Systems and methods for prostate treatment

Abstract

A minimally invasive treatment of benign prostatic hyperplasia (BPH) tissue. The system includes a sustained-release formulation containing a cytostatic or cytotoxic drug, and an applicator or delivery system for localized delivery to the prostate of a composition comprising or consisting essentially of the sustained-release formulation. The method includes introducing the composition into the prostate to achieve sustained release of the cytostatic or cytotoxic drug over a period of from about 14 days to about 12 months.

Description

[Technical Field]

[0001] (Field) A minimally invasive localized treatment for men's health, more specifically for lower urinary tract symptoms.

[0002] (Priority Claim) This application claims priority to U.S. Provisional Patent Application No. 63 / 081,865 (RTPROV-2), filed September 22, 2020, the drawings and specification of which are hereby incorporated by reference for all purposes, and to U.S. Nonprovisional Patent Application No. 17 / 092,079 (RTNPROV-1), filed November 6, 2020, the drawings and specification of which are hereby incorporated by reference for all purposes. [Background technology]

[0003] (background) Benign prostatic hyperplasia (BPH) is a noncancerous increase in prostate size due to proliferation of glandular epithelial tissue, smooth muscle, and connective tissue within the prostatic transition zone, resulting in lower urinary tract symptoms (LUTS). These symptoms include voiding or obstructive symptoms such as hesitancy, weak and / or intermittent urinary stream, straining, and a sense of incomplete emptying, as well as storage or irritative symptoms such as frequency, urgency, urge incontinence, and nocturia. It affects nearly half of men over the age of 50, and 90% of men by age 80. Treatment options consist of lifestyle changes, medications, various procedures, and surgery. Lifestyle changes consist of weight loss, exercise, and reduced caffeine consumption. For more pronounced symptoms, oral medications such as alpha-blockers (e.g., terazosin) or 5α-reductase inhibitors (e.g., finasteride) are prescribed. These drugs require daily dosing for patient compliance, may have a long onset of action to be effective, if at all, and may have side effects such as changes in ejaculation, erectile dysfunction, weakness, headaches, and decreased libido.

[0004] There is an unmet clinical need to treat BPH with improved and sustained efficacy delivered by less invasive techniques while reducing associated side effects. Summary of the Invention

[0005] (overview) In light of the foregoing, the present specification discloses devices, methods, and systems for the minimally invasive treatment of BPH with sustained efficacy and reduced adverse side effects using sustained release formulations.

[0006] The present disclosure is generally directed to achieving localized delivery of a concentration of sustained-effective treatment to target tissues associated with the prostate gland and / or providing relief of urinary tract symptoms caused by or associated with an enlarged prostate gland while reducing, if not avoiding, damage to nearby prostate structures or the urethra. The treatment may be used alone or in combination with other known treatments.

[0007] Thus, in one aspect, the treatments provided herein for BPH tissue include delivery of a drug or drugs to the tissue in a sustained release manner via a sustained release formulation, which may be used in conjunction with or in addition to treatments involving tissue ablation and / or delivery of energy to the tissue, and further administration of various medications.

[0008] Treatment of BPH according to the present disclosure can include, for example, delivery of pharmaceutical, biological, or chemical agents, such as pharmaceutical, biological, or chemical agents that can be delivered locally in conjunction with or supplemented with mechanical treatment of tissue (e.g., stenting, balloon dilation, thermal ablation, laser treatment, surgery), or introduction of sustained-release formulations into the body. Sustained-release formulations can be administered additionally or alternatively after treatment of BPH by other methods.

[0009] Access to prostate tissue can be achieved transurethrally, transrectally, or transperineally through existing body orifices. Accessing the tissue via either the transrectal or transperineal approach can be beneficial and less invasive. Advantages of the transrectal or transperineal approach include: (1) administration of oral and / or local anesthesia instead of general anesthesia; (2) reduced trauma to the urethra and consequently reduced side effects and reduced need for catheterization; (3) shorter patient recovery time; and (4) one or more procedures familiar to urologists similar to prostate cancer biopsies. For access via the transrectal or transperineal approach, guidance can be provided by ultrasound, x-ray, computed tomography, magnetic resonance imaging, or other imaging techniques. Given that ultrasound is utilized in prostate biopsies, ultrasound imaging can be beneficial. The transrectal approach is very similar to current prostate ultrasound and biopsy techniques familiar to urologists. Both the transrectal and transperineal approaches avoid interaction with the urethra, thereby limiting the caustic effect of urethral procedures and therefore minimizing the side effects and urinary dysfunction associated with current BPH procedures.

[0010] In another embodiment, a delivery vehicle and sustained-release formulation are provided for delivering a drug or combination of drugs in a manner effective for treating the prostate. The drug may be an anti-inflammatory, antiproliferative, cytoreductive, cytostatic, and / or cytotoxic agent that may affect prostate size and glandular growth. The delivery vehicle allows for the delivery of one or more drugs into the target tissue. Once delivered to the target tissue, the drug may then be optionally released in a slow, sustained-release manner, optionally delivering an initial burst of the drug followed by a slow, sustained release of the drug to target release. As will be appreciated, the amount of burst or lack of burst and / or the duration of the "slow, sustained-release" depends on the drug being delivered to the prostate. In some embodiments, the slow, sustained-release may occur, for example, over a 24-hour period, 3-7 days, 1-4 weeks, 1-12 months, 3 months, or 6 months.

[0011] In another embodiment, there is a system for treating BPH, comprising a delivery vehicle, the sustained release formulation, and an imaging device for locating target tissue in the prostate.

[0012] In another embodiment, there is a device for treating BPH comprising a delivery vehicle adapted to be introduced into the body to deliver said sustained release formulation in liquid form to a tissue target.

[0013] In another embodiment, there is a method for treating BPH comprising injecting said sustained release formulation into or near a target tissue using a delivery vehicle.

[0014] In another embodiment, there is a sustained release formulation for treating BPH, which can be delivered to a targeted tissue using a needle or catheter containing a composition comprising the sustained release formulation.

[0015] In another aspect, there are systems, devices, and methods adapted for the treatment of BPH by needle injection of SRF at target tissue, the benefits of which may include one or more of a less invasive procedure leading to improved patient acceptance and fewer complications during patient treatment, a reduced frequency of required procedures, and a reduced risk that the administered drug or performed procedure will have adverse consequences with respect to urinary or sexual function.

[0016] In another aspect, it is recognized that an SRF for treating BPH that can be delivered to a targeted tissue using a long needle or catheter containing a composition comprising SRF has a viscosity that allows for effective delivery through the needle or catheter (e.g., complete dosing at the target tissue by a medical professional without reflux or excessive pressure being applied to inject the composition), e.g., a dynamic viscosity of 1 to 200 centipoise (cP) and a gelation dynamic viscosity of greater than 200 cP. At the same time, the formulation should solidify or gel at a rate that allows the formulation to remain in the target tissue when the delivery system is removed.

[0017] In another aspect, it is recognized that the total volume of SRF for treating BPH that can be delivered to the targeted tissue using a long needle or catheter containing a composition comprising SRF needs to be small enough to avoid causing additional acute pressure on the urethra, which may cause additional discomfort to the patient immediately or shortly after the procedure. Another consideration includes using SRF that does not significantly swell due to fluid uptake from surrounding tissues. Furthermore, avoidance of high pressure may be justified to avoid reflux of the composition comprising SRF through the delivery device (e.g., needle or catheter) and / or to prevent the composition comprising SRF from being expelled from the targeted tissue due to increased pressure.

[0018] (Incorporated by reference) All publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event of any inconsistent usage of words and / or phrases between an incorporated publication or patent and this specification, these words and / or phrases shall have the consistent meaning in the manner in which they are used herein. [Brief explanation of the drawings]

[0019] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the drug release curves of sustained release formulations (SRF) A, B, and C.

[0020] [Figure 2] Figure 2 shows a gross pathology image of a trimmed, formalin-fixed, treated prostate from canine test acute animal 20C0083. Visible white material indicates successful local injection of SRF2.

[0021] [Figure 3] Figure 3 shows a histopathological H&E stained image of the treated prostate of acute animal 20C0083 with faintly stained injectate material (containing SRF2) (asterisk) in the left lateral lobe (U = urethra, arrow indicates needle track).

[0022] [Figure 4] Figure 4 shows a histopathological H&E stained image of chronic 30-day animal 20C0081 showing degenerated smooth muscle (arrow) in the left cranial prostate subspecimen (U = urethra).

[0023] [Figure 5] FIG. 5 shows a histopathological H&E stained image of chronic 30 day animal 20C0081 showing the prostate tissue surrounding the implant, indicating loss of adjacent acini (arrows).

[0024] [Figure 6A] FIG. 6A shows the acini of the target tissue of acute animal 20C0083 (histopathology H&E staining).

[0025] [Figure 6B]Figure 6B shows the target tissue of the chronic 30-day animal 20C0081 (Masson's Trichrome stain). The white area in the image is the site where SRF was injected into the target tissue. Comparing Figures 6A and 6B, there is a loss of acini in the 30-day animal compared to that shown in the acute animal (Figure 6A). The circled area B2, whose histological image is similar to that in Figure 6A, contrasts well with the tissue in B1 surrounding SRF2 and is therefore affected by the sustained release of the cytotoxic agent. This demonstrates the desired effect of SRF2 on the target tissue over the 30-day period.

[0026] [Figure 7] FIG. 7 shows the systemic drug concentrations measured by LCMS as a function of time after SRF1 injection for each animal.

[0027] [Figure 8] Figure 8 shows the mean systemic drug concentrations measured by LCMS (liquid chromatography / mass spectrometry) as a function of time after SRF1 injection per animal as a function of dosage. N=6 for days 0-30 and N=3 for days 60, with four animals starting at 5 mg and two animals starting at 10 mg.

[0028] [Figure 9] Figure 9 shows injection sites of SRF1 in the prostate. This represents the sites in Table 4 for collecting prostate samples for pharmacokinetic (pK) tissue analysis. Circles represent treatment samples ("tx"), and rectangles represent either adjacent reference samples ("adj") or distal reference samples ("distal"). Numbers in the figure refer to the sites corresponding to Table 4. DETAILED DESCRIPTION OF THE INVENTION

[0029] (Detailed explanation) For purposes of this disclosure, the following terms and definitions apply:

[0030] Below is an example of the nomenclature for polymer names that appear in the list of additional disclosed embodiments following the detailed description. Other examples not explicitly described herein also use the same rationale: PLGA8515A (0.3 dl / g) refers to poly(lactide-co-glycolide) having a monomer ratio of 85 / 15, end-capped with acid groups (A), and having an inherent viscosity of 0.3 dl / g; PLGA6535E (0.5 dl / g) refers to poly(lactide-co-glycolide) having a monomer ratio of 65 / 35, end-capped with ester groups (E), and having an inherent viscosity of 0.5 dl / g; poly(lactide-co-glycolide) is typically poly(D,L-lactide-co-glycolide), but can also be, for example, any one or a mixture of poly(D,L-lactide-co-glycolide), poly(D-lactide-co-glycolide), and poly(L-lactide-co-glycolide).

[0031] The terms "about" or "approximately" are defined herein as 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1.5%, 1%, 1-2%, 1-3%, 1-5%, or 0.5%-5% less or more than, less than, or more than a stated value, range, or each endpoint of a stated range, or as a 1σ, 2σ, 3σ variation (Gaussian distribution) from a stated mean or expected value. For example, a dl of about d2 means that dl differs from d2 by 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0%, or 1-2%, 1-3%, 1-5%, or 0.5%-5%. If dl is a mean value, then d2 being about dl means that d2 is within 1σ, 2σ, or 3σ of variation from dl. It is understood that any numerical value, range, or both endpoints of a range preceded by the words "about," "substantially," or "approximately" in this disclosure (including, for example, "approximately none," "about none," "about all," etc.) also describes or discloses the same numerical value, range, or both endpoints of a range not preceded by the words "almost," "substantially," or "approximately."

[0032] The term "drug" or "medication" as used herein is defined as a therapeutic substance other than a food used in the prevention, diagnosis, mitigation, treatment, or cure of disease. Unless otherwise specified, "drug" and "medication" have the same meaning.

[0033] As used herein, the term "cytostatic" refers to a drug that is non-toxic to cells but slows cell proliferation and allows cell migration. Cytostatic drugs include, but are not limited to, rapamycin, sirolimus, everolimus, zotarolimus, myolimus, temsirolimus, tacrolimus, macrolide antibiotics, ridaforolimus, biolimus, novolimus, deforolimus, structural derivatives and functional analogs of rapamycin and any macrolide immunosuppressant. Dual mTOR / PI3K inhibitors, including dactolisib, BGT226, SF1126, PKI-587, and NVPBE235, may also be used. Dual mTORC1 / mTORC2 inhibitors, including sapanisertib, AZD8055, and AZD2014, derived from morpholinopyrazolopyrimidines, may also be used.

[0034] As used herein, the term "cytotoxic" refers to drugs that inhibit cell growth and proliferation, such as chemotherapeutic agents. These drugs include, but are not limited to, pactlitaxel, taxanes, protaxel, vincristine, etoposide, nocodazole, indirubin, anthracycline derivatives, daunorubicin, daunomycin, plicamycin, tauromustine, bofumustane, and plicamycin. These drugs may be apoptotic, such as topoisomerase inhibitors, including TGF, 10-hydroxycamptothecin, irinotecan, and doxorubicin.

[0035] As used herein, the term "composition" refers to a product in which various elements or components are mixed or combined.

[0036] As used herein, the term "sustained release formulation (SRF)" refers to a substance for treating BPH, which comprises a drug carrier, including a drug(s) and a carrier or polymer composition for the drug(s), and is administered to a target tissue in liquid, gel, or solid form using a delivery vehicle, such that local delivery of the sustained release formulation to the target tissue is effective to cause sustained release of the drug(s) to the targeted tissue of the prostate, thereby producing effective results over a period of time, for example, about 1 to 12 months, or up to 2 years, after treatment.

[0037] Drugs or drug combinations used in SRF include cytostatic, cytotoxic, and / or other drugs. The other drug(s) may be used alone (i.e., the "other drug(s)" are the only active agents in the SRF) or in combination with cytostatic or cytotoxic drugs as part of a medical procedure for the treatment of BPH. For example, the other drug(s) may be contained with the SRF in a delivery vehicle containing the cytostatic or cytotoxic drug that is administered to the target tissue, administered before the SRF containing the cytostatic or cytotoxic drug is administered to the target tissue, or administered after the SRF containing the cytostatic or cytotoxic drug is administered to the target tissue.

[0038] Other drugs that may be administered together with or instead of the cytostatic or cytotoxic drugs include alpha-blockers or 5-alpha-reductase inhibitors. Alpha-blockers include terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin. 5-alpha-reductase inhibitors include finasteride and dutasteride. Anti-inflammatory drugs include, but are not limited to, corticosteroids such as dexamethasone, fluticasone propionate, triamcinolone acetonide, mometasone furoate, prednisone, hydrocortisone, estradiol, clobetasol, and budesonide. Non-steroidal drugs include acetaminophen, ibuprofen, and naproxen. These other classes of drugs may block cytokine activity or inhibit cytokine binding to inhibit inflammatory signals such as anti-IL1, anti-IL2, anti-IL3, anti-IL4, anti-IL8, anti-IL15, anti-IL18, anti-MCP1, anti-CCR2, anti-GM-CSF, anti-TNF antibodies, and others.

[0039] Bioabsorbable means that a compound breaks down into a different substance. Biodegradable means cell-mediated breakdown, resulting in cleavage of the polymer molecular weight and the generation of degradation by-products. Bioresorbable includes biodegradation as well as complete removal by dissolution, excretion, or assimilation.

[0040] The term "target tissue" as used herein is defined as the tissue of prostate tissue, including the transitional, peripheral, and central regions of the prostate gland, and the prostate gland. The term "dosage" as used herein is defined as the amount of sustained release formulation administered to the target tissue using a delivery vehicle, and unless otherwise specified, is the amount of one or more drug(s) component(s) and / or drug carrier of the sustained release formulation, and is intended to produce a programmed sustained release and effective results. This programmed sustained release and effective results can be measured using the International Prostate Symptom Score (IPSS), or more generally, can be measured by relieving lower urinary tract symptoms (LUTS), including urinary hesitancy, weak and / or intermittent urinary stream, straining, residual urine, and other voiding or obstructive symptoms, as well as urinary frequency, urgency, urge incontinence, and nocturia, and other urinary storage or irritative symptoms.

[0041] 5α-reductase inhibitors, when administered orally, reduce prostate volume by 50%. Minimal reduction occurs in less than 6 months. With appropriate therapy, up to a 50% reduction in prostate volume can be expected in 12 to 24 months, or possibly longer.

[0042] Alpha-blockers may also be used to treat symptoms during treatment by blocking alpha receptors and relaxing the smooth muscle of the prostate. Alpha-blockers, 5-alpha-reductase inhibitors, or both may be co-formulated with cytostatic or cytotoxic drugs within the SRF.

[0043] When expressing the % of a substance in an SRF, the % of that substance can be expressed as the percent weight of the drug(s) relative to the total weight of the SRF ("% X by wgt") or the percent weight of the drug(s) relative to the total volume of the SRF ("% X by vol"). Unless otherwise stated, percent dosage % will always by default mean % by weight relative to the total measured SRF. Unless otherwise stated, weights are given in grams ("g") or milligrams ("mg"), molecular weights are given in kilodaltons ("kDa"), volumes are given in microliters ("μL"), and viscosity units are expressed as inherent viscosity (i.e., the ratio of the natural logarithm of the relative viscosity to the mass concentration of a substance, such as a polymer). The units of inherent viscosity are deciliters per gram (dL / g). Another viscosity measure is intrinsic viscosity, which is a measure of the solute contribution to the total viscosity. Another viscosity is mechanical viscosity, whose units are centimeters·grams·seconds, also known as centipoise (cP).

[0044] The drug carrier portion of the SRF generally comprises a polymeric composition. Solvents and / or other substances used in the preparation of the SRF, such as ultrasound / echo-enhancing media or other imaging enhancements depending on the imaging technique used, may also be present with the SRF.

[0045] The SRF may contain 0.1-60% of the polymer composition, or more preferably 10-50% of the polymer composition. The SRF may contain 0-80% solvent. The drug-to-polymer weight ratio of the SRF may be 1:100, 1:50, 1:25, 1:20, 1:10, 1:5, 1:2, 1:1, 2:1, or 5:1. Once located in the target tissue, the SRF may release 1-10% or 11-50% of its drug load in less than 24 hours, 24-72 hours, 3-7 days, 1-4 weeks, 1-3 months, or more than 3 months. The SRF may release 80-100% in 24-72 hours, 3-7 days, 1-4 weeks, 1-3 months, or more than 3 months.

[0046] The drug carrier may be a polymeric composition such as silk-elastin-like protein polymers, Pluronic F68 or F127 or combinations thereof, poly(ε-caprolactone) (PC), polylactide (PLA), poly(D,L-lactide) (PDLA), poly(orthoesters), polyanhydrides, polycarbonates, polyethylene glycol (PEG), polyethylene oxide (PEO), polyesteramides, and any combination thereof, including, but not limited to, block and random copolymers such as poly(lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA. More specifically, the PLGA composition may consist of poly(D,L-lactide-co-glycolide) (50:50), poly(D-lactide-co-glycolide) (50:50), poly(L-lactide-co-glycolide) (50:50), poly(D,L-lactide-co-glycolide) (65:35), poly(D-lactide-co-glycolide) (65:35), poly(L-lactide-co-glycolide) (65:35), poly(D,L-lactide-co-glycolide) (75:25), poly(D-lactide-co-glycolide) (75:25), poly(L-lactide-co-glycolide) (75:25), poly(D,L-lactide-co-glycolide) (85:15), or mixtures thereof. PLGA may be end-capped with ester, acid, alcohol, thiol, or other terminal groups. The inherent viscosity of PLGA polymers may vary from 0.2 dL / g to greater than 1.0 dL / g. The molecular weight of PLGA polymers may vary from 10 kDa up to 150 kDa. The polymers may be linear, branched, hyperbranched, dendritic, have a star structure, or may be dendrimer-like star polymers.

[0047] Additional embodiments of drug carriers, SRFs, and compositions are provided below.

[0048] The drug carriers were poly(lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide), ester end-capped poly(D,L-lactide-co-glycolide) (50-50), ester end-capped poly(D,L-lactide-co-glycolide) (65-35), ester end-capped poly(D,L-lactide-co-glycolide) (75-25), ester end-capped poly(D,L-lactide-co-glycolide) (85-15), acid end-capped poly(D,L-lactide-co-glycolide) (95-15), and acid end-capped poly(D,L-lactide-co-glycolide). End-capped poly(D,L-lactide-co-glycolide) (50-50), acid end-capped poly(D,L-lactide-co-glycolide) (65-35), acid end-capped poly(D,L-lactide-co-glycolide) (75-25), acid end-capped poly(D,L-lactide-co-glycolide) (85-15), ester end-capped poly(D-lactide-co-glycolide) (50-50), ester end-capped poly(D-lactide-co-glycolide) (65-35), ester end-capped poly(D-lactide-co-glycolide) (85-15), End-capped poly(D-lactide-co-glycolide) (75-25), acid end-capped poly(D-lactide-co-glycolide) (50-50), acid end-capped poly(D-lactide-co-glycolide) (65-35), acid end-capped poly(D-lactide-co-glycolide) (75-25), ester end-capped poly(L-lactide-co-glycolide) (50-50), ester end-capped poly(L-lactide-co-glycolide) (65-35), ester end-capped poly(D-lactide-co-glycolide) (75-25), The polymer compositions may include polymer compositions such as end-capped poly(L-lactide-co-glycolide)(75-25), acid end-capped poly(L-lactide-co-glycolide)(50-50), acid end-capped poly(L-lactide-co-glycolide)(65-35), acid end-capped poly(L-lactide-co-glycolide)(75-25), ester end-capped poly(D,L-lactide-co-glycolide), acid end-capped poly(D,L-lactide-co-glycolide), or combinations thereof.

[0049] The drug carrier may comprise a bioabsorbable polymer, the inherent viscosity of which is 0.1 to 1.0 dL / g, 0.1 to 0.6 dL / g, or 0.1 to 0.4 dL / g, or 0.1 to 0.3 dL / g, and the ratio of DL-lactide to glycolide is from 30 / 70 to 90 / 10, 95 / 5, or 85 / 15.

[0050] The composition may contain the bioabsorbable polymer at a concentration of 20 to 80 wt %, 25 to 75 wt %, or 40 to 60 wt % of the bioabsorbable polymer, 80 to 20 wt %, 75 to 25 wt %, or 60 to 40 wt % of the solvent, and 0.5 wt % to 30 wt % of the drug; 1 wt % to 20 wt % of the drug, or 1 wt % to 5 wt % of the drug.

[0051] The drug carriers may generally be in amorphous or semi-crystalline, homogeneous or phase-separated form, and may be provided in the form of a liquid solution or suspension, or as nanoparticles, microspheres, or microparticles processed by spray drying, emulsion, electrospraying, or extrusion. The biodegradable polymer is preferably selected to substantially biodegrade over a period of about 3 to 6 months or 6 to 12 months.

[0052] In some embodiments, it may be desirable to formulate the SRF so that the drug carrier is completely biodegraded prior to the next treatment, e.g., 3, 6, or 12 months after the previous treatment. For example, the polymer may have a glycolide to lactide ratio of 70:30 to 15:85 if more hydrophilic in nature (faster degradation), and / or an inherent viscosity of less than about 1.0 dL / g if more hydrophilic in nature.

[0053] When forming a component of an SRF, the polymer composition is one that allows or achieves the desired "sustained release" of one or more drugs to the target tissue. In some embodiments, the polymer composition allows or can achieve at least 50%, or up to about 100%, or substantially all of the drug release between 30 and 90 days by a combination of diffusion and degradation. In other embodiments, up to 100% of the drug release occurs 90 to 120 days after treatment. Preferably, there is an initial burst (e.g., up to 50% of the drug), followed by a substantially reduced rate of release over the next month or subsequent months after treatment. For example, the drug has a release rate of 5% to 50% within the first 24 hours after injection of the composition into the prostate, and the drug has a release rate of 10% or less to 75% in the first month, 25% to 95% in the first three months, and / or 50% to 100% in the first six months.

[0054] Programmed sustained release, in which substantially all of the drug is eliminated from the carrier, for example, over 14 days or 1 to about 12 months, can be achieved by selecting the drug carrier (polymer structure) and / or adjusting its morphology and mechanical properties (polymer stiffness), the polymer / drug ratio, and controlling the physical shape / dimensions (volume) of the SRF and / or composition delivered to the target tissue. Other factors that affect the release rate include:

[0055] The swelling ability of the polymer (eg controlled by the choice of monomers and monomer ratio = polymer structure).

[0056] Porosity / morphology (e.g., controlled by polymer structure and concentration, polymer / solvent ratio and miscibility, and polymer / drug ratio—less drug is entrapped in the polymer than in the drug).

[0057] How quickly the material gels and whether it reaches a glass transition—a liquid to solid transition using water-soluble or water-insoluble solvents (faster gelation leads to a faster initial release / burst) (controlled, for example, by polymer structure and concentration, polymer / solvent ratio, and miscibility).

[0058] Drug / polymer miscibility and solvent polarity, and

[0059] Drug molecular weight and lipophilicity.

[0060] The SRF should keep drug exposure close to the prostate and minimize leakage or spillage into other surrounding organs. In addition, the SRF should not occupy an excessive volume in the prostate. The desired shape of the drug release curve would be a burst of drug and early tissue exposure for rapid efficacy, followed by a declining drug release rate over a 3- to 6-month period for sustained efficacy.

[0061] For example, a fast burst release rate followed by a slower rate is achieved using N-methylpyrrolidone (NMP) solvent-water solubility. This formulation can provide high release within the first 24 or 48 hours, or within the first week, two weeks, or up to three months, followed by a slower rate of release.

[0062] Figure 1 shows drug release curves for sustained release formulations (SRF) A, B, and C. These exemplary SRFs provide a burst followed by a slow release of drug over a period of up to six months. SRF A releases approximately 25% of the drug within the first month, followed by a slower, gradual release with approximately 95% released at six months. SRF B has an initial burst of approximately 50% within the first month, followed by approximately 100% release at two months. SRF C has an initial burst of approximately 75% within the first month, with approximately 100% released at about two months.

[0063] Table 1A below shows examples of SRF formulations for each of SRF A, B, and C. Examples A1 and A2 exhibit release rate profiles similar to SRF A in Figure 1. Examples B1 and B2 exhibit release rate profiles similar to SRF B in Figure 1. Examples C1 and C2 exhibit release rate profiles similar to SRF C in Figure 1. Table 1B shows examples of drugs released over time. [Table 1]

[0064] SRF can be delivered to a target tissue in the form of a liquid composition (i.e., the drug(s) and drug carrier of the SRF are in solution or suspension in a solvent when in the delivery vehicle), or as a gel-form composition either by contact with water at the target tissue or formulated and contained within a needle or catheter. The latter example of a composition containing SRF can be made by dissolving SRF in an appropriate solvent. Suitable solvents for these embodiments include water, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 2-pyrrolidone, propylene carbonate, caprolactam, triacetin, alcohol, benzyl benzoate, ethyl acetate, triethyl citrate, benzyl alcohol, glyme (dimethoxyethane), diglyme, and other glycol ethers, and dichloromethane, or any mixture thereof.

[0065] The composition should be formulated at a concentration and viscosity that allows it to pass through a needle-type applicator with an inner diameter of 16G or greater. The drug-to-polymer ratio can vary from 0.05 to 2.0. The drug and polymer concentrations in the solvent can range from 0.1% to 60% by weight. The injection volume of the drug portion of the SRF can range from 25 microliters to 5 mL per injection. The total drug dosage provided within the SRF can range from 50 to 200 mg. For example, a composition containing SRF can be 300 μg of everolimus or paclitaxel dissolved in NMP at a 50% wt concentration with 300 μg ("μg" - microgram) of poly(D,L-lactide-co-glycolide) (85:15).

[0066] The gel-like nature of some compositions can be beneficial in preventing infection from the rectal area along the needle path. A sufficiently high viscosity can hold the drug in place, reducing the likelihood of the drug migrating from the target tissue through the insertion path to the entry point. In this sense, the gel-like composition acts as a sealant.

[0067] The gel-like state of the composition (as delivered or after delivery) is believed to be advantageous because, once delivered to the target tissue, the SRF will tend not to dissipate or diffuse to other unintended treatment areas of the prostate in adjacent tissue. Thus, if the SRF is present in the target tissue in a gel-like form, the dosage may be reduced. More generally, for similar reasons, it would be desirable to formulate SRF that exhibits a high viscosity (e.g., gel-like), but not so high that it impairs the physician's ability to deliver the SRF to the target tissue.

[0068] Alternatively, the composition may be adapted to foam when placed on the target tissue.

[0069] Alternatively, sustained-release formulations can be provided in the form of rods prepared by melt or solvent casting, fiber spinning, electrospinning, injection molding, or extrusion. For extrusion, the drug in the SRF must be stable at the extrusion temperature required to melt the polymer. For example, paclitaxel (melting point: approximately 216°C) can be mixed at 60% by weight in poly(D,L-lactide-co-glycolide) (50:50) and extruded using a twin-screw extruder at temperatures below 200°C, above the glass transition, where the amorphous polymer flows through a die to form a rod, followed by cutting to length. Alternatively, everolimus (melting point: approximately 100°C) can be mixed at 60% by weight in polycaprolactone and extruded using a twin-screw extruder at temperatures below or above 100°C, above the glass transition, where the polymer flows through a die to form a rod, followed by cutting to length. To improve mixing, the drug and drug carrier may be premixed by methods such as spray drying, emulsion, electrospraying, extrusion, solvent casting, melt casting, etc. Alternatively, the polymer resin granules and drug powder may be mixed. Micronization may be achieved by known methods such as milling, jet milling, spray drying, electrospraying, emulsion, and / or cryogenic methods.

[0070] The following disclosure provides examples that include non-limiting embodiments of the invention for treating benign prostatic hyperplasia tissue in a patient. Localized drug delivery is in the form of a sustained release formulation that provides sustained delivery of a cytostatic or cytotoxic drug delivered to a patient using a delivery vehicle. The delivery vehicle may be in the form of a needle or catheter administered by a medical professional.

[0071] The local drug delivery device applicator may be a needle or catheter for delivering a composition containing SRF to a target tissue. The applicator portion of the delivery vehicle may include a chamber for keeping the drug and drug carrier separate from each other, a mixing element for combining the drug and drug carrier, such as a static mixing Y-adapter. Alternatively, two syringes connected using an adapter may be used to mix the drug and drug carrier by reciprocating the plunger. The applicator needle or catheter and / or other components may be imaged under ultrasound to visualize the treatment. Echogenicity may be enhanced by creating indentations in the applicator needle or coating. Echogenicity may also be enhanced by incorporating contrast-enhancing agents such as microbubbles, sulfur hexafluoride, octofluoropropane, air, lipids, and / or albumin shells. The applicator may have components for attachment to a rectal ultrasound probe. The applicator may have markings indicating the needle insertion length measurement. The applicator may have a user-friendly handle and plunger to deliver the needle or catheter to the target tissue. The applicator needle may range from 16G to 25G. The needle length may be 40 cm or less (e.g., 20 cm long) to reach the target tissue via a transrectal or transperineal approach.

[0072] In certain instances, the injection volume of SRF injectate has been minimized to between 10 and 200 microliters per injection over 1 to 10 injections from one side of the prostate to the other to reduce prostate tissue pressure against the urethra, which will reduce the likelihood of reflux through the delivery device and / or loss of therapeutic injectate from the prostate. A further injection volume range of between 50 and 100 microliters per injection over 1 to 5 injections from one side of the prostate to the other has been tested. Additionally, this injectate volume has been found to minimize prostate swelling and volume increase. Injectate volumes that are too large can cause undesirable prostate volume increase.

[0073] Precision delivery of low volumes of SRF at precise drug dosages for therapeutic retention can be achieved using novel delivery devices, such as novel delivery devices of 250-500 microliters or smaller. The delivery device can have an airtight glass or polypropylene syringe body with a Teflon or polypropylene plunger connected to a 20 cm long 22 g needle. The volume of the delivery syringe must be large enough to accommodate the dead volume in the needle of approximately 200 microliters. Thus, a 250 microliter airtight syringe can be utilized to deliver a single 50 microliter injection of SRF1. For multiple injections from the same delivery device, a 250-2,000 microliter airtight syringe volume can be used, allowing sufficient volume to overcome the needle dead volume and delivering at least 100 microliter injections to each lobe of the prostate.

[0074] Custom-made elongated glass-body airtight delivery syringes are available with increased accuracy of desired injection volume dosing control and precision, with volume graduation marks on the syringe. In lieu of volume graduations, these delivery device marks can also directly indicate to the user the calibrated dead volume of the needle for each injection and the drug dosage of the drug delivered in mg.

[0075] The SRF can be provided premixed in solution in the delivery device for each injection, resulting in delivery of a predominantly amorphous drug dissolved in the delivery SRF for improved onset of efficacy.

[0076] The SRF can be provided premixed in solution in delivery devices (number of pre-filled devices = total number of injections for each therapy) for each therapy, resulting in delivery of primarily amorphous drug dissolved in the delivery SRF for improved onset of efficacy.

[0077] The SRF can comprise a polymer injectate and drug powder in separate delivery syringes that are mixed by the user at or about the time of treatment. This would allow crystalline drug to enter directly into the injectate, increasing drug retention time and exposure and reducing systemic drug loss.

[0078] SRF may be mixed with ultrasound microbubble contrast agents to further enhance injectate visibility under transrectal ultrasound guidance, allow precise location control of the injection within the prostate capsule within each lobe, and further reduce the potential for drug loss to the urethra, surrounding organs, and systemic circulation.

[0079] Drug forms can include any combination of amorphous and crystalline drug to provide sufficient immediate drug release for onset of efficacy and to extend local drug exposure time and reduce systemic washout.

[0080] The drug's properties are lipophilic or hydrophobic, extending local drug exposure time and reducing systemic washout compared to hydrophilic drugs, peptides, or proteins that are more readily systemically bioavailable.

[0081] The drug-to-polymer ratio is an important factor. A too low drug-to-polymer ratio is unattractive, considering that if the drug dosage is too low, it will result in too low a local drug concentration. A too high drug-to-polymer ratio will result in too rapid drug release from the SRF, limiting longer-term local drug release and also resulting in systemic drug exposure. The optimal drug-to-polymer ratio is 5% to 30% by weight. More specifically, it may be preferable to utilize 7.5% to 12.5% ​​by weight for optimal drug release and retention.

[0082] SRF can be used before, with, or after other transurethral procedures of the prostate, such as Rezum, Urolift, TURP, or others, to reduce further prostate enlargement, scarring, and inflammation after the procedure, reducing the need for repeat procedures.

[0083] The SRF platform can be utilized to treat any localized hyperplastic tissue abnormality, such as vascular restenosis, localized tumors (such as prostate cancer), etc.

[0084] The various benefits of the present invention described herein, as previously mentioned, can be practiced in the form of a stand-alone treatment or in combination with known BPH treatments, such as balloon dilation, stenting, transurethral incision, transurethral resection (TURP), transurethral needle cauterization, transurethral microwave therapy, electrovaporation, water vapor thermotherapy, transurethral prostate lift (PUL) implants, and the like.

[0085] Known procedures have shown varying levels of effectiveness, as well as undesirable or adverse symptoms, complications, and / or negative patient experiences associated with the invasive aspects of treatment. TURP produces improved efficacy and improvements in urinary flow rate and symptom scores (IPSS), but is invasive with significant side effects such as incontinence, urgency, dysuria, acute urinary retention, stricture, ejaculatory dysfunction, and sexual dysfunction. Steam therapy and PUL have shown milder sexual dysfunction side effects, but are limited to use in small BPH prostates less than 80 ml in volume, and have shown lower efficacy with non-responders and higher retreatment rates compared to TURP. Furthermore, all procedures are invasive and require transurethral access and catheter placement.

[0086] Less invasive approaches to targeting drug delivery to the prostate region, such as single-dose pore-forming proteins and peptides in saline formulations, have been tried via the transrectal or transperineal route, but have shown only modest efficacy compared to a saline placebo in randomized clinical trials. Indian J Urol. 2008 Jul-Sep; 24(3): 329-335. doi: 10.4103 / 0970-1591.42613, PMCID: PMC2684358, PMID: 19468462; see "Injection therapy for prostatic disease: A renaissance concept" by Arash M. Saemi, Jeffrey B. Folsom, and Mark K. Plante. Furthermore, alcohol or pharmaceuticals injected into the prostate have not been effective. A single injection of alcohol is highly cauterizing and provides poor control over the area of ​​delivery. Intraprostatic injections of drugs are also ineffective because they are given in a single, less effective dose. Other attempts to treat the prostate with similar drugs, such as orally ingested drugs, have been used, or, if injected, the injections do not contain sustained-release formulations of the drug and therefore will not produce an effective response in the injected target tissue.

[0087] Delivery of SRF to target tissues as described above can also be used in conjunction with, prior to, or after delivery of a drug-eluting implant or stent designed to maintain urethral patency. The implant can be composed of a bioabsorbable polymer, such as nitinol or PLGA. The implant can be delivered via a transurethral, ​​transrectal, or transperineal approach. The implant can be made of a shaped nitinol wire or extruded polymer fiber that is subsequently coated with a drug in a sustained-release formulation by dip-coating, air-assisted, ultrasonic, or electrospray coating. The design can be such that the implant spirals around the urethral transition region, sparing the urethral lumen and minimizing adverse effects and side effects.

[0088] SRF can also be used in a complementary manner with implantable energy generators that deliver direct energy in a continuous or pulsed manner via activation of an external stimulus, which can alleviate lower urinary tract symptoms through neuromodulation of target tissues. [Example]

[0089] Example 1 A preclinical study was conducted to evaluate the safety and feasibility of a composition containing a sustained-release formulation (hereinafter "SRF2") injected intraprostatically into two canine models, each with a normal (non-enlarged) prostate. After 0 and 28 days of treatment, the model ("Animal No. 20C0081", acute model / animal) was humanely euthanized and evaluated to determine whether there were any acute toxic effects of the injectate. The daily behavior of a second model ("Animal No. 20C0083", chronic model / animal) was monitored for 28 days after treatment.

[0090] Data collected from each of the models (i.e., acute and 28-day studies):

[0091] Assessment of prostate morphology and measurement of prostate size / weight (ultrasound) at baseline and after treatment

[0092] Daily urinalysis, voided volume, and residual urine at baseline and after treatment until the end of treatment

[0093] -Gross necropsy and camera / microscope imaging upon termination and fixation

[0094] Histological examination (H&E) of the treatment site at the end

[0095] SRF2 is a sustained-release formulation prepared by adding 0.5 mL of N-methylpyrrolidone (NMP) to a vial containing 0.25 g of paclitaxel, vortexing until dissolved, and then withdrawing 100 microliters of the drug solution and adding it to 2.5 mL of 50 / 50 PLGA8515 NMP solution using syringe-to-syringe mixing with a female-female Luer connector. One hundred microliters of SRF2 was loaded into a 1 mL syringe fitted with a 20G x 20 cm Chiba biopsy needle.

[0096] Transrectal or transperineal ultrasound examination. Transrectal or transperineal prostate block with local anesthetic using a 20-gauge syringe. Insertion of medication into each lobe of the prostate with the same 20-gauge needle. Positioning of the implanted medication confirmed by ultrasound. Removal of the ultrasound probe and needle.

[0097] Transrectal ultrasound was used to assess the size and condition of the prostate before and after treatment. Each animal received three injections of SRF2 into the prostate under ultrasound guidance (total dose of 300 microliters).

[0098] (Animal number 20C0081)

[0099] At the end of treatment, animal number 20C0081 was humanely euthanized and sent for necropsy. For animal number 20C0081, a needle guide and biopsy needle were attached to an ultrasound rectal probe. The probe was advanced to the first lobe of the prostate. The prostate volume was determined to be 3.08 cm^3 by the following equation:

[0100] Prostate volume = 0.5233 × TRD × APD × LD

[0101] where TRD was 1.83 cm, APD was 1.19 cm, and LD was 2.70 cm.

[0102] (Transverse diameter (TRD), Anterior-posterior diameter (APD), Longitudinal diameter (LD))

[0103] Figure 1 of RTPROV-2 shows transrectal ultrasound volumetric measurements of the canine prostate in animal number 20C0081. 100 microliters of SRF2 was injected into the left lobe of the prostate as shown in Figure 2 of RTPROV-2. The probe was advanced to the second lobe of the prostate. 100 microliters of SRF2 was injected into the right lobe of the prostate. A second 100 microliter injection of SRF2 was injected into the right lobe of the prostate after the first injection was outside the lobe. The 200 microliter injection of SRF2 was visually visible under ultrasound as less than 10% of the prostate volume.

[0104] Successful treatment is shown in Figure 3 for RTPROV-2.

[0105] Figure 2 of RTPROV-2 is an image showing treatment (injection of SRF2 into the prostate) using a 20G x 20cm Chiba biopsy needle.

[0106] RTPROV-2 FIG. 3 is an image showing SRF2 injections visible in the dog prostate.

[0107] After treatment with SRF2, the animals were humanely euthanized and the prostate and surrounding bladder and urethra were explanted. SRF2 infusion was visible in the explanted prostate as shown in Figure 4 for RTPROV-2.

[0108] Figure 5 for RTPROV-2 shows that no significant adverse effects due to the treatment or infusion were observed.

[0109] (Animal number 20C0083)

[0110] For animal number 20C0083 (chronic model / animal), a needle guide and a 20G x 20cm Chiba biopsy needle were attached to an ultrasound rectal probe. The probe was advanced to the first lobe of the prostate. The prostate volume was determined to be 3.52cm^3 by the following equation:

[0111] Prostate volume = 0.5233 × TRD × APD × LD

[0112] where TRD was 1.88 cm, APD was 1.32 cm, and LD was 2.71 cm (Figure 6 in RTPROV_2).

[0113] One hundred microliters of SRF2 was injected into the left lobe of the prostate. The probe was advanced to the second lobe of the prostate. One hundred microliters of SRF2 was injected into the right lobe of the prostate. After the first injection was outside the lobe, a second injection of 100 microliters of SRF2 was injected into the left lobe of the prostate. The prostate SRF2 injection was retained and visible under ultrasound (Figures 7-9 of RTPROV-2). The animals recovered normally from anesthesia. They appeared cheerful, alert, and in good health, with a slightly nervous temperament. The animals also voided normal urine into the pan liner the morning after the procedure.

[0114] (Exam Observations)

[0115] Figure 2 shows gross pathology images of trimmed, formalin-fixed, treated prostates from canine test acute animal 20C0083. Visible white material indicates successful, localized injection of SRF. These areas are identified by white arrows in Figure 2. The delivery vehicle (needle injection, needle containing SRF2) is described above. The localization of SRF in the indicated areas indicates that no significant diffusion of SRF into adjacent tissues occurred, which is desirable. The SRF was localized to the area where the injectate was placed.

[0116] Figure 3 shows an H&E (hematoxylin and eosin)-stained histopathology image of the treated prostate from acute animal 20C0083, with unstained injectate material (confirming the presence of SRF) (asterisk) in the left lateral lobe. (U = urethra; arrow indicates needle track). This image further demonstrates that the injectate containing SRF (SRF2) was localized without any significant diffusion into adjacent tissues in the acute animal. Without the SRF formulation of drug and polymer, it is believed that there would be significant diffusion of the cytotoxic drug, which is undesirable for at least two reasons. First, a higher wt. % drug injectate may be required to effectively treat this region. This is because the concentration of drug in the target tissue would be reduced due to diffusion. Second, the drug may diffuse to other regions, resulting in adverse effects. Therefore, it is desirable to minimize the amount of diffusion so that only the target tissue receives an amount of drug effective to treat the tissue.

[0117] Figure 4 shows a chronic 30-day animal 20C0081 histopathology H&E stain image showing degenerated smooth muscle in the left cranial prostate subspecimen (arrow). (U = urethra) The key pathology of BPH is thought to be smooth muscle cell proliferation. The drug moiety of SRF2 is intended to degenerate smooth muscle cells or prevent their proliferation. This image shows that SRF2 was effective in degrading smooth muscle cells over a 30-day period.

[0118] Figure 5 shows a histopathological H&E stain image of chronic animal 20C0081 showing loss of prostate tissue surrounding the injectate and adjacent acini (arrows). The image showing localized loss of glandular tissue demonstrates both the efficacy of the drug and the desired treatment of only the target tissue.

[0119] Figures 6A and 6B are comparative images providing further evidence of the effect of SRF after 30 days and its localized treatment, i.e., the absence of drug diffusion to tissues adjacent or nearby to the target tissue. Figure 6A shows the morphology of the target tissue (histological H&E stain) from acute animal 20C0083. Figure 6B shows the target tissue (Masson's trichrome stain) from chronic animal 20C0081. The white areas in the images indicate the location of the target tissue where SRF was injected. Comparing Figures 6A and 6B, the acini shown in the acute animal (Figure 6A) are lost. The circled region B2 is a histological image similar to that in Figure 6A, but in contrast to the tissue identified in B1 surrounding the SRF. SRF affects the tissue in the region of B1 through sustained release of the cytotoxic agent. The images demonstrate that the desired effect of SRF on the target tissue occurred over a 30-day period. Additionally, the images show a lack of diffusion of the drug into nearby tissue, which is also desirable.

[0120] Example 2 A preclinical study was conducted to evaluate the safety and feasibility of a composition containing SRF (SRF1) injected into the prostate of six canine models, each with an enlarged prostate after 12 weeks of weekly testosterone injection treatment. The SRF1 treatment was delivered 12 weeks after the first testosterone injection. The SRF1-containing composition was delivered to these BPH canine models in the following manner:

[0121] SRF1 contained 5 mg of paclitaxel delivered to the BPH canine model prostate (N=4) in 100 microliter SRF1 injectates by injecting 50 microliters of injectate into each side of the prostate via transrectal ultrasound guidance using a 20G x 20 cm Chiba needle delivered by a 250 microliter gas-tight glass delivery syringe. The injectates were easy for the user to deliver and visualize under ultrasound without causing discomfort to the animal. A total of two injections were performed to deliver SRF1 to each BPH canine model.

[0122] 10mg of paclitaxel was delivered to the prostate of BPH dog model (N=2) in 200 microliters of SRF1 injection by injecting 100uL of injection solution into each side of the prostate through transrectal ultrasound guidance using a 20G x 20cm Chiba needle delivered by a 500 microliter gas-tight glass delivery syringe.The injection solution was easy for the user to deliver and visualize under ultrasound, and did not cause discomfort to the animal.A total of two injections were made to each BPH dog model to deliver SRF1.

[0123] Blood samples were collected from all animals at 0, 1, 3, 7, 14, 30, 60, and 90 days after treatment or until the animals were euthanized. At 30 and 90 days after treatment, the models were humanely euthanized and evaluated to determine any acute toxic effects of the injectate. At the time the animals were euthanized, tissue samples were also collected from the prostate, bladder, and urethra to determine residual drug concentrations. The daily behavior of all animals was also monitored for 30 and 90 days after treatment.

[0124] Data collected from each of the models (i.e., the 30-day and 90-day tests):

[0125] Prostate morphology and prostate size / weight (ultrasound) at baseline and after treatment.

[0126] Termination, gross necropsy at fixation and camera / microscope imaging

[0127] Histological examination (H&E) of treatment sites at termination.

[0128] Table 2 shows the prostate volume (cc) measured by ultrasound at baseline (i.e., before the animals received SRF1) and at 4 and 12 weeks after SRF1 treatment. Table 2 shows the reduction (%) in prostate volume after SRF1 treatment compared to baseline. [Table 2]

[0129] The BPH dog models tested are identified by number. Animal models 45, 46, 50, and 52 received a 5 mg drug dose of SRF1. BPH dog models 42 and 44 received a 10 mg drug dose. [Table 3]

[0130] Table 3 shows the mean change in canine prostate volume (cc) as a function of injected drug dose (5 mg and 10 mg) measured by transrectal ultrasound after testosterone injection (4 and 12 weeks) and after SRF1 treatment (4 and 12 weeks). [Table 4]

[0131] Table 4 shows the overall (N=3) means and standard deviations of drug concentrations (ug / g) in various organs and tissues after 30 days of SRF1 treatment. Table 4 also shows the means (and standard deviation for 5 mg) of drug concentrations (ug / g) in various organs and tissues after 30 days of SRF1 treatment for the two doses delivered: 5 mg (N=2) and 10 mg (N=1).

[0132] It is known that in older men with a history of BPH and reduced serum testosterone levels, prostate size does not decrease when serum total testosterone levels are reduced. See Xia, B.-W. et al., "Relationship between serum total testosterone and prostate volume in aging men," Scientific Reports, 11, 14122 (2021). This suggests that the significant reduction in prostate volume observed in this study, which may in some cases be due in part to reduced testosterone levels, was likely due to SRF1 injection and not to the reduction or discontinuation of testosterone treatment in the BPH canine model.

[0133] In light of the teachings in this disclosure and the observations in the studies, those skilled in the art will understand that needle injection of a composition comprising SRF at a target tissue is localized for the treatment of BPH, as opposed to other methods, and is capable of effective treatment. While these other methods may demonstrate effectiveness in reducing BPH, they may require more invasive procedures (compared to local treatment using a delivery device such as the needles used in animal studies, as disclosed herein), may require more frequent treatments due to diffusion, or may require more systemic treatment of BPH, increasing the potential for adverse effects due to higher dosages required to treat other areas, given leakage or diffusion of the drug to these areas. Adverse effects include decreased urinary or sexual function. It is desirable to have effective treatments that target only the target tissue and not other locations (e.g., avoid the urethra), and to perform the treatment in a less invasive manner for patient tolerance. In contrast to other methods, needle injection of SRF at a target tissue without significant diffusion demonstrates the ability to meet these objectives.

[0134] Example 2 describes a study in which two injection volumes were tested in a canine BPH model. As reported in Tables 2 and 3, both injection volumes demonstrated significant reductions in prostate size. Furthermore, as shown in Figures 7 and 8, the systemic drug concentrations present in the blood were very low, indicating that the drug was contained in the target tissue. Thus, Example 2 demonstrates that an SRF injectate according to the present disclosure (1) can reduce prostate volume over a 30-day and 90-day period and (2) confines substantially all of the active drug to the target tissue. Regarding point (2), it should be noted that other known products for treating BPH, in contrast, significantly distribute their active drug (systemic drug concentrations significantly higher than those shown in Figures 7 and 8). Furthermore, this study unexpectedly demonstrated a significant ratio of prostate 30-day drug concentration to peak plasma drug concentration of at least about 10,000. As noted throughout, controlling drug diffusion is important because it can cause adverse effects on nearby tissues and organs. Furthermore, in contrast to most conventional or existing techniques for treating BPH, relatively low volumes of SRF injectate are required to demonstrate efficacy. As mentioned above, the injection volume of SRF (SRF1) injectate is minimized to between 10 and 200 microliters per injection over 1 to 10 injections from one side of the prostate to the other, or between 50 and 100 microliters per injection over 1 to 5 injections from one side of the prostate to the other. Conventional approaches to treating BPH attempt to maximize injection volume to increase drug dosage. However, SRF does not require high drug dosages because the drug is maintained within the target tissue.

[0135] Additional considerations include the drug-to-polymer ratio of the SRF. An appropriate drug-to-polymer ratio consistent with the objectives set forth herein was determined. It should be noted that such a ratio was not easily determined; rather, it required research and discovery to achieve the desired localized efficacy and effectiveness specifically tailored to the target tissue. A drug-to-polymer ratio that is too low is unattractive because the local drug concentration is too low to be effective. A drug-to-polymer ratio that is too high results in too rapid drug release from the SRF, which can limit longer-term local drug release and increase the likelihood of undesirably high systemic drug exposure. A preferred drug-to-polymer ratio for optimal drug release and retention is 5% to 30% by weight, more preferably 7.5% to 12.5% ​​by weight.

[0136] The following is an additional list of disclosed embodiments:

[0137] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0138] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0139] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0140] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0141] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0142] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0143] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0144] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0145] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0146] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0147] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0148] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0149] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0150] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0151] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0152] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0153] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0154] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA5050 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0155] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA5050 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0156] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of sirolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA5050 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0157] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0158] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0159] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker. 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. Two hundred fifty microliters in a 1 mL syringe was loaded into a 20 G x 20 cm Chiba biopsy needle with depth markers.

[0160] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0161] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0162] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 800 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0163] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 800 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0164] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0165] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0166] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0167] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0168] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0169] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0170] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0171] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0172] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0173] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0174] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0175] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0176] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0177] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0178] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0179] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0180] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0181] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0182] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA5050 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0183] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA5050 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0184] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of everolimus and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA5050 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0185] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0186] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0187] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0188] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0189] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0190] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0191] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0192] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0193] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0194] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0195] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. Five hundred microliters of the drug solution was added to 2.5 mL of 50% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0196] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA8515 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0197] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 50 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0198] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0199] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 200 microliters of the drug solution was added to 2.5 mL of 50% PLGA7525 in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0200] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0201] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 100 microliters of the drug solution was added to 2.5 mL of 50% PLGA6535A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0202] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. Five hundred microliters of the drug solution was added to 2.5 mL of 50% PLGA6535E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0203] 0.5 mL of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. Five hundred microliters of the drug solution was added to 2.5 mL of 50% PLGA6535E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0204] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 20 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0205] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 30 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0206] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0207] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0208] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA5050A in NMP solution (#SRF1) using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0209] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0210] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 20 wt% PLGA5050E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0211] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 30 wt% PLGA5050E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0212] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA5050E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0213] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA5050E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0214] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA5050E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0215] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA5050E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0216] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 20 wt% PLGA8515A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0217] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 30 wt% PLGA8515A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0218] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA8515A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0219] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA8515A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0220] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA8515A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0221] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA8515A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0222] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 20 wt% PLGA8515E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0223] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 30 wt% PLGA8515E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0224] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA8515E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0225] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA8515E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0226] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA8515E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0227] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA8515E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0228] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 20 wt% PLGA6535A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0229] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 30 wt% PLGA6535A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0230] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA6535A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0231] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA6535A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth markers.

[0232] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0233] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA6535A in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0234] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 20 wt% PLGA6535E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0235] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 30 wt% PLGA6535E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0236] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA6535E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0237] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 40 wt% PLGA6535E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0238] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA6535E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0239] 1.08 g of N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g of paclitaxel and vortexed until dissolved. 400 mg of the drug solution was added to 2.9 g of 50 wt% PLGA6535E in NMP solution using syringe-to-syringe mixing with a female-to-female Luer connector. 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with a depth marker.

[0240] Additional aspects of the present disclosure are set forth in embodiments E1-E52 described below:

[0241] (E1) Sustained release formulations (SRF) containing cytostatic or cytotoxic drugs, and An applicator or delivery system for local delivery of a composition comprising or consisting essentially of SRF to target tissue in the prostate. 1. A system for the treatment of benign prostatic hyperplasia tissue, comprising:

[0242] (E2) The system of E1 or any claim dependent thereon, wherein the SRF is adapted to release the drug into the prostate for at least 14 days, or for a period of 30 to 90 days, or for a period of 90 to 180 days after injection into the prostate.

[0243] (E3) The system of E1 or any claim dependent on claim E1, wherein the composition comprises a solvent and the sustained release formulation.

[0244] (E4) The system of E1 or any claim dependent on claim E1, wherein the cytostatic drug comprises rapamycin, sirolimus, everolimus, temsirolimus, or zotarolimus.

[0245] (E5) The system of E1 or any claim dependent on claim E1, wherein the cytotoxic drug comprises paclitaxel.

[0246] (E6) the composition is an infusion solution; and The system of E1 or any claim dependent on E1, wherein the sustained release formulation becomes one or more or any combination of microparticles, nanoparticles, rods, or gels when in contact with the prostate gland.

[0247] (E7) the composition is an infusion solution; and The system of E1 or any claim dependent on E1, wherein the sustained release formulation forms one or more or any combination of microparticles, nanoparticles, rods, or gels.

[0248] (E8) The system of any claim dependent on E1 or E1, wherein the sustained release formulation is bioabsorbable and comprises a glycolide-based copolymer; optionally, poly(lactide-co-glycolide).

[0249] (E9) The system of E1 or any claim dependent on E1, wherein the applicator includes a needle for delivery of the composition via a transurethral, ​​transrectal, or transperineal approach.

[0250] (E10) The system of E1 or any claim dependent thereon, further comprising an ultrasound device for locating a target within the prostate.

[0251] (E11) sustained-release formulations containing an alpha-blocker and / or a 5-alpha-reductase inhibitor, and An applicator or delivery system for local delivery to the prostate of a composition comprising or consisting essentially of said sustained release formulation. 1. A system for the treatment of benign prostatic hyperplasia tissue, comprising:

[0252] (E12) The system of any claim dependent on E1 or E1, wherein the composition further comprises an anti-inflammatory agent, an alpha blocker, or a 5-alpha reductase inhibitor.

[0253] (E13) the composition further comprises an anti-inflammatory corticosteroid for sustained exposure; and The system of any claim dependent on E1 or E1, wherein the corticosteroid comprises dexamethasone, budesonide, mometasone furoate, triamcinolone acetonide, fluticasone propionate, or fluticasone furoate.

[0254] (E14) The system of any claim dependent on E1 or E1, wherein the composition comprises a bioabsorbable polymer in a concentration of 20-80 wt%, 25-75 wt%, or 40-60 wt%, 80-20 wt%, 75-25 wt%, or 60-40 wt% of the solvent, and 0.5 wt% to 30 wt% of the drug; 1 wt% to 20 wt% of the drug, or 1 wt% to 5 wt% of the drug.

[0255] (E15) The system of E1 or any claim dependent thereon, wherein the drug has a release rate of 10% or less to 75% in the first month, 25% to 95% in the first three months, and / or 50% to 100% in the first six months.

[0256] (E16) The system of any claim dependent on E1 or E1, wherein the drug has a release rate of 5% to 50% within the first 24 hour period following injection of the composition into the prostate.

[0257] (E17) the composition comprises a bioabsorbable polymer; and The inherent viscosity of the polymer is 0.1 to 1.0 dL / g, 0.1 to 0.6 dL / g, or 0.1 to 0.4 dL / g, or 0.2 to 0.3 dL / g; and the ratio of DL-lactide to glycolide is from 50 / 50 to 90 / 10, 95 / 5, or 85 / 15; A system according to E1 or any claim dependent on E1.

[0258] (E18) A system according to E1 or any claim dependent on E1, wherein the cytostatic or cytotoxic drug is from 0.1% to 10% or 20-30% by weight of the sustained release formulation.

[0259] (E19) the solvent is water-soluble and non-toxic; and the composition comprises a polymer that is soluble in the solvent; A system according to E1 or any claim dependent on E1.

[0260] (E20) the solvent is aqueous or non-aqueous and non-toxic; and / or the cytostatic or cytotoxic drug is soluble in the solvent; A system according to E1 or any claim dependent on E1.

[0261] (E21) The system of E1 or any claim dependent thereon, wherein the solvent comprises N-methyl-pyrrolidone.

[0262] (E22) the composition comprises a polymer; and The polymer is poly(DL-lactide). A system according to E1 or any claim dependent on E1.

[0263] (E23) A method of treatment using the system of E1 or any claim dependent on E1, comprising injecting the composition into the prostate.

[0264] (E24) 2. The method of any claim dependent on E23 or E23, wherein the cytostatic drug comprises rapamycin, sirolimus, everolimus, temsirolimus, or zotarolimus.

[0265] (E25) 2. The method of any claim dependent on E23 or E23, wherein the cytotoxic drug comprises paclitaxel.

[0266] (E26) The composition is injected into the prostate; and Upon reaching the prostate, the sustained release formulation forms one or more or any combination of microparticles, nanoparticles, rods, or a gel when in contact with the prostate. E23 or a method according to any claim dependent thereon.

[0267] (E27) 2. The method of any claim dependent on E23 or E23, wherein the sustained release formulation comprises poly(lactide-co-glycolide).

[0268] (E28) A method according to E23 or any claim dependent thereon, comprising: the applicator includes a needle for delivery of the composition; and The method comprises delivering the composition via a transurethral, ​​transrectal, or transperineal approach.

[0269] (E29) the composition is injected using a needle having a 16 gauge or larger needle; and The needle has a length of 10 cm to 40 cm. E23 or a method according to any claim dependent thereon.

[0270] (E30) When the composition is implanted into the prostate, the composition remains as a solid or gel implant and provides sustained release of the drug; The water-soluble solvent mixes with the hydrophilic tissue fluid and leaves the remaining drug and polymer as a solid implant or causes them to precipitate. E23 or a method according to any claim dependent thereon.

[0271] (E31) The method of E23 or any claim dependent on E23, wherein said composition comprising said polymer is selected from the set of poly(lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide)(50-50), poly(D,L-lactide-co-glycolide(75-25), poly(D,L-lactide-co-glycolide(85-15), poly(D,L-lactide), ester end-capped poly(D,L-lactide-co-glycolide), acid end-capped poly(D,L-lactide-co-glycolide), or any combination thereof.

[0272] (E32) 10. The method of claim 8 or any claim dependent thereon, wherein the injection is performed through the transurethral, ​​transrectal, and / or transperineal region of the prostate.

[0273] (E33) The method of E23 or any claim dependent thereon, wherein injecting the composition causes it to form a gel or foam when placed in contact with the prostate gland.

[0274] (E34) The method of E23 or any claim dependent on E23, wherein said injecting includes an ultrasound device to locate a target within the prostate.

[0275] (E35) 10. The method of claim E23 or any claim dependent thereon, wherein the injectate and / or applicator is visible by ultrasound imaging.

[0276] (E36) 2. The method of claim 1, wherein the composition keeps the drug localized to the prostate tissue enlargement and prevents unwanted destruction of surrounding tissue.

[0277] (E37) A system according to E1 or any claim dependent thereon, wherein the composition keeps the drug localized in the prostate tissue enlargement and prevents unwanted destruction of surrounding tissue.

[0278] (E38) The system of any claim dependent on E1 or E1, wherein the composition volume comprises 1% to 25% of the prostate volume or 5% to 15% of the prostate volume.

[0279] (E39) The system of E1 or any claim dependent thereon, wherein the composition biodegrades over a time frame of 3 to 6 months or 6 to 12 months.

[0280] (E40) The injection volume of the SRF injectate is minimized to between 10 and 200 microliters per injection to reduce prostate tissue pressure against the urethra and reduce reflux and loss of therapeutic injectate. Further preferred injection volume ranges are 10 to 50 microliters per injection, 50 to 100 microliters per injection, 100 to 300 microliters per injection, and 200 to 500 microliters per injection, for 1 to 5 injections from one side of the prostate to the other (this embodiment is not obvious, given that previous therapies have sought to maximize injection volume to increase dosage). Additionally, this optimal injectate volume will also minimize prostate swelling and volume increase. Injectate volumes that are too large will have the undesirable disadvantage of increasing prostate volume.

[0281] (E41) To precisely deliver low volumes for maintenance therapy, precise drug dosages require a novel delivery device of 250-500 microliters or smaller. This delivery device includes an airtight glass or polypropylene syringe with a Teflon or polypropylene plunger connected to a 22g needle 20 cm in length. The volume of the delivery syringe must be large enough to accommodate the dead volume in the needle, which is approximately 200 microliters. Thus, a 250-microliter airtight syringe can be utilized to deliver a single 50-microliter SRF injection. For multiple injections from the same delivery device, an airtight syringe volume of 400-500 microliters is preferred, allowing sufficient volume to overcome the needle's dead volume and then deliver up to two 100-microliter injections to each lobe of the prostate. (This embodiment is not obvious, given that previous therapies, such as prefilled syringe therapy, have a minimum volume of 1 mL.)

[0282] (E42) To provide optimal injection volumes, longer, controlled-dose, and high-precision custom-made elongated glass gas-tight delivery syringes are available with improved accuracy of the volume graduation markings on the syringe. In lieu of volume graduations, the markings on these delivery devices can also directly indicate the needle dead volume and the user's drug delivery drug dosage in mg for each injection.

[0283] (E43) The SRF can be provided premixed in solution within the delivery device for each injection, resulting in delivery of a predominantly amorphous drug dissolved in the delivery SRF for improved onset of efficacy.

[0284] (E44) The SRF can be provided premixed in solution within the delivery device for each therapy (total number of injections), resulting in delivery of a primarily amorphous drug dissolved in the delivery SRF for improved onset of efficacy.

[0285] (E45) The SRF can comprise a polymer injectate and a drug powder in separate delivery syringes that are then mixed by the user. This embodiment allows for the incorporation of crystalline drugs directly into the injectate, increasing drug retention time and exposure and reducing systemic drug loss.

[0286] (E46) SRF may be mixed with ultrasound microbubble contrast agents that further enhance the visibility of the injectate under transrectal ultrasound guidance, allowing precise location control of the injection within the prostate capsule within each lobe, and further minimizing the potential for drug loss to the urethra, surrounding organs, and systemic circulation.

[0287] (E47) The drug form may comprise any combination of amorphous and crystalline drug that provides sufficient immediate drug release for onset of efficacy, and that extends local drug exposure time and reduces systemic washout.

[0288] (E48) The drug may be lipophilic or hydrophobic in nature, extending local drug exposure time and reducing systemic washout compared to more readily bioavailable hydrophilic drugs, peptides, or proteins.

[0289] (E49) The drug-to-polymer ratio is an important aspect of the present invention. It is not obvious that the correct drug-to-polymer ratio is necessary to exhibit localized efficacy. A too low drug-to-polymer ratio is unattractive, considering that a too low drug dosage will result in too low a local drug concentration. A too high drug-to-polymer ratio will result in too rapid drug release from the SRF, limiting longer-term local drug release and also resulting in systemic drug exposure. The optimal drug-to-polymer ratio is 5% to 30% by weight. More specifically, it may be preferable to utilize 7.5% to 12.5% ​​by weight for optimal drug release and retention.

[0290] (E50) SRF can be used in conjunction with other transurethral procedures of the prostate, such as Urolift, TURP, or others, to reduce further prostate enlargement, scarring, and inflammation after the procedure and reduce the need for repeat treatment.

[0291] (E51) The SRF platform can be utilized to treat vascular restenosis, any localized hyperplastic tissue abnormality, such as localized tumors (eg, prostate cancer), and the like. The present application provides the following aspects of the invention. (Aspect 1) Sustained release formulations (SRF) containing cytostatic or cytotoxic drugs, and An applicator or delivery system for local delivery of a composition comprising or consisting essentially of SRF to target tissue in the prostate. 1. A system for the treatment of benign prostatic hyperplasia tissue, comprising: (Aspect 2) 2. The system of embodiment 1, wherein the SRF is adapted to release the drug into the prostate for at least 14 days, or for a period of 30 to 90 days, or for a period of 90 to 180 days after injection into the prostate. (Aspect 3) 2. The system of embodiment 1, wherein the composition comprises a solvent and the sustained release formulation. (Aspect 4) 2. The system of embodiment 1, wherein the cytostatic drug comprises rapamycin, sirolimus, everolimus, temsirolimus, or zotarolimus. (Aspect 5) 2. The system of embodiment 1, wherein the cytotoxic drug comprises paclitaxel. (Aspect 6) the composition is an infusion solution; and When the sustained release formulation contacts the prostate, the sustained release formulation becomes one or more or any combination of microparticles, nanoparticles, rods, or gels. 2. The system of embodiment 1. (Aspect 7) 2. The system of embodiment 1, wherein the sustained release formulation is bioabsorbable and comprises a glycolide-based copolymer; optionally, poly(lactide-co-glycolide). (Aspect 8) 2. The system of embodiment 1, wherein the applicator comprises a needle for delivery of the composition via a transurethral, ​​transrectal, or transperineal approach. (Aspect 9) 10. The system of embodiment 1, further comprising an ultrasound device for locating a target within the prostate. (Aspect 10) sustained-release formulations containing an alpha-blocker and / or a 5-alpha-reductase inhibitor, and An applicator or delivery system for localized delivery to the prostate of a composition comprising or consisting essentially of said sustained release formulation. 1. A system for the treatment of benign prostatic hyperplasia tissue, comprising: (Aspect 11) 10. The system of embodiment 1, wherein the composition further comprises an anti-inflammatory agent, an alpha blocker, or a 5-alpha reductase inhibitor. (Aspect 12) 2. The system of claim 1, wherein the composition comprises the bioabsorbable polymer in a concentration of 20-80 wt %, 25-75 wt %, or 40-60 wt % of the bioabsorbable polymer, 80-20 wt %, 75-25 wt %, or 60-40 wt % of the solvent, and 0.5 wt % to 30 wt % of the drug; 1 wt % to 20 wt % of the drug, or 1 wt % to 5 wt % of the drug. (Aspect 13) 2. The system of embodiment 1, wherein the drug has a release rate of less than 10% to 75% in the first month, 25% to 95% in the first three months, and / or 50% to 100% in the first six months. (Aspect 14) 2. The system of embodiment 1, wherein the drug has a release rate of 5% to 50% within the first 24 hour period after injection of the composition into the prostate. (Aspect 15) the composition comprises a bioabsorbable polymer; and The inherent viscosity of the polymer is 0.1 to 1.0 dL / g, 0.1 to 0.6 dL / g, or 0.1 to 0.4 dL / g, or 0.2 to 0.3 dL / g; and the ratio of DL-lactide to glycolide is from 50 / 50 to 90 / 10, 95 / 5, or 85 / 15; 2. The system of embodiment 1. (Aspect 16) 2. The system of embodiment 1, wherein the cytostatic or cytotoxic drug is from 0.1% to 10% or 20-30% by weight of the sustained release formulation. (Aspect 17) the solvent is water-soluble and non-toxic; and the composition comprises a polymer that is soluble in the solvent; 2. The system of embodiment 1. (Aspect 18) the solvent is aqueous or non-aqueous and non-toxic; and / or the cytostatic or cytotoxic drug is soluble in the solvent; 2. The system of embodiment 1. (Aspect 19) 2. The system of embodiment 1, wherein the solvent comprises N-methyl-pyrrolidone. (Aspect 20) A method of treatment using the system of embodiment 1, comprising injecting said composition into the prostate. (Aspect 21) Sustained release formulations (SRF) containing cytostatic or cytotoxic drugs, and An applicator or delivery system for local delivery of a composition comprising or consisting essentially of SRF to target tissue in the prostate. 1. A system for the treatment of prostate cancer, comprising:

Claims

1. 1. A composition for use in a method of treatment of benign prostatic hyperplasia (BPH), said method comprising: using a needle syringe containing the composition; and Dispensing multiple doses of the composition into the prostate at multiple respective locations within the prostate using the needle syringe. Including, The composition comprises: a cytotoxic drug that is paclitaxel; a glycolide-based bioabsorbable copolymer selected from the group consisting of poly(D,L-lactide-co-glycolide) (50:50), poly(D,L-lactide-co-glycolide) (65:35), poly(D,L-lactide-co-glycolide) (75:25), and poly(D,L-lactide-co-glycolide) (85:15); and a water-soluble solvent capable of dissolving the cytotoxic drug and the glycolide-based bioabsorbable copolymer; Including, the water-soluble solvent capable of dissolving the cytotoxic drug and the glycolide-based bioabsorbable copolymer is selected from the group consisting of N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO); and The composition, wherein the step of administering multiple doses comprises sequentially administering at least a first dose of the composition to a first location within the prostate and a second dose of the composition to a second location using the needle syringe.

2. 10. The composition of claim 1, wherein the dose comprises 100 microliters of the composition.

3. 2. The composition of claim 1, wherein the water-soluble solvent capable of dissolving the cytotoxic drug and the glycolide-based bioabsorbable copolymer is NMP.

4. 10. The composition of claim 1, wherein the cytotoxic drug has a total concentration of 0.5 to 30% by weight of the composition.

5. 10. The composition of claim 1, wherein the method comprises releasing the cytotoxic drug-containing composition into the prostate for at least 14 days after injection into the prostate.

6. 10. The composition of claim 1, wherein the cytotoxic drug has a release rate of no more than 10% to 75% during the first month.

7. 10. The composition of claim 1, wherein the cytotoxic drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

8. 10. The composition of claim 1, wherein the glycolide-based bioabsorbable copolymer has a viscosity of 0.2 to 0.6 dL / g.

9. The composition of claim 4, wherein the cytotoxic drug is 0.1 to 10% by weight of the composition.

10. 10. The composition of claim 1, wherein the water-soluble solvent comprises N-methyl-pyrrolidone, the cytotoxic drug is paclitaxel, and the glycolide-based bioabsorbable polymer is poly(D,L-lactide-co-glycolide) (85:15).

11. 1. A composition for use in a method of treatment of benign prostatic hyperplasia (BPH), said method comprising: using a needle syringe containing the composition; and Dispensing multiple doses of the composition into the prostate at multiple respective locations within the prostate using the needle syringe. Including, The composition comprises: a cytostatic drug selected from the group consisting of sirolimus and everolimus; a glycolide-based bioabsorbable copolymer selected from the group consisting of poly(D,L-lactide-co-glycolide) (50:50), poly(D,L-lactide-co-glycolide) (65:35), poly(D,L-lactide-co-glycolide) (75:25), and poly(D,L-lactide-co-glycolide) (85:15); and a water-soluble solvent capable of dissolving the cytostatic drug and the glycolide-based bioabsorbable copolymer; Including, the water-soluble solvent capable of dissolving the cytostatic drug and the glycolide-based bioabsorbable copolymer is selected from the group consisting of N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO); and The composition, wherein the step of administering multiple doses comprises sequentially administering at least a first dose of the composition to a first location within the prostate and a second dose of the composition to a second location using the needle syringe.

12. 12. The composition of claim 11, wherein the cytostatic drug is 0.1 to 10% by weight of the composition.

13. 13. The composition of claim 12, wherein the water-soluble solvent comprises N-methyl-pyrrolidone, the cytostatic drug is sirolimus, and the glycolide-based bioabsorbable copolymer is poly(D,L-lactide-co-glycolide) (85:15).

14. 13. The composition of claim 12, wherein the cytostatic drug is sirolimus.

15. The composition of claim 1, wherein the cytotoxic drug has a total concentration of 1 to 20% by weight of the composition.

16. The composition of claim 4, wherein the cytotoxic drug is 20-30% by weight of the composition.

17. 12. The composition of claim 11, wherein the cytostatic drug is 20-30% by weight of the composition.

18. 10. The composition of claim 1, wherein the method comprises releasing the cytotoxic drug into the prostate over a period of 30 to 90 days.

19. 10. The composition of claim 1, wherein the method comprises releasing the cytotoxic drug into the prostate over a period of 90 to 180 days.

20. 10. The composition of claim 1, wherein the glycolide-based bioabsorbable copolymer has a viscosity of 0.2 to 0.4 dL / g.

21. 21. The composition of claim 20, wherein the glycolide-based bioabsorbable copolymer has a viscosity of 0.2 to 0.3 dL / g.

Images