination of the melting and the mechanical energy to improve continuous processing for a reproducible analysis of materials and on-line monitoring.

(47) The HME process is used to disperse API (medicinal agents) in a matrix at the molecular level thus forming a solid solution. As shown in FIGS. 5A-5C, the process uses an extruder 80 and the die in the configuration of a mini-jet implant formation unit 82. In the subject HME process shown in FIGS. 5A-5C, the medicinal agent 20 and the polymers 22, 54 are weighted and supplied to a feeder 84. All components 20, 22, 54 are sheared, heated, mixed, and dispersed, and finally shaped by pressing them through the die opening (mini jet) 82 to form implants 18.

(48) Developing the HME manufacturing process requires control of numerous process parameters that affect the resulting implant. A computer system 90 controls and monitors the process parameters, which may be input in the computer system by an operator. Among the most important parameters which influence the quality of the resulting product, i.e., the implant 18, are mechanical energy consumption parameters, such as the temperature of the melt at the extruder die, pressure at the die, the torque in the extruder. The injection time at the die and mixing time are also among the process parameters which are critical for the quality of the resulting implant.

(49) As shown in FIGS. 5A-5C, the system underlying the subject HME process uses a twin-screw extruder 80 encased in a barrel 83 which can be easily inserted in and removed from the equipment as presented in FIG. 5A. As depicted in FIG. 5C, the twin screw extruder 80 is designed with various screw elements 88 of different predetermined dimensions connected into a sequence train which provides mixing elements with configurable shear rates along the barrel's length. The screw elements 88 constitute a plurality of mixing/shearing zones 85 having different dimensions for mixing/shearing the mixture received from the feeder 84 with controllable shear rates which provide an optimal mixing of the mixture of the API 20, the medicine release controlling polymers 22 and PEG 54 of the subject formulation composition at the molecular level.

(50) In addition to the number of the mixing/shearing zones 85, the HME process equipment may have a number, for example, six, heating zones 92 of different temperature configurations provided along the twin screw extruder 80. The computer control block 90 interfaces with a user who establishes regimes for various heating zones 92 while the composition passes these zones.

(51) The feeder 84 is disposed at the beginning of the HME process s for forming the initial mixture of the medicinal agent (API) 20, polymer compounds 22 and PEG 54. Preferably, the feeder 84 is a dual feeder with separate inlet and temperature control for the medicinal agent and polymers, respectively. In the chamber 96 of the feeder 84, the initial mixture is exposed to the mixing action by the feed motor 98. From the chamber 96, the mixture of the medicinal agent 20 and the polymers 22, 54 passes to the entrance of the barrel 83 with the twin screw extruding structure 80 detailed in FIG. 5B-5C.

(52) The twin-screw extruder 80 is actuated into the rotational motion of the screws 88 through the action of the drive motor 100 connected to the gear box 102. The mixture of the API (naltrexone) and the polymers (poly (LD-lactide), polycaprolactone, and PEG) passes from the chamber 96 into the twin-screw extruder 80 and, by the rotational motion of the screws 88, advances from the entrance of the extruder 80 to its exit 104. The mini jet 82 is positioned at the end 104 of the extruder 80. The mini jet 82 serves as a die (mold) for forming the implants 18 in the preferred shape (as shown in FIGS. 2A-2D), which are output from the die 82.

(53) The process presented in previous paragraphs has been optimized with the unique process design space shown in FIG. 6. The HME process boundary for the optimal process producing the defect-free highly homogeneous product (implant) 18, depends on numerous parameters of the process, including the speed of the screws 88, mixing time in the extruder 80, injection time at the die 82, as well as the temperature at the heating zones 92, etc. The current manufacturing process has been analyzed and studied and optimized with a unique process design where the temperature in the extruder 80 changes between 170° C. and 180° C., with the mixing time in the extruder 80 ranging between 8 minutes and 12 minutes, and the injection time (in the die 82) ranging between 8 seconds and 12 seconds. Manufacturing in conditions outside the zone 106 shown in FIG. 6 may either result in the defective or inhomogeneous implants.

(54) Although this invention has been described in connection with specific forms and embodiments thereof, it will be appreciated that various modifications other than those discussed above may be resorted to without departing from the spirit or scope of the invention as defined in the appended claims. For example, functionally equivalent elements may be substituted for those specifically shown and described, certain features may be used independently of other features, and in certain cases, particular locations of elements, steps, or processes may be reversed or interposed, all without departing from the spirit or scope of the invention as defined in the appended claims.