Benign Prostatic Hyperplasia Treatment System

Abstract

A method for minimally invasive treatment of benign prostatic hyperplasia (BPH) tissue. The system includes a sustained release formulation comprising a cytostatic or cytotoxic drug, and an applicator or delivery system for locally delivering a composition comprising or consisting essentially of the sustained release formulation to the prostate. The applicator containing the composition is characterized by a KIR value of 15 to 1,000 centipoise per unit area.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 304,599, filed January 29, 2022, and also to U.S. Publication No. 17 / 727,675, filed April 22, 2022, and U.S. Publication No. 17 / 727,680, also filed April 22, 2022. Each application is incorporated by reference in its entirety for all purposes.

[0002] Field

[0002] Men's health, more specifically minimally invasive localized treatments for lower urinary tract symptoms. [Background technology]

[0003] background Benign prostatic hyperplasia (BPH) is a non-cancerous 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. Lower urinary tract symptoms (LUTS) include voiding or obstructive symptoms such as urinary hesitancy, weak and / or intermittent urinary flow, urinary tenesmus, residual urine, and storage or irritation symptoms such as urinary frequency, urgency, urge incontinence and nocturia. It affects approximately half of men over the age of 50, with 90% of men affected by age 80. Treatment options consist of lifestyle changes, medications, various procedures and surgery. Lifestyle changes consist of weight loss, exercise and reduced caffeine intake. In severe cases, oral medications such as alpha blockers (e.g., terazosin) or 5-alpha reductase inhibitors (e.g., finasteride) are prescribed. These medications must be taken daily for patient compliance, take a long time to be effective, if at all, and can be associated with side effects such as ejaculation changes, erectile dysfunction, weakness, headaches, and decreased libido. Summary of the Invention [Problem to be solved by the invention]

[0004]

[0004] There remains an unmet clinical need for a treatment for BPH with improved and sustained efficacy that can be administered via less invasive procedures and has fewer associated side effects. [Means for solving the problem]

[0005] Summary of the Invention

[0005] In one embodiment, the present specification provides a method for treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising using a needled syringe containing a composition comprising a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent capable of dissolving the drug and the copolymer, and dispensing a total volume of the composition into the prostate gland to produce an outcome effective in treating BPH, including dispensing no more than a unit volume of the composition into a first prostatic location of the prostate gland using the needled syringe.

[0006]

[0006] In a second embodiment, the present specification provides a method for treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising using a needled syringe containing a composition comprising a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent capable of dissolving the drug and the copolymer, and dispensing a total volume of the composition into the prostate gland to produce an outcome effective in treating BPH, including dispensing a plurality of unit volumes of the composition into a first prostatic location of the prostate gland using the needled syringe.

[0007]

[0007] In a third embodiment, there is provided herein a method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising using a device including a needled syringe containing a composition comprising a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent capable of dissolving the drug and the copolymer, wherein the composition has an absolute viscosity μ, and the needled syringe has a needle length L with an inner diameter D; and dispensing a plurality of unit volumes v of the composition to a respective plurality of different locations in the prostate using the needled syringe, wherein the unit volume is 0.05 ml to 0.2 ml, the plurality of unit volumes being equal to a total volume for the treatment of BPH, the device having a KIR of 10 to 300 or 40 to 400, and the KIR is

number

[0008] In a fourth embodiment, there is provided herein a device for treating a prostate volume PV, the device comprising: a composition having an absolute viscosity μ and comprising SRF in an amount of at least one unit volume v; and a syringe, the syringe housing the composition in a barrel thereof, the needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition, the syringe holding at least n unit volumes v, where n is related to the PV as n=PV / (200×v), and the n unit volumes equal a total volume for the treatment of BPH, the device having a KIR of 10-1000, 10-300, or 40-400, where KIR is (μ)×(L) 2 / (vD)×10 (-6) It is defined as:

[0009] In a fifth embodiment, there is provided herein an apparatus for treating a prostate volume PV, the apparatus comprising: a composition having an absolute viscosity μ and comprising SRF in an amount of at least one unit volume v; a syringe containing the composition in a barrel of the syringe, the syringe including a needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition, the syringe holding at least n unit volumes, and n being related to the PV as n=PV / (200×v), L being 15-20 cm, the barrel having a slenderness ratio of about 10 and 30, the needle having an inner diameter of 0.06 cm to about 0.08 cm, v being 0.05 ml to 0.1 ml, and μ being 1065 cP to 4000 cP, the apparatus comprising: (μ)×(L) 2 / (vD)×10 (-6) , defined as having 10 to 1000 KIRs.

[0010]

[0010] In a sixth embodiment, there is provided herein a guide for providing incremental dosages from a syringe coupled to the guide, the syringe including an outer barrel, a finger hook extending from the outer barrel, and a plunger movable relative to the outer barrel, the guide including: (1) a body extending along a central axis between a first end and a second end, the body defining an interior space, the body including (a) an outer wall, (b) an inner wall disposed radially inward of the outer wall, and (c) a plurality of return detents extending from the inner wall into the interior space, the plurality of return detents being spaced apart from one another along a central axis of the body; and (2) a second end of the body. and a finger hook fastening portion at the portion configured to engage with the finger hook of the syringe to prevent the barrel from moving relative to the body, wherein when the syringe is provided in the guide, the plunger extends into the interior space of the body, and when the plunger is moved relative to the barrel, a first detent of the plurality of detents is configured to engage the plunger to resist movement of the plunger relative to the barrel, and the plunger is movable beyond the first detent of the plurality of detents to a second detent of the plurality of detents.

[0011]

[0011] In a seventh embodiment, a delivery device configured to mix a first composition with a second composition is shown herein, the delivery device including a barrel extending between a first end and a second end, the first end of the barrel being adapted for attachment to a needle, a septum disposed within the barrel, dividing the barrel into a first chamber and a second chamber, the first chamber receiving the first composition and the second chamber receiving the second composition, and a plunger extending from the second end of the barrel, movable relative to the barrel and configured to break the septum to allow the first composition to mix with the second composition to form a mixture, and to push the mixture from the first end of the barrel into the needle. In some embodiments, the mixture may be mixed by oscillating back and forth in the barrel two or more times. In some embodiments, the mixture may be mixed using a distal static mixing attachment distal to the syringe but proximal to the needle.

[0012]

[0012] In an eighth embodiment, the present specification provides a kit comprising at least two or more prefilled syringes, wherein one of the at least two or more prefilled syringes comprises a composition comprising a cytotoxic drug powder or a cytostatic drug powder, and one of the at least two or more prefilled syringes comprises a composition comprising a glycolide-based bioabsorbable copolymer and a water-soluble solvent, and the kit also comprises instructions for mixing the prefilled syringes.

[0013]

[0013] In a ninth embodiment, the present specification provides a kit comprising at least one syringe containing a composition comprising a cytotoxic or cytostatic drug powder, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent, and instructions for administering the composition.

[0014]

[0014] In a tenth embodiment, there is provided herein a method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising providing a guide as described herein, an instrument as described herein, a kit as described herein, or a combination thereof, and dispensing a total volume of a composition into the prostate to produce an outcome effective in treating BPH, comprising dispensing no more than a unit volume of the composition into a first prostatic location of the prostate using a needled syringe.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0016] [Figure 1]

[0016] FIG. 1 is a perspective view of a prior art needle syringe. [Figure 2A]

[0017] FIG. 1 is a schematic side view of a prostatic type needle syringe for delivering a composition including a sustained release formulation (SRF). [Figure 2B]

[0018] FIG. 1 is a schematic side view of a prostatic type needle syringe for delivering a composition including a sustained release formulation (SRF). [Figure 3A]

[0019] Examples of K Injection Ratings (KIRs) for transrectal and perineal BPH treatment are provided. [Figure 3B]

[0020] Examples of K Injection Ratings (KIRs) for transrectal and perineal BPH treatment are provided. [Figure 3C]

[0021] The drug release curves for SRF A, B and C are shown. [Figure 4]

[0022] 1 shows histopathology H&E stained microscopy images of sectioned canine prostate lobes 30 days after SRF1 treatment in BPH animal #21C0042. Boxes indicate the necrotic core and extent of drug effect around the 100 μL volume of SRF injection (arrows). Scale bar equals 1 mm. [Diagram 5]

[0023] 1 shows histopathology H&E stained microscopy images of sectioned canine prostate lobes 90 days after SRF1 treatment in BPH animal #21C0046. Boxes indicate the necrotic core and extent of drug effect around the 50 μL volume of SRF injection (arrows). Scale bar equals 1 mm. [Figure 6]

[0024] 1 shows histopathology H&E stained microscopy of sectioned canine prostate lobes 90 days after SRF1 treatment in BPH animal #21C0050. Boxes indicate the necrotic core and extent of drug effect around the 50 μL volume of SRF injection (arrows). Scale bar equals 1 mm. [Figure 7]

[0025] Shown is the systemic drug concentration as measured by liquid chromatography mass spectrometry (LCMS) as a function of time after SRF1 injection for each animal. [Figure 8]

[0026] Shown are mean systemic drug concentrations measured by LCMS as a function of time after SRF1 injection for each animal as a function of drug dose: N=6 for days 0-30 and N=3 for days 60-90, 4 animals starting at 5 mg and 2 animals at 10 mg. [Figure 9]

[0027] Figure 9 shows the injection locations of SRF1 in the prostate. Figure 9 shows the locations in Table 7 for collecting prostate samples for pharmacokinetic ("pk") tissue analysis. Circles indicate treatment samples ("tx") and rectangles indicate either adjacent reference samples ("adj") or distal reference samples ("distal"). Numbers in the figure are the corresponding locations in Table 7. [Figure 10A]

[0028] 1 shows a transurethral type needle syringe for delivering a composition containing a sustained release formulation (SRF). [Figure 10B]

[0029] A syringe having a depth limiter for preventing needle injection from exceeding a predetermined depth and for dispensing a predetermined unit volume of a composition including a sustained release formulation (SRF) into the prostate gland. [Figure 10C]

[0030] 1 shows an example of a transurethral needle with depth markers. [Figure 10D]

[0031] 1 shows an example of a transurethral needle with depth markers. [Figure 11A]

[0032] Shown are male and female syringes for the point in the procedure where the SRF drug (headed Syringe B: drug powder) is mixed with the solvent and polymer solution (headed Syringe A: polymer and solvent solution). Figure 11A also shows the male and female syringes connected for mixing (headed Mixing). Figure 11A also shows the rectal 20G x 2cm needle and syringe with the SRF composition therein, headed Formulated Ready to Inject with Rectal 20G x 2cm Needle Product. [Figure 11B]

[0033] A self-contained multi-chamber syringe delivery device is shown with a drug powder in the first chamber and a water-soluble solvent and polymer solution in the second chamber. A transrectal needle with a protective cover is also shown. [Figure 12]

[0034] Point of care kit for the treatment of BPH is shown in Figure 12. Desiccant and drug product polyethylene terephthalate glycol (PETG) packaging tray. [Figure 13]

[0035] 1 shows a cross section of the prostate where a transurethral needle injection has passed through the urethral wall. [Figure 14A]

[0036] 1 provides examples of K Injection Ratings (KIRs) for transurethral BPH treatment. [Figure 14B]

[0037] 1 provides examples of K Injection Ratings (KIRs) for transurethral BPH treatment. [Figure 15]

[0038] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 16]

[0039] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 17]

[0040] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 18]

[0041] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 19]

[0042] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 20]

[0043] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 21]

[0044] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 22]

[0045] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Diagram 23]

[0046] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 24]

[0047] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Diagram 25]

[0048] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 26]

[0049] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 27]

[0050] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 28]

[0051] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. [Figure 29]

[0052] A self-contained syringe is shown containing a drug powder in a first chamber and an aqueous solvent and polymer solution in a second chamber. [Diagram 30]

[0053] 1 illustrates an embodiment of a guide for providing a unit volume dosage from a syringe. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description

[0054] The present disclosure generally relates to achieving localized delivery of sustained release formulations at the level of effective treatment of target tissues associated with the prostate gland and / or providing relief from urinary symptoms caused by or associated with prostate enlargement, while reducing, if not avoiding, damage to nearby prostatic structures or the urethra.The treatment can be used alone or in combination with other known treatments.The treatment can be used to administer a composition to a subject in need thereof.

[0018]

[0055] In view of the above, disclosed herein is a method for delivering sustained release formulations (SRF) in an effective manner and with reduced side effects to patients compared to known BPH treatment methods. The method uses a device that includes a needled syringe that contains a composition including SRF (hereinafter, "composition" refers to a composition including SRF unless otherwise specifically noted). The method includes dispensing one or more unit volumes of the composition from the needled syringe into each of one or more target tissue locations in the prostate. The device has the following relationships:

number

[0019]

[0056] In the formula, μ is the absolute viscosity of the composition (cP), L is the needle length measured from the tip to the base of the needle (cm), D is the needle diameter (cm), and v is the unit volume of the composition contained in the syringe barrel (cm 3or cc). Each unit volume corresponds to the maximum volume of composition that will be dispensed into a single location of the target tissue. In some embodiments, the syringe holds multiple unit volumes, which allows a unit volume to be dispensed into each of multiple corresponding separate locations of the target tissue to achieve the total volume of the composition to be injected at the target tissue. In some embodiments, the total volume within the syringe barrel is a multiple of the unit volumes plus some excess to allow for priming of the needle dead volume.

[0020]

[0057] Also disclosed is a device for treating the prostate gland, the device including a needled syringe and a composition contained within the syringe, the device adapted to deliver one or more unit volume increments of the composition to a target tissue as defined by its KIR value.

[0021]

[0058] The KIR values ​​of the methods, devices, medical devices, and systems of the present disclosure may range from 10 to 1000, 10 to 300, or 40 to 400. The units of KIR are centipoise per unit area. In some embodiments, the KIR values ​​in this paragraph are useful for transurethral administration using needles with needle lengths of 35 cm to 70 cm.

[0022]

[0059] The KIR values ​​of the methods, devices, medical devices and systems of the present disclosure may range from 10 to 1200, 100 to 900, or 300 to 600. The units of KIR are centipoise per unit area. In some embodiments, the KIR values ​​in this paragraph are useful for transrectal / perineal administration using needles with needle lengths of 15 cm to 20 cm.

[0023]

[0060] The prostate treatment according to the present disclosure can be described as a prostate treatment having three characteristics: minimal uncontrolled drug diffusion (e.g., as shown in Table 8), sustained release and efficacy, and unit volume as defined herein. The KIR identifies needled syringes capable of delivering one or more of these unit volumes of the composition in a safe and reproducible pattern in the hands of a medical professional, without significantly compromising the composition's ability to achieve minimal uncontrolled drug diffusion, sustained release, and efficacy.

[0024]

[0061] Thus, in one aspect, the treatment of prostatic hyperplasia tissue as provided herein comprises the delivery of one or more drugs to the tissue of a subject in need thereof in a sustained manner using a needled syringe containing SRF.This treatment can be used in conjunction with or in addition to treatments involving tissue removal / ablation and / or delivery of energy to tissue and further administration of various drugs.The method according to the present disclosure can also or alternatively be administered after the treatment of BPH according to other methods.

[0025]

[0062] Access to the prostate tissue may be achieved transurethrally, transrectally, or transperineally through existing body orifices. Access to the tissue via either a transrectal or transperineal approach may be beneficial and less invasive. Advantages of a transrectal or transperineal approach include one or more of the following: (1) no general anesthesia, but instead oral and / or local anesthesia; (2) less trauma to the urethra resulting in fewer side effects and reduced need for catheter placement; (3) faster recovery time for the patient; and (4) a procedure familiar to urologists similar to prostate cancer biopsy. To access via a transrectal or transperineal approach, guidance may be provided by ultrasound, x-ray, computed tomography, magnetic resonance imaging, or other imaging modalities. Given that ultrasound is utilized for prostate biopsy, ultrasound imaging may be beneficial. A 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, limiting the cauterizing effect of urethral procedures and thus minimizing the side effects and dysuria associated with currently available BPH procedures.

[0026]

[0063] Instead, it may be beneficial to reach the prostate tissue by a transurethral approach. The advantages of a transurethral approach include one or more of the following: (1) the urethra and blockage can be optically visualized during treatment by cystoscopy; (2) drug prostate lesions can be created with a continuous and consistent treatment depth across the urethral transition zone; (3) trauma to the urethra can be minimized using a flexible scope and / or delivery device; (4) the pain of a transperineal approach and the need for additional devices are avoided; (5) the risk of minor infection of a transrectal approach is avoided; and (6) the treatment is familiar to urologists, similar to other BPH procedures such as transurethral resection of the prostate (TURP), implants such as Urolift™ and Rezum™, and ablation procedures. To reach the transurethral approach, guidance can be provided by direct optical imaging, ultrasound, computed tomography, magnetic resonance imaging, or other imaging modalities. Optical imaging may be beneficial given that SRF can be delivered with direct visualization of the urethral obstruction. The transurethral approach closely resembles the current techniques with which urologists are familiar with treating prostate BPH. The transurethral approach avoids interaction with the rectum, limiting the risk of minor infections associated with the transrectal approach.

[0027]

[0064] The drug portion of the composition may be an anti-inflammatory, anti-proliferative, cytoreductive, cytostatic and / or cytotoxic drug that will affect prostate size and prostate proliferation. The device allows for the delivery of one or more drugs into the target tissue. Once delivered to the target tissue, the drug may then be released from the SRF in a slow, sustained manner, optionally delivered as an initial burst of drug followed by a slow, sustained release of the drug into the target tissue. The amount or lack of burst and / or the release period of the "slow, sustained release" may depend on the drug delivered to the prostate, the SRF characteristics and the KIR value, as will be understood in light of the present disclosure. 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.

[0028]

[0065] In another aspect, there is a system for treating BPH, including a needled syringe, a sustained release formulation (SRF), and an imaging device for locating a target tissue in the prostate. An optical imaging device, such as a cystoscope, can be used both to guide the needle to the target tissue and to determine the size of the prostatic transition zone urethral length (TZUL). Once the prostatic transition zone urethral length is determined, the number n of unit volumes v to be injected can be determined. The needled syringe according to the present disclosure can hold one or more unit volumes that can be dispensed from the needle to treat the prostate in a controlled manner as determined by the KIR value of the syringe containing the composition. The KIR value is, in some embodiments, 10-1200, 100-900, or 300-600.

[0029]

[0066] In another aspect, there is a method of making a medical device for treating the prostate, the method comprising the step of forming a composition comprising SRF by combining at least one drug with at least one polymeric carrier, the composition being contained within a needled syringe, the needled syringe containing the composition having a KIR value of 10 to 1200, 100 to 900, or 300 to 600. In some embodiments, a water soluble solvent capable of dissolving the polymeric carrier and the at least one drug is also present with the polymeric carrier.

[0030]

[0067] Treating BPH with small unit volumes at multiple locations in target tissues via needle injection offers several advantages over other methods, including increased patient acceptance due to a less invasive procedure, fewer complications during patient treatment, less frequent need for procedures, and a lower incidence of outcomes where drugs affect nearby tissues and adversely affect urinary or sexual function.

[0031]

[0068] For purposes of this disclosure, the following terms and definitions apply.

[0032]

[0069] The following are examples of polymer nomenclature that appear in the listing of additional embodiments disclosed following the detailed description. Other examples not explicitly detailed here use the same rationale. PLGA8515A (0.3 dl / g) refers to poly(lactide-co-glycolide) with an 85 / 15 monomer ratio, end-capped with an acid group (A), and an intrinsic viscosity of 0.3 dl / g, and PLGA6535E (0.5 dl / g) refers to poly(lactide-co-glycolide) with an 85 / 15 monomer ratio, end-capped with an ester group (E), and an intrinsic viscosity of 0.5 dl / g, and PLGA5050A (0.2 dl / g or 0.1 dl / g) refers to poly(lactide-co-glycolide) with an 85 / 15 monomer ratio, end-capped with an acid group (A), and an intrinsic viscosity of 0.5 dl / g. g) means a 50 / 50 monomer ratio poly(lactide-co-glycolide) endcapped with acidic groups (E) and having an intrinsic viscosity of 0.2 dl / g, and the poly(lactide-co-glycolide) is typically poly(D,L-lactide-co-glycolide), but can 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).

[0033]

[0070] The term "about" or "approximately" is 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 a stated value, range, or the respective endpoints of a stated range, or as 1 sigma, 2 sigma, or 3 sigma variance from a stated mean or expected value (Gaussian distribution). For example, dl is about d2, which 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%. When dl is an average value, d2 is about dl, which means that d2 is within 1 sigma, 2 sigma, or 3 sigma variance from dl. In this disclosure, any numerical value, range, or either range endpoint preceded by the terms "about," "substantially," or "approximately" (including, for example, "about none," "about none," "about all," etc.) is understood to also describe or disclose the same numerical value, range, or either range endpoint not preceded by the terms "about," "substantially," or "approximately."

[0034]

[0071] The term "drug" or "medication" as used herein is defined as a non-food therapeutic substance used in the prevention, diagnosis, mitigation, treatment or cure of disease. Unless otherwise specified, "drug" and "medication" shall have the same meaning.

[0035]

[0072] The term "cytostatic drug" as used herein refers to a drug that is non-toxic to cells, but actually reduces cell proliferation and allows cell migration. Cytostatic drugs can include, without limitation, rapamycin, sirolimus, everolimus, zotarolimus, myolimus, temsirolimus, tacrolimus, macrolide antibiotics, ridaforolimus, biolimus, novolimus, deforolimus, structural derivatives and functional analogs of rapamycin, and any macrolide immunosuppressant. mTOR / PI3K dual inhibitors can also be utilized, including dactolisib, BGT226, SF1126, PKI-587, and NVPBE235. mTORC1 / mTORC2 dual inhibitors can also be utilized, including sapanisertib, AZD8055, and AZD2014, which are derived from morpholinopyrazolopyrimidines.

[0036]

[0073] The term "cytotoxic drug" as used herein refers to drugs that inhibit cell growth and proliferation, such as chemotherapeutic drugs. Such drugs can include, but are not limited to, paclitaxel, taxanes, protaxel, vincristine, etoposide, nocodazole, indirubin, anthracyclines, daunorubicin, daunomycin, tauromustine, bohumustine, carboplatin, carmustine, cisplatin, docetaxel, cabazitaxel, gemcitabine, mitomycin, procarbazine, and plicamycin. Such drugs can also be apoptotic drugs, such as TGF, topoisomerase inhibitors, including 10-hydroxycamptothecin, irinotecan, and doxorubicin.

[0037]

[0074] The term "composition" as used herein means a product of mixing or combining various elements or components. Whenever the phrase "composition" is used, it will be understood that the composition includes SRF. However, the term "polymer composition" does not include a composition that includes SRF.

[0038]

[0075] The term "absolute viscosity" as used herein means viscosity measured relative to the viscosity of a known material. Unless otherwise specified, "absolute viscosity" (as compared to intrinsic viscosity) is represented by the symbol μ. Absolute viscosity may be measured on 10 mL of solution in a 40 mL polypropylene vial in contact with approximately 50% immersion spindle solution using a calibrated digital rotational viscometer spindle (size 1), with the measurement being performed at room temperature conditions.

[0039]

[0076] The term "partial solution" as used herein means a composition that contains a mixture of dissolved drug in SRF and a suspension of undissolved drug in SRF. The term "solution" as used herein means a composition that contains dissolved drug in SRF and no undissolved drug. A solution means that the concentration of drug is below the saturation limit in the solvent.

[0040]

[0077] The term "depth setting" as used herein refers to the penetration depth of the needle head into the prostate. From canine preclinical studies, it has been determined that the SRF caused lesion size is about 0.5 cm 30 days after the procedure. Therefore, in some embodiments, a needle depth setting of at least 2.5 mm is required to maximize the SRF drug prostate effect required to treat prostate BPH. Furthermore, it is desirable to have a depth setting of about half or more of the lesion size.

[0041]

[0078] The term "unit volume" as used herein refers to the maximum volume (v) of the composition for an individual injection when treating BPH. In most cases, there will be multiple unit volumes of the composition for each patient. For example, n=2, 3, 4, 5, 6 or more may be used depending on the size of the prostatic transition zone urethral length, which can be determined before or during treatment from ultrasound imaging and / or by direct optical cystoscopy. Herein, n is the number of unit volumes. The larger the size of the prostatic transition zone urethral length, generally speaking, the greater the number of unit volumes dispensed from the needle at different locations of the prostate. In preclinical studies, it was found that using unit volumes of the composition of 0.05ml to 0.1ml for prostatic treatment can significantly reduce prostate size over a 90-day period. Furthermore, it is believed that unit volumes of 0.05ml to 0.5ml, 0.05ml to 0.1ml, 0.1 to 0.2 or 0.05 to 0.2ml will also result in positive clinical outcomes without adverse indications.

[0042]

[0079] Prostate volume between 19.5 and 44.1 cm, discussed in more detail below 3 Range (average 30cm 3 From preclinical studies in dogs, a total injection volume of the prostate for injection of unit volumes of 0.050-0.100 mL and two unit volumes of 0.100 mL and 0.200 mL, respectively, produced the desired results (human prostate volume is typically 20-80 cubic centimeters) or grams (prostate mass density can be approximated as 1 g / cc). In this study, local drug retention and drug efficacy were observed, with no damage to surrounding organs and a reduction in prostate volume at 30 and 90 days after SRF treatment.

[0043]

[0080] A normal adult human prostate weighs about 20-25 grams (g). The majority of BPH prostate sizes are 30 g or larger, most often ranging from 30 g to 80 g, but some may be significantly larger. The number (n) of unit volumes (v) injected per prostate to achieve a size reduction of more than about 25% can be selected based on the prostate size. Thus, increasing numbers of unit volumes can be utilized to achieve the same amount of reduction in larger prostate size. For example, the number (n) of unit volumes injected to achieve a reduction of more than 15% or more than 25% in prostate size can be determined from Table 1A.

[0044] [Table 1]

[0045]

[0081] The term "total volume" of the composition (i.e., the sum of n unit volumes of the composition injected into the prostate during a single treatment session, defined as within 1-2 hours or within 24 hours of each other) is the total volume of the composition administered to the patient in the treatment of BPH in an effective amount that produces a planned sustained effective outcome. This planned sustained effective outcome may be measured using the International Prostate Symptom Score (IPSS). This planned sustained effective outcome may also be measured more generally using the relief of lower urinary tract symptoms (LUTS), including voiding or obstructive symptoms, such as urinary hesitancy, weak and / or intermittent urinary flow, urinary tenseness, residual urine, and storage or irritation symptoms, such as urinary frequency, urgency, urge incontinence, and nocturia. The total volume is expected to result in a reduction of more than 15% of the prostate volume or a reduction of more than 25% of the prostate volume. Preclinical studies using dog models have shown that prostate volume is reduced by up to 30% over a 30-90 day period (dog prostate size averaged 30cc at the time of treatment, ranging from 19.5-44.1cc, but averaged 10cc 30 and 90 days after treatment). In some embodiments, the number n of unit volumes v required to achieve a total volume of the composition for prostate treatment is related to the prostate volume PV as n=PV / (200×v) (rounded down to the nearest integer). For example, for a prostate volume of 30cc and a unit volume of 0.07ml, the required value is 2.14, which is then rounded down to n=2.

[0046]

[0082] The majority of human BPH transition zone urethral lengths (TZUL) are in the range of 1.5 cm to 3.5 cm or greater. The number (n) of unit volumes (v) injected per prostate to achieve a size reduction of greater than approximately 25% can be selected based on the prostate TZUL. Thus, an increasing number of unit volumes can be utilized to achieve the same amount of reduction in large TZUL. For example, the number (n) of unit volumes injected to achieve a reduction in prostate size of greater than 15% or greater than 25% can be determined from Table 1B.

[0047] [Table 2]

[0048] [Table 3]

[0049]

[0083] FIG 10A shows a syringe coupled to a needle with a depth limiter at the end of the needle syringe. FIG 10B shows a flexible needle, labeled 1050, that can be coupled to the syringe. The rightmost needle tip, labeled 1090, of FIG 10B shows a needle tip with depth limiting indicators labeled 2mm, 3mm, 4mm, and 5mm. Also shown is an adapter, labeled 1070, for controlling the needle penetration depth. FIG 10C shows another example of a flexible needle for administration of the SRF compositions described herein. FIG 10D shows the needle tip assembly.

[0050]

[0084] Figures 10A, 10B, 10C and 10D show examples of commercially available transurethral cystoscopy needles from Laborie (https: / / www.laborie.com / product / injetak-cystoscopy-needles / ), Coloplast (https: / / iu.coloplast.us / products / bonee-needle), and Cook (https: / / www.cookmedical.com / products / uro_wcin_webds / ), with either fixed or adjustable needle insertion depth. The entire contents of these network addresses as of January 27, 2023 are incorporated herein by reference in their entirety for all purposes.

[0051]

[0085] In some embodiments, including any of the above, the SRF syringe is connected to a luer hub at the proximal end of a needle, which is then inserted into a commercially available rigid or flexible cystoscope (https: / / medical.olympusamerica.com / procedure / flexible-cystoscopy) and the SRF is injected or implanted transurethrally into the prostate gland under optical guidance from the cystoscope. The cystoscope also allows for direct imaging of urethral obstruction and obstruction length, allowing for precise determination of the number of unit volumes injected and the location of each injection. The entire contents of the network addresses in this paragraph as of January 27, 2023 are incorporated herein by reference in their entirety for all purposes.

[0052]

[0086] The correlation between unit volume and TZUL is also important to create a continuous SRF drug lesion over the TZUL to treat LUTS caused by BPH and provide efficacy and symptom relief to the patient, and not to create further trauma and / or pain. It is known that excessive necrosis and lesion size in the prostate can lead to prostate enlargement and urethral pressure during the lesion healing phase and worsening of BPH symptoms for about 30 days or more before symptom relief, which can delay symptom relief for 90 days or more. The present disclosure shows a method and device that delivers multiple precise unit volumes of SRF according to TZUL correlation and with precise depth settings so that the patient can get symptom relief in 30 days without prostate enlargement and urethral pressure caused by excessive drug lesion effect.

[0053]

[0087] The term "sustained release formulation (SRF)" as used herein refers to a substance for the treatment of BPH, comprising a drug (or drugs), a solvent for the drug, and a drug carrier comprising a polymeric composition that is administered to a target tissue in liquid, gel or solid form using a carrier or delivery vehicle such as a needled syringe for the drug or drugs, and upon localized delivery of the composition (including the SRF) to the target tissue, the SRF is effective to provide a sustained release of the drug or drugs to the target tissue of the prostate, thereby providing effective results for a period of time after treatment, such as 14 days, 30 days, 1-3 months, up to 6 months, up to 12 months or up to 2 years, with minimal uncontrolled drug diffusion. Other substances may also be present in the composition (e.g., ultrasound / echo contrast agents or other imaging contrasts depending on the imaging modality used). For example, a planned sustained release of 14 days or 1-12 months to dissipate substantially all of the drug from the carrier is achieved by selection of the drug carrier (polymer composition) and / or modification of the morphology and mechanical properties, polymer / drug ratio, and control of the physical shape / dimensions (volume) of the SRF and / or composition delivered to the target tissue. Other factors that affect the release rate are described in more detail below.

[0054]

[0088] The term "target tissue" as used herein is defined as prostatic tissue, including the transitional, peripheral and central regions of the prostate and the prostate gland. Treatment of the lateral and middle lobes of the prostate via a transurethral approach is also included.

[0055]

[0089] The most common type of prostate treatment is the treatment of cancerous or precancerous conditions (i.e., non-malignant tumors) and prostate enlargement, more commonly known as benign prostatic hyperplasia / hyperplasia (BPH). The types of tissues are very different between the treatment of cancer or precancerous tumors and BPH, calling for different formulations of similar drugs that may be effective in treating either condition. Most notably, the volume of drug (based on prostate volume and / or TZUL) at a particular time is very different when treating tumors or cancer compared to when treating BPH. The TZUL correlation is not valid given that the treatment of cancerous tissue requires the removal of excess amounts of cellular necrosis to remove cancerous cells and prevent them from spreading, and the risk of swelling due to the resulting inflammation is not as much of a concern when treating cancer. Finally, when treating cancer or tumors, it may be desirable to release the entire amount of drug from the carrier quickly, i.e., within the first 24 hours after the composition is injected into the patient. In contrast, slow release means that the drug is released over a period of at least 1 to 3 months from the time the composition is injected into the patient. This results in an extended effect of the drug without causing further damage and swelling to the prostate. Unlike cancer treatments, where the goal may be to remove all cancerous tissue at the expense of some healthy tissue, this disclosure describes a treatment that similarly achieves sufficient volume reduction of diseased tissue without causing excessive damage to surrounding tissue.

[0056]

[0090] In some embodiments, the patient to be treated has cancer elsewhere in the body (other than the prostate) but is being treated for BPH according to the present disclosure. In some embodiments, the patient does not have cancer elsewhere in the body and is being treated for BPH.

[0057]

[0091] In some embodiments, including any of the foregoing, the methods herein include administering an SRF or composition described herein to a subject in need thereof, wherein the subject does not have prostate cancer.

[0058]

[0092] In some other embodiments, the methods herein, including any of the foregoing, comprise administering an SRF or composition described herein to a non-cancer subject in need thereof.

[0059]

[0093] In yet other embodiments, the methods herein, including any of the foregoing, comprise administering SRF or a composition described herein to a subject in need thereof, wherein the SRF has no effect on a cancer that the subject has.

[0060]

[0094] BPH treatment procedures have demonstrated varying levels of efficacy and are often accompanied by undesirable or adverse effects. For example, TURP provides improved efficacy and improved urinary flow rate and symptom score (IPSS), but is invasive and associated with significant side effects, including incontinence, urgency, dysuria, acute urinary retention, stricture, ejaculatory dysfunction, and sexual dysfunction. Steam therapy and PUL have demonstrated low side effects of sexual dysfunction, but are limited to use in small BPH prostates less than 80 ml, and have shown lower efficacy and higher retreatment rates in non-responders compared to TURP. Furthermore, these procedures are invasive, requiring transurethral access with large rigid delivery devices of 20 Fr (French size catheter) or more, and catheter placement due to excessive prostate injury and swelling during healing after treatment.

[0061]

[0095] Minimally invasive targeted drug delivery approaches to the prostatic region have been attempted by transurethral, ​​transrectal or transperineal routes, such as single-dose pore-forming proteins and peptides in saline formulations, but randomized clinical trials have demonstrated limited efficacy compared to saline placebo. Indian J Urol. 2008 Jul-Sep; 24(3): 329-335. doi: 10.4103 / 0970-1591.42613, PMCID: PMC2684358, PMID: 19468462; Injection therapy for prostatic disease: A renaissance concept. Arash M. Saemi, Jeffrey B. Folsom, and Mark K. Plante. In addition, alcohol, Botox (onabotulinumtoxinA) or medications injected into the prostate have not shown efficacy. A single injection of alcohol is highly cauterizing and does not allow for adequate control of the delivery area. Drug therapy injections into the prostate have also not shown efficacy, as they are not effective when given in a single dose. Other attempts to treat the prostate using similar drugs and / or peptide drugs have been used. Even if injected, these injections will not provide a long-lasting effective response in the injected target tissue, as they do not contain a sustained release formulation of the drug.

[0062]

[0096] While the aforementioned methods may demonstrate efficacy in reducing BPH, they require either more invasive procedures (compared to localized treatments using the delivery devices and methods disclosed immediately herein), more frequent treatments due to diffusion, or more generalized BPH treatments that increase the likelihood of adverse effects due to the relatively high dosages of drug required to treat the area (i.e., at least 2-3 times the dose of drug compared to the drug dosage per unit volume of SRF) with the attendant consideration of leakage or diffusion of the drug to other areas. This often results in a larger total volume of SRF relative to the affected area than would be required if the devices and methods disclosed herein were used. Adverse effects may include reduced urinary or sexual function. It is desirable to have an effective treatment that targets only the target tissue and not others (e.g., avoiding the bladder, urethra, and nerves surrounding the prostate) and to perform the procedure in a minimally invasive manner for patient acceptance.

[0063]

[0097] With these objectives in mind, the inventors have sought to develop a formulation and method that can be delivered using localized prostatic needle injection and overcome the aforementioned shortcomings of existing BPH treatment procedures. The formulation developed is an SRF, which is described in more detail below, followed by a description of several embodiments of the SRF. An embodiment of a device that involves the use of a needle syringe and a method for delivering the SRF using the device is also described.

[0064]

[0098] SRF for the treatment of BPH according to the present disclosure is preferably delivered to the target tissue transurethrally (i.e., via the patient's urethra), transrectally, or transperineally using a needled syringe having a relatively long and thin needle (e.g., a needle 15 cm to 20 cm long and a needle tube of 0.02 cm to 0.12 cm, or a needle 35 cm to 45 cm long and a needle tube of 0.02 cm to 0.04 cm). In some embodiments, a 23G needle is used. In some embodiments, the needle has a slenderness ratio defined as the needle length divided by the tube diameter. In some embodiments, including any of the foregoing, The slenderness ratio is between 200 and 400, or more preferably between 250 and 340 for a transrectal approach or greater than 850 for a transurethral approach. In some embodiments, including any of the above, the slenderness ratio is less than 2100 for a transrectal or transurethral approach. In some embodiments, including any of the above, the slenderness ratio is between 200 and 400. In some other embodiments, including any of the above, the slenderness ratio is between 200 and 300. In some embodiments, including any of the above, the slenderness ratio is between 300 and 400. In some embodiments, including any of the above, In some embodiments, including any of the above, the slenderness ratio is 250 to 350. In some embodiments, including any of the above, the slenderness ratio is 250 to 340. In some embodiments, including any of the above, the slenderness ratio is 250 to 330. In some embodiments, including any of the above, the slenderness ratio is 250 to 320. In some embodiments, including any of the above, the slenderness ratio is 250 to 310. In some embodiments, including any of the above, the slenderness ratio is 250 to 300. In some embodiments, including any of the above, the slenderness ratio is 250 to 290. In some embodiments, including any of the foregoing, the slenderness ratio is 250 to 280. In some embodiments, including any of the foregoing, the slenderness ratio is 250 to 270. In some embodiments, including any of the foregoing, the slenderness ratio is 250 to 260. In some embodiments, including any of the foregoing, the slenderness ratio is 260 to 350. In some embodiments, including any of the foregoing, the slenderness ratio is 270 to 350. In some embodiments, including any of the foregoing, the slenderness ratio is 280 to 350. In some embodiments, including any of the foregoing, the slenderness ratio is 290 to 350.In some embodiments, including any of the above, the slenderness ratio is 300 to 350. In some embodiments, including any of the above, the slenderness ratio is 310 to 350. In some embodiments, including any of the above, the slenderness ratio is 320 to 350. In some embodiments, including any of the above, the slenderness ratio is 330 to 350. In some embodiments, including any of the above, the slenderness ratio is 340 to 350. In some embodiments, including any of the above, the slenderness ratio is 260 to 340. In some embodiments, including any of the above, the slenderness ratio is 270 to 340. In some embodiments, including any of the above, the slenderness ratio is 280 to 340. In some embodiments, including any of the above, the slenderness ratio is 290 to 340. In some embodiments, including any of the above, the slenderness ratio is 300 to 340. In some embodiments, including any of the above, the slenderness ratio is 310 to 340. In some embodiments, including any of the foregoing, the thinness ratio is between 320 and 340. In some embodiments, including any of the foregoing, the thinness ratio is between 330 and 340. In some embodiments, including any of the foregoing, the thinness ratio is between 340 and 340. First, the fluid properties and injectate volume requirements of compositions using this type of needle were examined to determine if there were any limitations, special considerations, or modifications to the SRF (and / or delivery device) were required to deliver this injectate to the prostate.

[0065]

[0099] In certain embodiments, different needles will be used for different modes of administration. For example, in one embodiment, the mode of administration is transurethral and the needle length is 35-70 cm. For example, in one embodiment, the mode of administration is transperineal and the needle length is 10-20 cm. For example, in one embodiment, the mode of administration is transrectal and the needle length is 10-20 cm.

[0066] [000100] In some embodiments, when the mode of administration is perineal or rectal, the KIR is in the range substantially as shown in Figures 3A and 3B.

[0067] [000101] In some embodiments, when the mode of administration is transurethral, ​​the KIR is in the range substantially as shown in Figures 14A and 14B.

[0068] [000102] In some embodiments, when the mode of administration is rectal or perineal, the KIR ranges from 2 to 1300. In some embodiments, the needle length is from 10 cm to 20 cm. In some embodiments, the needle length is from 15 cm to 20 cm.

[0069] [000103] In some embodiments, when the mode of administration is transurethral, ​​the KIR ranges from 16 to 1200. In some embodiments, the needle length is from 35 cm to 70 cm.

[0070] [000104] The question posed by the inventors of the present disclosure was whether SRF could be delivered to the prostate in a consistent and reproducible manner that ensured that the total volume for each prostate size was substantially reached but not exceeded by the administering medical practitioner without adverse indicators (e.g., infection, post-treatment pain or discomfort, drug diffusion to nearby areas such as the urethra or bladder) to achieve the desired outcome (reduction in prostate volume over a period of time with a planned sustained release of drug). After extensive bench testing and evaluation of several trials of both delivery devices and candidate SRF formulations, the inventors found a needled syringe suitable for delivering SRF in the manner they desired.

[0071] [000105] The prostate treatment according to the present disclosure can be described as a prostate treatment having three distinct features.

[0072] [000106] 1. Minimal uncontrolled drug diffusion: Sufficient solidification or gelation of the SRF is achieved in a relatively short period of time upon contact with the prostate, so that the SRF remains in the target tissue when the needle is removed, thus resulting in little or no drug diffusion that could affect unintended adjacent tissues such as the urethra or bladder (e.g., as demonstrated by little or no drug diffusion outside of the prostate for the canine model studied, see Table 8).

[0073] [000107] 2. Sustained release and efficacy: Allows for a programmed release of drug from the SRF over time (see, e.g., FIG. 3C, Tables 4A and 4B). The SRF allows for sustained release of drug to treat target tissues over time, delivered in a total volume sufficient to achieve effective results in reducing prostate size.

[0074] [000108] 3. Small unit volume: Delivery of the total volume of the composition to the prostate as one or more unit volumes (i.e., "unit volumes" as defined herein) using a needled syringe. This mode of delivery avoids causing additional acute urethral compression that may cause additional discomfort to the patient immediately or shortly after the procedure, or avoids excessive swelling due to fluid uptake from surrounding tissues. In addition, the small unit volume of the composition avoids compression at the injection site, which can counteract and reduce the flow of the composition into surrounding tissues and organs and / or backflow of the composition through the delivery device or needle path after the needle is removed, and / or inhibit the composition from being removed from the target tissue due to pressure buildup. It may be desirable to inject unit volumes smaller than the total volume administered into several separate nearby locations to achieve a target clinical outcome, as this can optimize the diffusion of the drug compared to the diffusion from a large volume injected into one location.

[0075] [000109] We now discuss the factors influencing and the manner in which we have arrived at SRF formulations and compositions that enable prostate treatment with these characteristics. We later provide more specific examples of SRF embodiments.

[0076] [000110] Drug to polymer ratio. Drug to polymer ratio as well as drug to solvent ratio of SRF formulations were investigated. Too low drug to polymer ratio is not attractive. Too low drug dosage results in too low local drug concentration. Too high drug to polymer ratio results in too rapid drug release from SRF, limiting long-term local drug release and also leading to drug exposure of surrounding tissues and / or the whole body.

[0077] [000111] Polymer-to-solvent ratio and polymer molecular weight. Polymer-to-solvent ratios and polymer molecular weights relevant to SRF formulations were investigated. A polymer-to-solvent ratio that is too low is unattractive. If the polymer concentration and / or molecular weight is too low, the result is slow gelation and too fast drug release from the SRF, limiting long-term local drug release and also resulting in drug exposure to surrounding tissues and / or the whole body. As discussed in more detail below, the desire to achieve high gelation rates was balanced with the need to be deliverable using needles characterized by high slenderness ratios. A polymer-to-solvent ratio and molecular weight that is too high results in a composition with high viscosity that needs to be delivered using needles characterized by low slenderness ratios of relatively large volumes. However, such polymer-to-solvent ratios and molecular weights can pose significant challenges to deliver a unit volumetric dose using needles characterized by high slenderness ratios, in addition to the challenge of determining whether the selected polymer-to-solvent ratio and molecular weight will result in the desired gelation rate and not also result in too slow drug release. It was this kind of compromise or balance that led us to identify the optimal combination of needles and compositions represented by KIR.

[0078] [000112] It should be noted that the above ratios and polymer molecular weights (examples are provided below) are easily determined for the clinical uses contemplated herein. Rather, it took a long period of research and discovery to arrive at the desired local efficacy and efficacy specifically tailored to meet all three characteristics of BPH treatment.

[0079] [000113] For example, it is desirable to provide a planned sustained release of 14 days or 1 month to 12 months for substantially all drugs that will be dispersed from the carrier. This requires the selection of drug carriers (polymer compositions) and / or modification of morphology and mechanical properties, polymer / drug ratio, and control of the physical shape / dimensions (volume) of the SRF and / or composition delivered to the target tissue. Other factors that affect the release rate include: [000114] · In vivo polymer swelling (controlled by polymer architecture, e.g., monomer selection, monomer ratio, molecular weight, end groups and porosity / morphology). [000115] Porosity / morphology (e.g., controlled by polymer structure and concentration, polymer / solvent ratio and miscibility and polymer / drug ratio). For example, if there is less drug than polymer, the drug can be entrapped longer. [000116] How fast the material gels and whether the SRF is above or below the wet glass transition temperature - the transition from liquid to solid with a water soluble or insoluble solvent (faster gelation leads to faster initial release / burst). The gelation rate depends on the polymer structure, molecular weight and concentration, polymer / solvent ratio and miscibility. [000117] Polymer degradation (controlled by polymer structure, e.g. monomer selection, monomer ratio, molecular weight, end groups and porosity / morphology). [000118] · Drug / polymer miscibility and polarity of the solvent, and [000119] · Molecular weight and lipophilicity of the drug.

[0080] [Table 4]

[0081] [Table 5]

[0082] [Table 6]

[0083] [Table 7]

[0084] [Table 8]

[0085] [Table 9]

[0086] [Table 10]

[0087] [000120] The SRF polymer concentration and molecular weight (MW) will affect the viscosity term in the KIR. If the polymer concentration and molecular weight values ​​are outside the claimed range, the KIR may not function. For example, at high viscosity, the KIR value will be outside the acceptable range if the SRF does not function, e.g., because the viscosity is too high. Table 2 shows compositions with KIR values ​​that are useful for treating BPH transurethrally, transperineally, or transrectally. Compositions with KIR values ​​that are not useful for treating BPH include, but are not limited to: 5% drug, 60% polymer, 35% NMP 7% drug, 65% polymer, 28% NMP 10% drug, 60% polymer, 30% NMP 12% drug, 60% polymer, 28% NMP The SRF or composition may include

[0088] [000121] Certain compositions having greater than 55% by weight bioabsorbable copolymer or less than 25% by weight bioabsorbable copolymer may have KIR values ​​that are not useful for treating BPH.

[0089] [000122] In some embodiments, including any of the above, the composition may include a bioabsorbable polymer in a concentration of 10-55%, 15-50% by weight, and a drug in a concentration of 1-20% by weight, or 1-5% by weight. In certain embodiments, the composition also includes a solvent, which comprises the remainder of the composition. In some embodiments, the solvent represents 20-60% by weight of the composition. The weight percent of the formulated polymer drug and solvent totals 100% by weight. In some examples, the solvent is the majority species, and the bioabsorbable polymer and drug are dissolved in the solvent. In some embodiments, including any of the above, the solvent is a water-soluble solvent. In some embodiments, including any of the above, the solvent is a water-soluble solvent capable of dissolving the drug and the bioabsorbable polymer. In certain embodiments, the drug and bioabsorbable polymer are present in the solvent above their saturation points. In some of these embodiments, the drug and bioabsorbable polymer may be present as a suspension in the solvent.

[0090] [000123] Number of injections / total injection volume. In the first preclinical dog study, the composition was delivered to the prostate as a single relatively large volume by needle injection, but some backflow was observed through the needle. This approach resulted in the injection fluid diffusing from the target tissue, which is undesirable for reasons previously discussed. In response to this, in the second preclinical dog study (below), the inventors instead tried a low injection volume of the composition, minimizing it to 10-200 microliters per injection with 1-10 injections over each side of the prostate, reducing prostatic tissue compression on the urethra and thereby reducing any possibility of the therapeutic injection fluid backflowing through the delivery device and / or being lost from the target tissue. Further injection volume ranges of 50-100 microliters per injection with 1-5 injections over each side of the prostate were studied. The small unit volume injection (herein 0.05ml-0.2ml) is designed to minimize swelling and enlargement of the prostate.

[0091] [000124] Taking a distributed unit volume approach (third feature) also provided unexpected and effective benefits. A second preclinical study discussed below achieved a greater than 30% reduction in prostate size in a dog model. Of note, a higher volume of drug (based on prostate weight) was used in the first study compared to the total volume of drug in the second study. SRF also distributed unit volumes throughout the prostate in the second study, but the total volume of drug (based on prostate weight) in the second study was less than that used in the first study. This indicates that using small unit volumes distributed throughout the prostate is a more effective way to reduce prostate size than injecting a relatively high unit volume at one location, which is the typical approach taken by other BPH practitioners. This approach of distributing unit volume compositions also demonstrated controlled drug diffusion from the treatment area (i.e., minimal drug lost to surrounding tissues and circulation) (see Figures 7 and 8 and accompanying text summarizing the results).

[0092] [000125] In addition to searching for a composition that could meet the first two of our three desired characteristics (minimal uncontrolled drug diffusion, sustained release rate and efficacy), it was also necessary to determine what type of needle syringe could effectively deliver the total volume of the composition in one or more small unit volumes in a reproducible manner without having to compromise the efficacy of the SRF after injection. Thus, an investigation was also required into whether delivery of the composition to a patient was possible.

[0093] [000126] A long, thin needle (e.g., 20 cm, 0.06 cm canal diameter for a transrectal approach or 45 cm, 0.03 cm canal diameter for a transurethral approach) is desirable as a mode of delivery of the composition to the target tissue. This is a less invasive approach to reach the target tissue compared to other BPH treatment methods and is likely to be generally accepted by patients. However, the use of this type of delivery device has presented special challenges that may need to be overcome before the three characteristics of prostate treatment can be met when using this delivery device. In one embodiment, the needle is a transurethral needle, which is discussed in more detail below.

[0094] [000127] The delivery of SRF, including compositions characterized by a relatively high viscosity for dispensing from a needle, is a challenge when using long, thin needles with high slenderness ratios and dispensing small volumes due to fluid shear stresses that are influenced by the internal surface area of ​​the needle. The resistance to flow by a composition forced through a long, thin needle is more severe the more viscous the liquid, and care must be taken. Thus, for relatively high viscosity fluids that are more susceptible to wall-fluid shear stresses compared to less viscous fluids, the inaccuracy of the volume dispensed from the needle is more pronounced, and this varies proportionally with the slenderness ratio of the needle (defined as the needle length L divided by the tube diameter D). Thus, the inaccuracy of the delivered volume varies proportionally with L / D and directly proportional to the viscosity of the composition, so the smaller the desired volume dispensed and the more viscous the composition, the greater the inaccuracy is expected to be. Recognizing this challenge of accurately dispensing viscous compositions for prostate treatment, the inventors had to identify both an embodiment of the composition that meets the first two of the KIR requirements (i.e., minimal uncontrolled drug diffusion, sustained release rate and efficacy requirements) and an embodiment of one or more needle syringes that would allow a medical practitioner to meet the third KIR requirement themselves at the time of use (a small unit volume is distributed throughout the prostate until the total volume of the composition is reached) without unduly compromising the efficacy of the SRF upon introduction to the prostate.

[0095] [000128] On the one hand, bench tests have shown promising SRF formulations, but the corresponding compositions could not be reliably delivered using long thin needles. On the other hand, reducing the viscosity of the composition to facilitate dispensing the composition in the desired unit volume may result in either the desired drug release profile and / or gelation rate not being achieved, or there may be unacceptable levels of drug diffusion to adjacent tissues or organs. Either the drug elutes from the SRF too quickly, the polymer gel is not thick enough or entangled enough, or the gelation rate is not fast enough to prevent the injection fluid from backing up into the needle and being withdrawn with the needle after the injection is completed, leaving the target tissue. Examples of compositions that did not meet the KIR for these reasons are mentioned above.

[0096] [000129] Thus, a careful balance of the components in the formulation was finally achieved - polymer structure, molecular weight, concentration, drug ratio, and dose:solvent ratio (e.g., as shown in Figure 1, Table 1) that would result in the desired SRF with controlled release. However, it was then discovered that the desired composition could not be reliably delivered in several unit volumes using the long needles required for treatment of the prostate. It was not uncommon to abandon a more preferred, more viscous formulation for a less viscous formulation so that the correct unit volume of the composition with the desired drug release could be repeatedly delivered using a long, thin needle.

[0097] [000130] SRF1, used in the second preclinical study discussed below, is an example of an SRF that meets the first two KIR requirements (minimal uncontrolled drug diffusion, sustained release rate and efficacy) and has the ability to be delivered accurately and repeatedly in a small unit volume, thus meeting the third KIR requirement. SRF1 is only one of many examples disclosed herein that meet the three KIR requirements after undergoing the validation, testing and testing described above (see Figures 14A, 14B and Tables 3A, 3B for other examples of SRFs that meet the KIR requirements).

[0098] [000131] Two unit volumes (0.05ml and 0.10ml) were examined in preclinical studies. Both injection volumes showed significant reduction in prostate size, as reported in Tables 5 and 6. In addition, as shown in Figures 7 and 8, the systemic drug concentration present in the blood was very low, indicating that the drug was contained in the target tissue. Thus, preclinical studies indicate that the SRF injection solution of the present disclosure (1) can reduce prostate volume over a 30- and 90-day period, and (2) can confine substantially all of the active drug exclusively to the target tissue. Furthermore, the study unexpectedly indicated a significant ratio of at least 10,000 of prostate 30- and 90-day drug concentration to peak plasma drug concentration. The unit volume of SRF injection solution required for efficacy was also demonstrated. SRF (SRF1) injection volumes were kept to a minimum, 10-200 microliters per injection for 1-10 injections over each side of the prostate or 50-100 microliters per injection for 1-5 injections over each side of the prostate.

[0099] [000132] For compositions comprising SRF, the drug and polymer concentrations in the composition may range from 0.1% to 60% by weight or less. The injection volume of the SRF may range from 25 microliters to 5 mL or less per injection. The total dosage of drug provided in the SRF may range from 50 ug to 200 mg or less. For example, the composition may include 300 μg of sirolimus dissolved in NMP with 3,000 μg ("μg" - microgram) poly(D,L-lactide-co-glycolide) (85:15) at about 50% solids by weight concentration.

[0100] [000133] In some embodiments, including any of the above, the composition comprises 300 μg of paclitaxel dissolved in NMP with 3,000 μg ("μg"-micrograms) poly(D,L-lactide-co-glycolide) (85:15) at about 50% solids by weight. In some embodiments, including any of the above, the composition comprises 500 μg of sirolimus dissolved in NMP with 2,900 μg ("μg"-micrograms) poly(D,L-lactide-co-glycolide) (85:15) at about 50% solids by weight. In some embodiments, including any of the above, the composition comprises 500 μg of paclitaxel dissolved in NMP with 2,900 μg ("μg"-micrograms) poly(D,L-lactide-co-glycolide) (85:15) at about 50% solids by weight. In some embodiments, including any of the above, the composition comprises 300 μg of sirolimus dissolved in NMP with 3,000 μg ("μg"-micrograms) poly(D,L-lactide-co-glycolide) (50:50) at about 50% solids by weight. In some embodiments, including any of the above, the composition comprises 300 μg of paclitaxel dissolved in NMP with 3,000 μg ("μg"-micrograms) poly(D,L-lactide-co-glycolide) (50:50) at about 50% solids by weight. In some embodiments, including any of the above, the composition comprises 500 μg of sirolimus dissolved in NMP with 2,900 μg ("μg"-micrograms) poly(D,L-lactide-co-glycolide) (50:50) at about 50% solids by weight. In some embodiments, including any of the foregoing, the composition comprises 500 μg of paclitaxel dissolved in NMP with 2,900 μg ("μg" - microgram) poly(D,L-lactide-co-glycolide) (50:50) at about a 50% solids weight concentration. As used herein, the term solvent refers to a solvent that has the ability to completely or uniformly dissolve a substance added thereto.

[0101] [000134] Further examples of compositions that meet the first two characteristics (effectiveness and sustained release and low diffusion) are provided in the examples below.

[0102] [000135] Accurate delivery of small volumes of SRF for therapeutic retention with precise drug dosages can be achieved using needled syringes of 250-500 or 250-2500 microliters or less. The delivery device can have an airtight glass, cyclic olefin polymer, or polypropylene syringe body with a Teflon, polyethylene, cyclic olefin polymer, or polypropylene plunger connected to a 20 cm long 20 g needle with a 0.06 cm tube diameter. As used herein, 20 g is 20 gauge. The volume of the delivery syringe must be large enough to accommodate the dead volume in the needle of about 150 microliters. Thus, a 250 microliter airtight syringe can be utilized to deliver one to two 50 microliter unit volumes of the composition. For multiple injections from the same delivery device, gas-tight syringe volumes of 250 to 1,000 microliters can be used, which allows sufficient volume to eliminate needle dead volume and deliver at least eight 100 microliter unit volume injections to each lobe of the prostate.

[0103] [000136] Alternatively, 1,000 microliter or 1 milliliter cyclic olefin polymer and / or polypropylene syringes may be utilized. For example, the SRF may be provided as a kit containing one syringe with a female luer lock containing PLGA dissolved in NMP solvent and another with a male luer lock containing drug powder. The syringes are then directly connected and mixed back and forth multiple times (50 times) to completely dissolve the drug so that no drug particles remain. Fewer mixing times (10 times) may also be utilized so that the SRF produces a partially mixed partial solution where the remaining drug particles may provide extended drug release times in vivo due to the additional drug particle dissolution requirements in the SRF. After mixing, the SRF is loaded into a graduated syringe for delivery with a long thin needle.

[0104] [000137] Accurate delivery of small volumes of SRF for therapeutic retention with accurate drug dosage can also be achieved using a 2,000 microliter or 2 milliliter syringe. The delivery device can have an airtight glass, cyclic olefin polymer, or polypropylene syringe body with a Teflon, polyethylene, cyclic olefin polymer, or polypropylene plunger connected to a 45 cm long 23 g needle with a 0.03 cm tube diameter. The volume of the delivery syringe must be large enough to accommodate the dead volume in the needle of about 1.26 milliliters. Thus, a 1,500 microliter airtight syringe can be utilized to deliver one to two 50 microliter unit volumes of the composition. For multiple injections from the same delivery device, a 2,000 to 3,000 microliter airtight syringe volume can be used, allowing sufficient volume to eliminate the needle dead volume and deliver at least eight 100 microliter unit volume injections to each lobe of the prostate. Alternatively, 3,000 microliter or 3 milliliter cyclic olefin polymer and / or polypropylene syringes may be utilized.

[0105] [000138] For example, the SRF can be provided as a kit containing one syringe with a female luer lock containing PLGA dissolved in NMP solvent and another with a male luer lock containing drug powder. The syringes are then directly connected and mixed back and forth many times (50 times) to completely dissolve the drug so that no drug particles remain. Fewer mixing times (10 times) can also be used to create a partially mixed SRF so that remaining drug particles can provide extended drug release times in vivo due to the additional drug particle dissolution requirements in the SRF. After mixing, the SRF is loaded into a graduated syringe for delivery with a long thin needle. An exemplary embodiment is shown in Figures 11A and 11B.

[0106] [000139] Figures 11A and 11B show embodiments of a syringe that, in some embodiments, may be included in the kits disclosed herein.

[0107] [000140] For example, see FIG. 11A. FIG. 11A shows syringe A, which contains a solution of bioabsorbable polymer PLGA in NMP solvent. FIG. 11A also shows syringe B, which contains a drug powder. FIG. 11A shows syringe A and syringe B connected with a female luer lock on syringe A under the heading "Mixing." In the "Mixing" configuration, where the two syringes are connected with a luer lock, the solution of bioabsorbable polymer PLGA in NMP solvent can be mixed with the drug powder to form a second solution in which both the drug and the bioabsorbable polymer are dissolved. This second solution is shown at the bottom of FIG. 11A under the heading "Ready-to-inject product via rectal 20G x 20cm needle."

[0108] [000141] Figure 11B shows a syringe barrel with two chambers separated by a septum. One of the two chambers can contain a solution of the bioabsorbable polymer PLGA in NMP solvent. The other of the two chambers can contain a drug powder. Upon breaking or puncturing the separating septum, the contents of the two chambers can mix to form a second solution in which both the drug and the bioabsorbable polymer are dissolved. Figure 11B also shows a transurethral needle and needle cover.

[0109] [000142] See also Figure 12, which shows an embodiment of a kit disclosed herein. Figure 12 shows, among other things, a preformed sterile PETG tray with molded cavities for holding the kit components. For example, Figure 12 shows a desiccant cavity for holding a desiccant and / or oxygen absorber. Figure 12 shows a delivery tool and needle cavity for holding a delivery tool and needle. The delivery tool and needle cavity includes space for accommodating the finger loop of the delivery tool. Figure 12 shows the PETG tray as having a tray step and a tray opening.

[0110] [000143] Referring to FIG. 1, a typical needle syringe includes an applicator portion (plunger, barrel) and a hub portion that connects the needle to the interior chamber of the barrel to form a fluid-tight connection as fluid contained within the barrel passes through the needle tube.

[0111] 2A and 2B, side schematic views of needle syringes 20, 21 according to the present disclosure are shown. More specifically, the illustrated needle syringes are sized to hold a unit volume and dispense it through a long, thin needle tip 28a. Needle 28 has a length L n and pipe diameter D n (The length measurement L is measured from the upstream opening 28b that forms a liquid-tight connection between the outer cylinder and the needle 28 body to the end, i.e., the most downstream tip that first pierces the skin. n (The hub is shown in phantom to illustrate this.) The needle may be made of stainless steel.

[0112] [000145] The needle syringe of FIG. 2A is shown with exemplary graduations of 500 / 400 / 300 / 200 / 100 / 50 / 25 microliters for dispensing unit volumes of, for example, 0.05 ml (50 microliters). The barrel has a capacity of 1000 microliters. Barrel 24 has a length L b and outer cylinder inner diameter or tube diameter D b The prefilled syringe barrel (1000 microliters) has a needle length L of 20 cm. n2B may be attached to the needle, which may have a dead volume of 150-200 microliters. The syringe, which may need to be of the prefilled type, may also incorporate a stabilizing device 22c to guide the plunger head 22b toward the needle opening 28b. The composition containing the SRF (contained in the syringe barrel 24, in a volume of up to about 500 microliters) is expelled from the needle tip 28a by applying finger pressure to the plunger head 22a. In this example, the barrel may hold 500 microliters of the composition, for example up to seven 50 microliter unit volumes, allowing for a dead volume of 150 microliters. The needled syringe of FIG. 2B is in some respects the same as the syringe of FIG. 2A, except that it has a barrel capacity of 3000 microliters instead. It may also incorporate a stabilizing device 22c. In another example, a 3000 microliter capacity syringe has markings of 200Ul, 100Ul, and 50Ul to facilitate more accurate dispensing of small unit volumes of the composition.

[0113] [000146] The needle syringe of FIG. 2A may be provided with features or additional structures that enable the needle syringe to provide incremental dosages of the composition contained therein. According to one example, incremental dosages correspond to single unit volumes or incremental increments of percentages of a unit volume (e.g., half a unit volume, quarter a unit volume, etc.). According to one example, the additional structure may be a dose administration guide. The dose administration guide may be made of plastic or any other desired material and may be economically manufactured by injection molding or any other desired processing method. The dose administration guide is easily attachable and detachable to the needle syringe and may be adapted to various sizes of needle syringes.

[0114] [000147] Figure 13 shows an illustration of the prostate gland with the urethra running through its center. In Figure 13, a needle passes through a catheter 107 and exits its end at an angle to inject a unit volume of the composition at location 106. The end of the needle has a depth restrictor associated with it. As the needle travels through the urethra, it injects a unit volume v of the composition comprising SRF at locations 101, 102, 103, 104, 105, and 106 (the number of injection sites is based on the length of the transition zone urethral length (TZUL)). The needle has a retractable tip that pierces the tissue at locations 101, 102, 103, 104, 105, or 106 and delivers a unit volume to each of these locations. Delivery of the unit volume can be aided by using a dose guide attached to the syringe, such as the dose guide shown in Figure 16. The number of injection sites based on the TZUL is provided in Table IB. The number of injections, n, was found to be related to TZUL as n=TZUL / (11×v). Figure 13 illustrates n=6 deliveries of a composition comprising SRF at six different locations along the length of the urethra with length TZUL. Each oval represents the drug tissue exposure from a unit volume treatment.

[0115] [000148] FIG. 15 shows an embodiment of a dose administration guide 1502 prior to installation on a needled syringe. The dose administration guide 1502 may have four (or more) detents (1501) on the inner wall. Embodiments including more or fewer detents are contemplated herein. As described herein, the distance between the detents may correspond to a single unit volume or incremental percentages of a unit volume. The dose administration guide 1502 is open at the bottom so that when the dose administration guide 1502 engages the syringe plunger and barrel shown below the dose administration guide, the dose administration guide rests on the finger loop 1504. The plunger 1503 and barrel 1505 are also shown. In this embodiment, an operator can engage the bottom of the finger loop 1504 when a needled syringe is coupled with the dose administration guide 1502.

[0116] [000149] Figure 16 shows an embodiment in which the dose administration guide 1603 surrounds the finger loop 1606. Also shown is the plunger 1602 and barrel 1605 being pressed down by the thumb 1601. Position 1604 represents the position of the index finger and forefinger creating a force against the thumb 1601. In this embodiment, when the needled syringe is coupled with the dose administration guide 1603, the operator does not directly engage the bottom of the finger loop 1606. Instead, as shown in Figure 16, the operator engages the surface of the dose administration guide 1603. The finger loop is contained within. This arrangement may be preferred as it provides a more secure hold of the guide against the top part of the syringe when compared to the arrangement of Figure 17. When the finger 1604 is pressed into the guide (in response to the thumb pressing down on the plunger head), the guide is securely held in place on the syringe. Thus, as shown, there is less chance of the guide moving around as fingers 1604 press the guide sleeve against the syringe wings during use.

[0117] [000150] Figure 16 shows guide wings completely encircling the syringe wings or finger hooks. In an alternative embodiment, the syringe wings may extend partially outwardly from the guide wings. The partially encircling embodiment may be the same as shown (fingers 1604 pressing the guide into the syringe wings), except that the left and right outer ends of the syringe wings extend outwardly from openings provided in the left and right guide wings, respectively.

[0118] [000151] Figures 17 and 19-23 herein show other embodiments of the dosage administration guide.

[0119] [000152] Figure 17 shows an embodiment of a dose administration guide 1702 that sits on a finger loop 1703. The embodiment shown in Figure 17 is similar to the embodiment shown in Figure 15, except that it omits the wings that extend downwardly relative to the portion of the dose administration guide 1702 that sits on the finger loop 1703. Also shown is a plunger 1706 and barrel 1705 being depressed by thumb 1701. Position 1704 represents the position of the index finger and forefinger that creates a force against the thumb 1601.

[0120] [000153] Figure 18 shows an embodiment of a dose administration guide 1802 mounted above and below a finger loop 1803. In this embodiment, the finger loop 1803 extends through an opening provided in the body of the dose administration guide 1802. Also shown is a plunger 1806 and barrel 1805 being depressed by thumb 1801. Position 1804 represents the position of the index finger and forefinger creating a force against thumb 1801.

[0121] [000154] Figure 19 shows an embodiment of a dose administration guide similar to that of Figure 15, where an operator can directly engage the bottom of the finger loop when a needled syringe is coupled to the dose administration guide. As shown in Figure 19, the dose administration guide has a top portion 1901 that can enclose a plunger 1903 when the bottom portion 1902 is seated on the finger loop 1904. A barrel 1905 is also shown. An opening 1906 with a hinge 1907 is also shown. The opening 1906 separates the dose administration guide into a first half and a second half that are connected by the hinge 1907. The hinge 1907 (e.g., a living hinge) allows the first and second parts to move relative to each other in a clamshell type arrangement. This relative movement facilitates attachment of the dose administration guide to a needle syringe and also facilitates removal of the dose administration guide from the needle syringe. According to this embodiment, the first and second parts can move relative to each other about the hinge 1907, thereby creating an opening for receiving a needle syringe or removing it from the dose administration guide.

[0122] [000155] Figure 20 shows the embodiment of Figure 19 after the dose administration guide has received the needle syringe. As shown, the dose administration guide has a top portion 2002 that surrounds the plunger 2001 when the bottom portion 2003 is seated on the finger rest 2004. Also shown is the barrel 2005. Also shown is the barrel 1905. Also shown is the hinged opening 2006 (not numbered), which is directly behind the opening 2306. According to one embodiment, the needle syringe is primed before being received by the dose administration guide. In other words, the dead volume of the needle syringe is eliminated from the barrel 1905 before the dose administration guide receives the needle syringe. After the needle is primed, the syringe is enclosed within the dose administration guide, as shown in Figures 24 and 25. The dose administration guide thereby calibrates the plunger head position against the detents in the top portion of the guide so that the needled syringe dispenses a desired unit volume or incremental fractions of a unit volume as the plunger 2001 advances between the spaced detents. According to one embodiment, the dose administration guide is sized and configured such that when the needled syringe is primed and received in the dose administration guide, the plunger 2001 is located adjacent to the terminal end of the top portion 2002. In other embodiments, the dose administration guide is sized and configured such that when the needled syringe is primed and received in the dose administration guide, the plunger 2001 engages the terminal end of the top portion 2002. It will be appreciated that in general, the plunger head position will not be resting directly on the detents in the top portion of the guide when primed. In such cases, the medical practitioner will need to remove any additional composition until the head rests on or is close to the detents in the top portion. This will ensure that the desired unit volume may be dispensed when the plunger head has advanced past the top detent and rests between it and the next detent.

[0123] [000156] Figure 21 shows the embodiment of Figure 19 after a needled syringe has been received in the dose administration guide and the plunger has been depressed. As shown, the dose administration guide has a top portion 2101 that surrounds the plunger 2005 being depressed, and a bottom portion 2102 that sits on a finger rest 2103. Also shown is the barrel 2104. Also shown is the barrel 1905. Also shown is an opening 2106 with a hinge 2107. As shown in Figure 21, the plunger 2005 is depressed, causing it to move into the interior space of the top portion 2101.

[0124] [000157] Figure 22 shows the cross-sectional view of Figure 21 after the plunger has been further depressed. As shown, the dose delivery guide has a top portion 2201 that surrounds the plunger 2205 that has been depressed past the first detent, and a bottom portion 2202 that sits on the finger rest 2203. The barrel 2104 is also shown. In Figure 22, the detents are equally spaced from each other. According to one embodiment, the distance between one detent 2201(a) and an adjacent detent 2201(b) corresponds to a single unit volume of the needle syringe contained therein. In an alternative embodiment, the distance between adjacent detents 2201(a), 2201(b) corresponds to incremental fractions of the unit volume (e.g., half a unit volume, quarter a unit volume, etc.).

[0125] [000158] The detents 2201 are configured to engage the plunger 2205 as it is moved. This engagement resists further movement of the plunger 2205, thus facilitating administration of a unit volume or increments thereof. The user can overcome this resistance and move the plunger 2205 past one detent to engage another adjacent detent, thus administering another unit volume. The radial flexibility of the detents and barrel (in response to movement of the plunger) can be such as to facilitate convenient, easily detected tactile or audio feedback to the healthcare professional indicating that the plunger has moved between the detents. The relationship between the movement of the plunger head between the detents and the volume of the composition dispensed will depend on the inner diameter of the syringe used. Different sizes of dose guides can be provided and the corresponding volumes dispensed using different sized syringes can be identified. The relationship between the spacing, or distance, LDC, between detents 2201a and 2201b and the unit volume v and inner diameter d of the syringe is LDC=[4 / (πd 2 )]v. As the plunger head advances past the detents, the detents spaced apart by a vertical distance LDC (in the direction of plunger travel) relate to a unit volume v that can be dispensed using a syringe of diameter d.

[0126] [000159] The term "detent" may refer to any of the following surfaces formed on the inner wall of the upper portion: a rim extending at least partially around the inner wall, a lip or ridge (e.g., a continuous or discontinuous 90, 180, 270 or 60 degree section of a cylindrical wall), semicircular bumps spaced circumferentially at 20, 30, 45 or 60 degrees from one another. In each of these examples, the vertical spacing between the detents (i.e., the spacing in the direction of plunger movement) is scaled to the inner diameter of the syringe, as described further below, so that the syringe dispenses a unit volume as the plunger moves from one detent to another.

[0127] [000160] The detents provide some resistance to the plunger head, but desirably only as much as is necessary to provide tactile or audio feedback. If the resistance is too great, it will interfere with unit volume dispensing and ease of use. To ensure that the resistance is not too great, vertical slits or notches may be formed in the top portion to reduce the radial or circumferential stiffness of the top portion as a single cylinder. For example, with reference to FIG. 23, while each half of the clamshell top portion forms a cylinder, they may instead be two sections that extend upward from the guide wing portions, each forming a 90 degree section of the cylinder shown. These half cylinder sections may instead be formed by 360 degree sections, which should result in a softer top portion in response to plunger movement while still providing the desired tactile and audio feedback to the medical practitioner. As just described, rather than separate cylinder portions, the sections may correspond to vertical notches.

[0128] [000161] Figure 23 shows a variation of the embodiment shown in Figure 20. As shown, the dose administration guide has an upper portion 2302 that surrounds the plunger 2301 when the bottom portion 2303 is seated on the finger rest 2304. A barrel 2305 is also shown. A hinged (not numbered) opening 2306 is also shown, with the hinge being directly behind the opening 2306. In Figure 23, the opening defined by the upper portion 2302 has a substantially rounded rectangular configuration, in contrast to the arrangement shown in Figure 20, where the opening defined by the upper portion 2302 has a substantially circular configuration. Additionally, in Figure 23, the detents are provided only on a portion of the inner wall (i.e., discontinuous), in contrast to the configuration shown in Figure 20, where the detents extend continuously around the inner wall. In alternative embodiments, the opening defined by the upper portion may have any desired configuration and may be selected to mimic the shape of a plunger head. In other alternative embodiments, the detents may extend around any percentage of the inner wall and may be provided in a continuous or discontinuous manner as previously described.

[0129] [000162] Figure 24 shows an embodiment of a dose administration guide 2402 having a living hinge 2401 such that the dose administration guide can be opened at location 2403 like a clamshell, as described above. The hinge 2401 allows the dose administration guide 2402 to engage with a plunger 2404 and finger rest 2405. Desirably, it may be preferred that the front of the guide wings shown open instead so that the syringe wings can more easily fit within the dose guide when the clamshell is closed around them. A barrel 2405 is also shown. As with the embodiment shown in Figure 19, the hinge 2401 allows portions of the dose administration guide 2402 to move relative to one another, facilitating attachment and removal of the dose administration guide 2402 from a needle syringe.

[0130] [000163] Figure 25 illustrates the embodiment of the dose administration guide of Figure 24 after the two portions of the dose administration guide have been moved to enclose a needled syringe. As shown, the dose administration guide 2503 has a closed hinge 2502 and the dose administration guide is closed in position 2505. The plunger 2501 and barrel 2504 are also shown.

[0131] [000164] Figure 26 illustrates how the embodiment of the dose administration guide of Figure 24 may be manipulated to facilitate attachment or removal of the dose administration guide. As shown, the dose administration guide 2602 has a hinge 2601 that allows the dose administration guide to open like a clamshell at location 2603. The arrows show how the hinge 2601 allows the portions of the dose administration guide 2602 to move. Specifically, the arrows show how the portions of the dose administration guide 2602 may move relative to one another to create an opening for receiving or removing a needle syringe from the dose administration guide.

[0132] 27 shows another embodiment of a dose administration guide 2703 in use with a needle syringe. The needle syringe includes a plunger 2701, a finger loop 2702, and a barrel 2704, which extends from the bottom of the dose administration guide 2703. The dose administration guide includes an aperture 2705 (i.e., a notched opening). When a needle syringe is received in the dose administration guide 2703, the finger loop 2702 extends through the aperture 2705. The position of the finger loop 2702 within the aperture 2705 prevents relative movement between the dose administration guide 2703 and the needle syringe.

[0133] [000166] Figure 28 shows dose administration guide 2802 with plunger 2801 shown in phantom. Also shown is cutout portion 2804 between 2803 and 2805. This cutout portion 2804 allows the finger loop of the syringe barrel to extend outwardly through the dose administration guide when the dose administration guide is attached to the syringe and its finger loop. This arrangement is similar to the dose administration guide embodiment shown in Figure 27 and prevents relative movement between dose administration guide 2802 and the needled syringe housed therein. Also shown is a clamshell opening 2806. When 2806 is opened, the syringe barrel and finger loop can be engaged with the dose administration guide and the dose administration guide can be closed around the syringe barrel at position 2806. This arrangement is similar to the embodiment shown in FIG. 19 and allows portions of the dose administration guide to be moved relative to one another, thereby creating an opening for accepting or removing a needle syringe from the dose administration guide 2802.

[0134] [000167] Figure 29 shows a barrel 2901 having two chambers - 2902 and 2903. One chamber - 2902 - may contain a drug powder. The other chamber - 2903 - may contain a solution of a water soluble solvent and a bioabsorbable polymer. Separating the two chambers is a septum 2908. Depressing plunger 2904 as shown at 2909 ruptures septum 2908, allowing the solution in chamber 2907 to mix with the drug powder in chamber 2906.

[0135] [000168] Figure 30 is a variation of the dose administration guide shown in Figure 16. As shown, dose administration guide 3001 surrounds finger hook 3002. Plungers 3004 and 3003 are also shown. In Figure 30, the detents have a triangular configuration compared to the semicircular configuration of the detents shown in Figure 16. In alternative embodiments, the detents may have any desired shape. Regardless of the shape of the detents, the spacing between adjacent detents may correspond to a single unit volume or incremental percentages of a unit volume, as discussed above. Additionally, regardless of the shape of the detents, the detents may be configured to resist movement of the plunger to facilitate administration of a unit volume, and may be configured to provide tactile or audio feedback to inform the user that the plunger has moved between the detents, as discussed above.

[0136] [000169] Although separate embodiments have been shown and described above with respect to the dose administration guide, it is understood that the disclosed features are not limited to only each of the described embodiments. Instead, various features may be combined as desired in a dose administration guide. For example, the detent shape of FIG. 30 may be used with the cutout portion arrangement shown in FIG. 28.

[0137] [000170] In some cases, an SRF delivery dose guide may be included with the needle syringe to aid in accurate dispensing of unit volumes. This dose guide is attached to the proximal syringe plunger body 22 exposed on the outside of the needle. When attached, the dose guide only allows translation of the syringe plunger to deliver an accurate unit volume of, for example, 0.05 mL (50 microliters). The distance traveled is calibrated based on the inside diameter of the barrel. Alternatively, there will be a lookup table or chart (e.g., provided with the instructions) accompanying the dose guide that shows the volume dispensed using the guide for different size syringes. For example, a 1 mL syringe barrel has an inside diameter of 5 millimeters. To dispense a unit volume of 0.05 mL, the dose guide will have a distance LDC of 2.55 mm for each unit volume. The dose guide, while attached to the plunger, can be inserted flush with the proximal body of the syringe barrel. After injection of each unit volume, depending on the unit volume size and / or total volume required, it can be removed and reloaded for the next unit volume, or the total volume can be dispensed without the need to remove the dose guide.

[0138] [000171] The dose guide may be used as follows: First, the dead volume is removed from the needle. Then, the dose guide is secured to the syringe by wrapping the barrel (hinged, such as a living hinge, FIG. 24) and securing the opposite end with a clip. Additional composition is then expelled until the plunger head should rest on a detent or it rests on the top detent. Then, as the plunger head advances through one or more detents, a unit volume is dispensed from the needle tip according to the number of detents the plunger head has passed.

[0139] [000172] The syringes in Figures 2A and 2B are sized to allow the medical practitioner to accurately dispense unit volumes (e.g., 0.05 ml or 0.1 ml) to individual / discrete locations within the target tissue. The syringes may be pre-filled to hold a total volume sufficient to fully treat the patient (e.g., 4 unit volumes of injections at different locations of the prostate tissue). In some embodiments, the applicator portion may include a mixing element to combine the drug and drug carrier, such as a syringe chamber to keep the SRF drug and drug carrier separate and separate from each other, a static mixing Y-shaped adapter fed into a long thin / long or high thin / distance (L / D) ratio needle 28, etc. Alternatively, the drug, drug carrier and solvent may be mixed using two syringes connected by an adapter, which are pushed back and forth to mix the drug, drug carrier and polymer. Alternatively, the two syringes may be directly connected and mixed using mated female and male Luer fittings at the tip of each syringe. The applicator portion may have indicia indicating needle insertion length or composition volume measurement.

[0140] [000173] The syringe control required to dispense a unit volume of a composition comprising SRF from barrel 22 through needle tip 28 (FIGS. 2A-2B) or in the case of a transurethral needle barrel (FIG. 2C) is a challenge either when a long thin needle is used or when individual injections do not exceed a unit volume amount. Both of these issues are present in the present disclosure as explained above. The range of SRF formulations found to be suitable for achieving the therapeutic goals and deliverable in unit volume amounts in the composition is described below. b , D b , L n and D. n It has been found that the following values ​​of the needle length L can be applied: n The needle length L may be 35 cm to 70 cm, more preferably 25 cm to 45 cm. n The needle length L can be 35cm to 70cm for transurethral use. n can be 10cm to 20cm for the transrectal approach. nThe slenderness ratio of the needle (L n / D n ) may be 600 to 2100 or 600 to 1350.

[0141] [000174] In some embodiments, the slenderness ratio (L b / D b The barrel slenderness ratio (which may be 5 and 50 or 10 to 30) is an important factor to consider. Barrel slenderness ratios in these ranges have been found to facilitate more accurate dispensing of small unit volumes of the composition.

[0142] [000175] In some embodiments, the slenderness ratio (L b / D b The barrel slenderness ratio (which may be 5 and 50 or 10 to 30) is an important factor to consider. Barrel slenderness ratios in these ranges have been found to facilitate more accurate dispensing of small unit volumes of the composition.

[0143] [000176] Desired injection volume control and precision Custom elongated glass body gas-tight delivery syringes can be utilized, which provide greater accuracy with volume scale markings on the syringe. Instead of volume scale markings, these delivery device markings can also directly show the user the calibrated dead volume of the needle and the drug delivery drug dosage in mg for every injection.

[0144] [000177] Pre-filled syringes preferably contain the composition as a premixed solution for each injection, thus delivering the predominantly amorphous drug already dissolved in the polymer carrier, resulting in a faster drug release and enhanced onset of efficacy, followed by a slower sustained release of the predominantly crystalline drug.

[0145] [000178] In some embodiments, the SRF may be provided with the polymer injectate and drug powder in separate delivery syringes (discussed above) that the user may mix and place into a syringe barrel at or near the time of treatment. This may allow crystalline or semi-crystalline drug directly into the injectate, which may increase drug residence time and exposure time and reduce systemic drug loss, given that some drug may remain in crystalline or semi-crystalline form after preparation by the user.

[0146] [000179] In some embodiments, the SRF generating composition can be mixed with an ultrasound microbubble contrast agent to further enhance visibility of the injectate under transrectal ultrasound guidance, allowing precise location control of the injection within the prostatic capsule within each lobe of the prostate, further minimizing potential drug loss into the urethra, surrounding organs, and systemic circulation.

[0147] [000180] In the process of testing different formulations for effective SRF, the inventors have tried to find parameters or relationships that can be used to remove formulations from consideration as unsuitable because they cannot be reliably delivered.This is necessary because the repeated work of designing a certain formulation and then evaluating whether it can meet all three characteristics of prostate treatment in combination with delivery vehicle is a long and time-consuming work.When trying to find a formulation that finally meets these requirements, they found that it cannot be reliably delivered the required small volume using a long and thin needle, making this work much more laborious.

[0148] [000181] Furthermore, it should be emphasized that the purpose of adapting the composition to a needle syringe was not to unnecessarily compromise the effectiveness of the SRF to ensure its deliverability. The inventors sought an advantageous solution, not just a way to save time or reduce the amount of work required to adapt an acceptable SRF to a delivery device. Unexpectedly, it was discovered that there is a range of values ​​that gives information on whether a needle of length L and lumen diameter D can be used to accurately and repeatedly deliver a unit volume v of a composition containing SRF (as represented by its absolute viscosity μ).

[0149] [000182] Needle inner diameters smaller than 25G (0.3 mm) or larger than 18G (0.8 mm) are excluded from certain embodiments herein.

[0150] [000183] Needles with lengths less than 15 cm or greater than 75 cm are excluded from certain embodiments herein.

[0151] [000184] By adopting this numerical range as the syringe needle requirement for the composition in addition to the three characteristics required for prostate treatment, a more effective SRF formulation will be found, as this value addresses the issue of deliverability and does not unnecessarily compromise the efficacy of the SRF. The numerical range is calculated using the K injection rating, or KIR, defined as follows:

number

[0152] [000185] It may be concluded that a needle having a length L, canal diameter D, absolute viscosity μ of the composition, and unit volume v for a KIR of 40-400 in centipoise per unit area can be used to reliably and consistently deliver SRF in unit volume increments. For transperineal or transrectal treatment, the KIR is defined for L of 10-30 cm, more preferably 15-20 cm, and canal diameter D of 0.06 cm or 0.06-0.08 cm, and in some embodiments 0.02 cm to 0.12 cm or less. For transurethral treatment, the KIR is defined for L of 35 cm to 70 cm, and canal diameter of 0.02 cm to 0.05 cm. The needle's thinness ratio (L / D) may be 200-400 or 250-350. In some other embodiments, the needle's thinness ratio (L / D) may be 167-500.

[0153] [000186] In some embodiments, the KIR can be between 10 and 1000 for transurethral administration.

[0154] [000187] In some embodiments, the KIR can be 16-1200 for transurethral administration.

[0155] [000188] In some embodiments, the KIR can be a value in Table 10 for transurethral administration.

[0156] [000189] In some embodiments, the KIR can be between 10 and 1000 for rectal or perineal administration.

[0157] [000190] In some embodiments, the KIR can be between 16 and 1200 for rectal or perineal administration.

[0158] [000191] In some embodiments, the KIR can be the value in Figure 14A or 14B for rectal or perineal administration.

[0159] [000192] In some embodiments, the KIR can be from 10 to 1000. In situations where a more delayed release rate and / or a faster gelation rate and smaller unit volume are desired, the higher ranges may be preferred.

[0160] [000193] Table 3 (shown in Figures 3A, 3B) discloses an embodiment of a device for delivering a unit volume of a composition comprising an SRF according to the present disclosure.

[0161] [000194] Figures 3A and 3B also disclose embodiments of devices intended to reach the prostate via a transrectal or transperineal approach for delivering a unit volume of a composition comprising SRF according to the present disclosure.

[0162] [000195] Figures 14A and 14B also disclose an embodiment of a device for delivering a unit volume of a composition comprising SRF according to the present disclosure, intended to reach the prostate via a transurethral approach.

[0163] [000196] As explained above, it is desirable to use a long and thin needle for injection of a relatively high viscosity composition including SRF, which will provide effective results without adverse effects on the patient's health due to diffusion, infection, or pain / discomfort during or after the procedure. It is also important that the medical personnel treating the patient have proper control over the volume of the composition injected so that a unit volume can be dispensed at each injection site, since volume control is required to achieve the desired clinical outcome. The KIR ranges in Table 3 and Figures 14A and 14B are believed to be useful in identifying compositions that meet the first two characteristics of the prostate treatment of the present disclosure and syringe needles that meet the third characteristic of the prostate treatment of the present disclosure.

[0164] [000197] The lower end of the KIR range in Table 3 and Figures 14A and 14B represents compositions with minimal viscosity, shorter needle length and larger unit volume that are representative of the ability of SRF to meet two of the characteristics of prostate treatment (effectiveness, sustained release and minimal uncontrolled drug diffusion) while allowing relatively easy dispensing of small unit volumes (for a fixed needle length, e.g., 15 cm). The upper end of the KIR range in Table 3 and Figures 14A and 14B represents compositions with higher viscosity, longer needle length and smaller unit volume (for a fixed needle length, e.g., 20 cm). For these compositions, when the formulation is injected, the two characteristics of prostate treatment will be easily met, but any increase in viscosity may challenge the ability of the medical practitioner to deliver the total volume of the composition in a unit volume amount, especially along the longer needle length. Therefore, for high KIR values, the capabilities of the delivery device are limited.

[0165] [000198] In addition to the KIR, in some embodiments, the slenderness ratio (L b / D b Barrel slenderness ratios in these ranges have been found to facilitate more accurate dispensing of small unit volumes of the composition, and may be preferred for meeting deliverability requirements (the third feature).

[0166] [000199] In some embodiments, including any of the foregoing, the devices herein include a needle having a depth restrictor and a selectable unit volume dispensing feature.

[0167] [000200] Figure 10B is a schematic side view of a syringe with a depth limiter to prevent needle injection from exceeding a predetermined depth and to dispense a predetermined unit volume of sustained release formulation (SRF) into the prostate. The guidance to the physician provided by the depth markers and the selectable unit volume dispensing feature more easily allows operation within the specified KIR range.

[0168] [000201] The following description therefore provides further detailed information regarding embodiments of an SRF and various components and properties that may be included in an SRF for the treatment of BPH using a needled syringe according to the present disclosure.

[0169] [000202] The drug or combination of drugs used in SRF includes cytostatic drugs, cytotoxic drugs, and / or other drugs. The other drug or drugs may be used alone (i.e., the "other drug or drugs" are the only active agents in the SRF) or may be used in combination with the cytostatic or cytotoxic drug as part of a medical procedure for treating BPH. For example, the other drug or drugs may be administered before the composition is injected into the target tissue using a needle syringe, or the other drug or drugs may be included in a composition with the SRF. Or, the other drug or drugs may be administered after the SRF containing the cytostatic or cytotoxic drug is administered to the target tissue.

[0170] [000203] These other drugs may be administered with or instead of cytostatic or cytotoxic drugs, and include alpha blockers or 5-alpha reductase inhibitors. Alpha blockers may include, but are not limited to, terazosin, doxazosin, tamsulosin, alfuzosin, and silodosin. 5-alpha reductase inhibitors may include, but are not limited to, finasteride and dutasteride. Anti-inflammatory drugs may include, but are not limited to, corticosteroids, such as dexamethasone, fluticasone propionate, triamcinolone acetonide, mometasone furoate, prednisone, hydrocortisone, estradiol, clobetasol, and budesonide. Nonsteroidal drugs may include acetaminophen, ibuprofen, and naproxen. These other drug types may inhibit inflammatory signals by blocking cytokine activity or inhibiting cytokine binding, 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, etc. Combinations of the drugs listed above and herein may also be administered together.

[0171] [000204] 5α-reductase inhibitors reduce prostate volume by 50% when given orally. Minimal reduction occurs in less than 6 months. With appropriate therapy, up to a 50% reduction in prostate volume is expected in 12-24 months or possibly longer.

[0172] [000205] Alpha blockers can also be used for symptomatic treatment at the time of the procedure by blocking alpha receptors and relaxing prostatic smooth muscle. Alpha blockers, 5-alpha reductase inhibitors, or both can be co-formulated with cytostatic or cytotoxic drugs into the SRF.

[0173] [000206] When expressing a % of a substance in an SRF, the % of the substance may be expressed in terms of the weight volume percentage of one or more drugs relative to the total weight of the SRF ("% x weight basis") or relative to the total volume of the SRF ("% x volume basis"). Unless otherwise stated, percent dosage % will by default refer to weight % of the total SRF measurement. 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") or milliliters ("mL"), and viscosity units are expressed as the ratio of the natural logarithm of the intrinsic viscosity (i.e., the relative viscosity to the mass concentration of a substance such as a polymer). The units of intrinsic viscosity are deciliters per gram (dL / g). A different measure of viscosity is the intrinsic viscosity, which is a measure of the contribution of a solute to the total viscosity. Another viscosity is the kinematic or absolute viscosity, which has units of centimeter-gram-second, also known as centipoise (cP).

[0174] [000207] The SRF may contain 0.1-60% of the polymer composition or more preferably 30-50% of the polymer composition. The SRF may contain 0-80% solvent, with the solvent being the majority component and present as the remainder after considering the amount of drug and bioabsorbable polymer. 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 the drug load in less than 24 hours (h), 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.

[0175] [000208] The drug carrier can be a polymeric composition including, but not limited to, silk-elastin-like protein polymers, including block and random copolymers such as poly(lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA, 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. More specifically, the PLGA composition can 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. The PLGA may be end-capped with ester, acid, alcohol, thiol or other terminal groups. The intrinsic viscosity of the PLGA polymer may vary from 0.1 dL / g to over 1.0 dL / g. The molecular weight of the PLGA polymer may vary from 10 kDa to up to 150 kDa. The polymer may be linear, branched, hyperbranched, dendritic, may have a star structure, or may be a dendrimer-like star polymer.

[0176] [000209] Additional embodiments of drug carriers, SRFs and compositions follow.

[0177] [000210] Drug carriers include poly(lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide), ester endcapped poly(D,L-lactide-co-glycolide)(50-50), ester endcapped poly(D,L-lactide-co-glycolide)(65-35), ester endcapped poly(D,L-lactide-co-glycolide(75-25), ester endcapped poly(D,L-lactide-co-glycolide(85-15), Acid endcapped poly(D,L-lactide-co-glycolide) (50-50), acid endcapped poly(D,L-lactide-co-glycolide) (65-35), acid endcapped poly(D,L-lactide-co-glycolide) (75-25), acid endcapped poly(D,L-lactide-co-glycolide) (85-15), ester endcapped poly(D-lactide-co-glycolide) (50-50), ester endcapped poly(D-lactide-co-glycolide) (65-35), acid endcapped poly(D,L-lactide-co-glycolide) (75-25), acid endcapped poly(D,L-lactide-co-glycolide) (85-15), poly(D-lactide-co-glycolide) (65-35), ester endcapped poly(D-lactide-co-glycolide) (75-25), acid endcapped poly(D-lactide-co-glycolide) (50-50), acid endcapped poly(D-lactide-co-glycolide) (65-35), acid endcapped poly(D-lactide-co-glycolide) (75-25), ester endcapped poly(L-lactide-co-glycolide) (50-50), ester endcapped poly(L-lactide-co-glycolide) (50-50), Poly(L-lactide-co-glycolide) (65-35), ester endcapped poly(L-lactide-co-glycolide) (75-25), acid endcapped poly(L-lactide-co-glycolide) (50-50), acid endcapped poly(L-lactide-co-glycolide) (65-35), acid endcapped poly(L-lactide-co-glycolide) (75-25), ester endcapped poly(D,L-lactide-co-glycolide), acid endcapped poly(D,L-lactide-co-glycolide) or a combination thereof.

[0178] [000211] In some embodiments, the drug carrier may comprise a bioabsorbable polymer composition, the intrinsic viscosity of the polymer composition is 0.1-1.0 dL / g, 0.1-0.6 dL / g, or 0.1-0.4 dL / g, or 0.1-0.3 dL / g, and the ratio of DL-lactide to glycolide is 30 / 70-90 / 10 or less, 95 / 5, or 85 / 15.

[0179] [000212] In some embodiments, the composition may comprise a bioabsorbable polymer at a concentration of 10-55% by weight, 15-50% by weight of the bioabsorbable polymer composition, 85-45% by weight of solvent, and 0.5% to 30% by weight of drug, 1% to 20% by weight of drug, or 1% to 10% by weight of drug.

[0180] [000213] The drug carrier (polymer composition) 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, a gel, or as a solid implant fabricated by injection molding, casting or extrusion. The biodegradable polymer composition is preferably selected to undergo substantial biodegradation in a period of about 1-3 months, 3-6 months, or 6-12 months.

[0181] [000214] In some embodiments, including any of the above, the SRF is a solution comprising a drug, a solvent, and a bioabsorbable polymer.

[0182] [000215] 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 months, 6 months, or 12 months after the previous treatment. For example, the polymer will have a glycolide to lactide ratio of 70:30 to 15:85 or less for a less hydrophobic structure (faster degradation), and / or an intrinsic viscosity of less than about 1.0 dL / g, or more preferably less than 0.3 dL / g.

[0183] [000216] The polymer composition is one that, when forming a component of the SRF, allows or achieves the desired "slow release" of one or more drugs to the target tissue. In some embodiments, the polymer composition allows or achieves at least 50% or up to about 100% or substantially all of the drug release in 30-90 days by a combination of diffusion and degradation. In other embodiments, up to 100% drug release occurs 90-120 days after treatment. Preferably, there is an initial burst (e.g., up to 50% of the drug), followed by a substantially decreased release rate over the next month or months after treatment. For example, the drug has a release rate of 5%-50% during the first 24 hours after injection of the composition into the prostate, the drug has a release rate of not more than 10%-75% over the first month, not more than 25%-95% over the first three months, and / or not more than 50%-100% over the first six months.

[0184] [000217] As discussed above, the SRF must preserve drug exposure to the prostate and minimize leakage or spillage to other surrounding organs. In addition, the SRF must not occupy too much volume in the prostate. The desired shape of the drug release curve may be a burst of drug and initial tissue exposure for immediate efficacy, followed by a decrease in drug release rate over a period of 3-6 months for sustained efficacy. In some cases, the drug release curve may be a burst of drug and initial tissue exposure for immediate efficacy, followed by a decrease in drug release rate over a period of 1-4 months for sustained efficacy. For example, a fast burst release rate followed by a decrease in rate was achieved with N-methylpyrrolidone (NMP) solvent, which is water soluble. This formulation may provide a fast release within the first 24 or 48 hours, or within the first week, 2 weeks, or up to 3 months, followed by a decrease in release rate.

[0185] [000218] Figure 3C shows the drug release curves of sustained release formulations (SRF) A, B, and C. These exemplary SRFs provide a burst followed by a gradual release of drug over a period of up to 6 months. SRF A releases about 25% of the drug within the first month followed by a slower gradual release where about 95% is released at 6 months. SRF B has an initial burst of about 50% within the first month followed by about 100% release at 2 months. SRF C has an initial burst of about 75% within the first month followed by about 100% release at about 2 months.

[0186] [000219] Table 4A below shows examples of SRF formulations for each of SRF A, B, and C. Examples A1, A2 exhibit release rate characteristics similar to SRF A in Figure 3C. Examples B1, B2 exhibit release rate characteristics similar to SRF B in Figure 3C. Examples C1, C2 exhibit release rate characteristics similar to SRF C in Figure 3C. Table 4B shows examples of drug released over time.

[0187] [Table 11]

[0188] [Table 12]

[0189] [000220] The SRF is delivered to the target tissue in the form of a liquid-form composition that gels upon contact with water at the target tissue (i.e., the drug or drugs and drug carrier of the SRF are in solution or in suspension in a solvent if in a delivery vehicle). The SRF may be made by dissolving the SRF components in a suitable solvent. Suitable solvents for these embodiments include water, N-methylpyrrolidone (NMP), dimethylsulfoxide (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. In some embodiments, including any of the foregoing, the solvent is N-methylpyrrolidone (NMP). In some embodiments, including any of the foregoing, the solvent is dimethylsulfoxide (DMSO). In some embodiments, including any of the foregoing, the solvent is 2-pyrrolidone. In some embodiments including any of the foregoing, the solvent is propylene carbonate. In some embodiments including any of the foregoing, the solvent is caprolactam. In some embodiments including any of the foregoing, the solvent is triacetin. In some embodiments including any of the foregoing, the solvent is an alcohol or a mixture of alcohols. In some embodiments including any of the foregoing, the solvent is benzyl benzoate. In some embodiments including any of the foregoing, the solvent is ethyl acetate. In some embodiments including any of the foregoing, the solvent is triethyl citrate. In some embodiments including any of the foregoing, the solvent is benzyl alcohol. In some embodiments including any of the foregoing, the solvent is glyme (dimethoxyethane). In some embodiments including any of the foregoing, the solvent is diglyme. In some embodiments including any of the foregoing, the solvent is a glycol ether. In some embodiments including any of the foregoing, the solvent is dichloromethane.

[0190] [000221] As explained above, the composition must be formulated at a concentration and viscosity that allows it to be passed through a long, thin needle with a slenderness ratio within a defined range that allows delivery in a small unit volume and controls drug release and drug distribution. The drug to polymer ratio, which affects the viscosity of the composition, can vary from 0.025 to 2.0. The drug and polymer concentrations in the solvent can range from 0.1% to 60% by weight or less, or more preferably from 30% to 50% by weight. The unit volume can range from 0.025mL to 0.15mL or less per injection, or more preferably from 0.05mL to 0.10mL per injection. The total volume of the composition for treatment can range from 0.050mL to 1.5mL or less, or more preferably from 0.10mL to 1.0mL. The total dosage of the drug provided to the SRF can range from 50ug to 200mg or less, or more preferably from 5mg to 50mg. For example, a composition containing SRF is 300 μg of sirolimus or paclitaxel dissolved in NMP at a 50% concentration by weight with 3000 μg ("μg" - microgram) poly(D,L-lactide-co-glycolide) (85:15).

[0191] [000222] The following disclosure provides further non-limiting examples of treating prostatic hyperplastic tissue within a patient's body using an apparatus or medical device according to the present disclosure, and provides a description and results of the second preclinical study referenced above.

[0192] [000223] As discussed above, the local drug delivery device is a syringe needle for delivering a composition comprising SRF to a target tissue, as shown and described above with reference to Figures 2A and 2B. In other embodiments, the applicator portion of the delivery vehicle may include a syringe chamber for keeping the drug and drug carrier separate from each other, a mixing element for combining the drug and drug carrier for feeding into a long thin or high thinness ratio needle, such as a static mixing Y-shaped adapter. Alternatively, the drug and drug carrier may be mixed using two syringes connected by an adapter, mixing the drug and drug carrier by pushing back and forth. The syringe needle may be imaged under ultrasound to visualize the treatment. Echogenicity may be enhanced by dimpling or coating the applicator needle. Echogenicity may also be enhanced by incorporation of contrast agents, such as microbubbles, sulfur hexafluoride, octafluoropropane, air, lipids and / or albumin shells. The applicator may have a component for attachment to a transrectal ultrasound probe. The applicator may have indicia showing needle insertion length or composition volume measurements. The applicator may have a user-friendly handle and plunger for comfortable delivery of the needle to the target tissue. Applicator needle sizes may range from 16G to 25G or less. Needle lengths may range from 10cm to 30cm (e.g., 15cm, 20cm long) to reach the target tissue from a transrectal or transperineal approach. EXAMPLES

[0193] 2021 Dog Research [000224] Working Example [000225] A preclinical dog study was conducted to evaluate the safety and feasibility of a composition containing SRF (SRF1) injected into the prostate of six dogs, each with prostate enlargement, after weekly treatment with testosterone injections over a 12-week period. SRF1 treatment was delivered 12 weeks after the initial testosterone injection. The composition containing SRF1 was delivered to these BPH dog models in the following manner.

[0194] [000226] SRF1 with PLGA5050 and NMP is loaded with 5mg paclitaxel and delivered to BPH dog model prostate (N=4) by injecting 2 50 microliter injections of this composition into each side or lobe of the prostate gland using a 20G×20cm Chiba needle delivered with a 250 microliter airtight glass delivery syringe while being imaged by transrectal ultrasound guidance. This composition is easy for the user to deliver without causing discomfort to the animal and can be visualized under ultrasound. SRF1 is delivered by performing a total of 2 injections (50 microliters each) for each BPH dog model.

[0195] [000227] 10mg paclitaxel was delivered to the BPH dog model prostate (N=2) with a 200 microliter (μl) composition by injecting two 100uL compositions into each side or lobe of the prostate, delivered with a 500 microliter airtight glass delivery syringe using a 20G×20cm Chiba needle while being imaged by transrectal ultrasound guidance. This composition was easily observable because it was delivered by the user and visualized under ultrasound, and did not cause any discomfort to the animal. SRF1 was delivered by performing a total of two injections (100 microliters each) for each BPH dog model.

[0196] [000228] Blood samples were taken from all animals at 0, 1, 3, 7, 14, 30, 60 and 90 days after treatment or until the animals were euthanized. After 30 and 90 days from the procedure, the model was humanely euthanized and evaluated to determine whether there was any acute toxic effect of the injection. At the time of euthanasia of the animals, tissue samples were also taken from the prostate, bladder and urethra to determine residual drug concentration. The daily behavior of all animals was also studied over a period of 30 and 90 days after the procedure.

[0197] [000229] Data collected from each of the models (i.e., 30-day and 90-day studies): [000230] Prostate morphology and prostate size / weight (ultrasound) at baseline and after treatment [000231] Gross necropsy and camera / microscope imaging at time of sacrifice and fixation [000232] Histological imaging (H&E) of treatment sites at time of sacrifice

[0198] [000233] Table 5 shows the prostate volume (cc or cm) as measured by ultrasound at baseline (i.e., before the animals received SRF1) and after 4 and 12 weeks of SRF1 treatment. 3 ) Table 5 shows the relative prostate volume reduction (%) after SRF1 treatment compared to baseline.

[0199] [Table 13]

[0200] [000234] The BPH dog models in this study are differentiated by number. Animal numbers 45, 46, 50, and 52 received a 5 mg drug dose of SRF1. BPH dog animal numbers 42 and 44 received a 10 mg drug dose. Prostate volume was reduced by as much as 80% at 4 and 12 weeks of treatment (animal number 44). For example, prostate volume in animal number 50 was reduced by 72.9% ([(10.6 / 39.2)-1] x 100 = -72.9%).

[0201] [Table 14]

[0202] [000235] Table 6 shows the mean change in dog prostate volume (cc) as a function of drug dose (5 mg and 10 mg) injected and measured by transrectal ultrasound after SRF1 injection (4 and 12 weeks) and after SRF1 treatment (4 and 12 weeks).

[0203] [Table 15]

[0204] [000236] Table 7 shows the overall (N=3) means and standard deviations of drug concentrations (μg / g) in various organs and tissues after 30 days of SRF1 treatment. Table 7 also shows the means (and standard deviation for 5 mg) of drug concentrations (μg / 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).

[0205] [Table 16]

[0206] [000237] Table 8 shows the overall (N=3) means and standard deviations of drug concentrations (μg / g) in various organs and tissues after 90 days of SRF1 treatment. Table 8 also shows the means (and standard deviation for 5 mg) of drug concentrations (μg / 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).

[0207] [Table 17]

[0208] [000238] Table 9 summarizes the histopathological scoring from histopathology H&E microscopic images following SRF1 injection in each of the canine BPH prostates. Scoring ranges from 0 to 4 (0=none, 1=minimal, 2=mild, 3=moderate, and 4=marked / severe / complete). Minimal to moderate values ​​of necrosis and inflammation over time are evidence of a local drug effect in the necrosis observed in the histopathology images. Minimal to mild fibrosis that resolves over time from 30 to 90 days is seen as evidence of a drug effect in reducing prostate volume (StDev=standard deviation).

[0209] [000239] It is known that for older men with reduced serum testosterone levels and a history of BPH, the prostate size does not decrease even though the serum total testosterone level decreases. See Xia, B.-W. et al, Relationship between serum total testosterone and prostate volume in aging men, Scientific Reports, 11, 14122 (2021).

[0210] [000240] As mentioned above, the prior art methods may show efficacy in reducing BPH, but they require higher dosages to treat the area while considering leakage or diffusion of the drug to other areas, which may require either more invasive procedures (compared to localized treatments using a delivery device as disclosed herein, such as needles used in animal testing), more frequent treatments due to diffusion, or more generalized BPH treatments with increased chances of adverse effects. Adverse effects may include reduced urinary or sexual function. It is desirable to have an effective treatment that targets only the target tissue and nothing else (e.g., avoids the urethra) and to perform the procedure in a minimally invasive manner for patient acceptance.

[0211] [000241] As mentioned above, both injection volumes of SRF1 showed significant reduction in prostate size as reported in Tables 5 and 6. In addition, as shown in Figures 7 and 8, the systemic drug concentration present in the blood was very low, indicating that the drug was contained in the target tissue. This example (Preclinical Study 2) indicates that the effective SRF injection solution of the present disclosure (1) significantly reduces prostate volume over a 30 and 90 day period, (2) substantially confines all of the active drug to the target tissue, and (3) can be delivered as a series of small unit volumes using a needle syringe. With regard to item (2), it must be mentioned that other known products for treating BPH, in contrast, significantly distribute their active drug (systemic drug concentration is much higher than that shown in Figures 7-8). Furthermore, this study indicates a high ratio of prostate 30-day drug concentration to peak plasma drug concentration of at least about 10,000. As discussed throughout, it is important to control the diffusion of drugs, since drugs can cause adverse effects on nearby tissues and organs. In addition, in contrast to most prior art or existing BPH treatment techniques, the volume of SRF injection required to be effective is relatively small. In this example (preclinical study), the unit volume of the composition containing SRF1 was 10-200 microliters per injection for 1-10 injections over each side of the prostate, or 50-100 microliters per injection for 1-5 injections over each side of the prostate. Prior art BPH treatment techniques attempt to maximize the injection volume to increase drug dosage. However, SRF does not require as high a drug dosage because the drug is retained in the target tissue.

[0212] [000242] Listed below are further disclosed embodiments that are KIR values ​​useful for treating BPH.

[0213] [000243] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.3 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 depth marker.

[0214] [000244] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (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 depth marker.

[0215] [000245] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.3 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 depth marker. The "E" in PLGA8515E means it is ester capped.

[0216] [000246] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (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 depth marker.

[0217] [000247] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.7 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 depth marker.

[0218] [000248] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 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 depth marker.

[0219] [000249] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.3 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 depth marker.

[0220] [000250] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.3 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 depth marker.

[0221] [000251] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (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 depth marker.

[0222] [000252] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 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 depth marker.

[0223] [000253] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0224] [000254] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0225] [000255] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0226] [000256] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515 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 depth marker.

[0227] [000257] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0228] [000258] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0229] [000259] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0230] [000260] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA5050 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 depth marker.

[0231] [000261] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA5050 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 depth marker.

[0232] [000262] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g sirolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA5050 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 depth marker.

[0233] [000263] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.3 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 depth marker.

[0234] [000264] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.3 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 depth marker.

[0235] [000265] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (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 depth marker. 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.3 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 20cm Chiba biopsy needle with depth markers.

[0236] [000266] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0237] [000267] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0238] [000268] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% 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 depth marker.

[0239] [000269] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.7 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 depth marker.

[0240] [000270] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.7 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 depth marker.

[0241] [000271] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 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 depth marker.

[0242] [000272] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515 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 depth marker.

[0243] [000273] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515 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 depth marker.

[0244] [000274] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0245] [000275] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0246] [000276] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525A (0.3 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 depth marker.

[0247] [000277] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525E (0.3 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 depth marker.

[0248] [000278] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% 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 depth marker.

[0249] [000279] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525E (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 depth marker.

[0250] [000280] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525A (0.7 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 depth marker.

[0251] [000281] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525E (0.7 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 depth marker.

[0252] [000282] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535E (0.3 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 depth marker.

[0253] [000283] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535A (0.3 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 depth marker.

[0254] [000284] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535E (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 depth marker.

[0255] [000285] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535A (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 depth marker.

[0256] [000286] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0257] [000287] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0258] [000288] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA5050 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 depth marker.

[0259] [000289] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA5050 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 depth marker.

[0260] [000290] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g everolimus and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA5050 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 depth marker.

[0261] [000291] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515 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 depth marker.

[0262] [000292] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.3 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 depth marker.

[0263] [000293] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.3 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 depth marker.

[0264] [000294] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (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 depth marker.

[0265] [000295] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (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 depth marker.

[0266] [000296] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.7 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 depth marker.

[0267] [000297] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 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 depth marker.

[0268] [000298] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0269] [000299] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0270] [000300] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515A (0.7 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0271] [000301] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 500 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515E (0.7 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 depth marker.

[0272] [000302] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA8515 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 depth marker.

[0273] [000303] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 50 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0274] [000304] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0275] [000305] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 200 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA7525 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 depth marker.

[0276] [000306] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535A (0.3 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0277] [000307] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 100 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535A (0.5 dl / g) in NMP solution using syringe-to-syringe mixing with a female-female Luer connector. 500 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0278] [000308] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 500 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535E (0.3 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 depth marker.

[0279] [000309] 0.5 mL N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 500 microliters of drug solution was added to 2.5 mL of 50 wt% PLGA6535E (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 depth marker.

[0280] [000310] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 20 wt% PLGA5050A 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 depth marker.

[0281] [000311] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 30 wt% PLGA5050A 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 depth marker.

[0282] [000312] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA5050A 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 depth marker.

[0283] [000313] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA5050A 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 depth marker.

[0284] [000314] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA5050A in NMP solution using syringe-to-syringe mixing with a female-female Luer connector (#SRF1). 250 microliters in a 1 mL syringe was loaded into a 20G x 20 cm Chiba biopsy needle with depth marker.

[0285] [000315] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA5050A 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 depth marker.

[0286] [000316] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 20 wt% PLGA5050E 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 depth marker.

[0287] [000317] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 30 wt% PLGA5050E 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 depth marker.

[0288] [000318] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA5050E 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 depth marker.

[0289] [000319] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA5050E 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 depth marker.

[0290] [000320] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA5050E 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 depth marker.

[0291] [000321] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA5050E 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 depth marker.

[0292] [000322] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 20 wt% PLGA8515A 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 depth marker.

[0293] [000323] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 30 wt% PLGA8515A 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 depth marker.

[0294] [000324] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA8515A 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 depth marker.

[0295] [000325] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA8515A 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 depth marker.

[0296] [000326] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA8515A 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 depth marker.

[0297] [000327] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA8515A 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 depth marker.

[0298] [000328] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 20 wt% PLGA8515E 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 depth marker.

[0299] [000329] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 30 wt% PLGA8515E 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 depth marker.

[0300] [000330] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA8515E 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 depth marker.

[0301] [000331] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA8515E 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 depth marker.

[0302] [000332] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA8515E 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 depth marker.

[0303] [000333] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA8515E 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 depth marker.

[0304] [000334] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 20 wt% PLGA6535A 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 depth marker.

[0305] [000335] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 30 wt% PLGA6535A 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 depth marker.

[0306] [000336] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA6535A 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 depth marker.

[0307] [000337] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA6535A 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 depth marker.

[0308] [000338] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA5050A 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 depth marker.

[0309] [000339] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA6535A 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 depth marker.

[0310] [000340] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.25 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 20 wt% PLGA6535E 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 depth marker.

[0311] [000341] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 30 wt% PLGA6535E 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 depth marker.

[0312] [000342] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA6535E 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 depth marker.

[0313] [000343] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 40 wt% PLGA6535E 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 depth marker.

[0314] [000344] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA6535E 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 depth marker.

[0315] [000345] 1.08 g N-methylpyrrolidone (NMP) was added to a vial containing 0.50 g paclitaxel and vortexed until dissolved. 400 mg of drug solution was added to 2.9 g of 50 wt% PLGA6535E 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 depth marker.

[0316] [000346] Please also see the tables in Figures 14A and 14B, reproduced below.

[0317] [Table 18]

[0318] [Table 19]

[0319] [000347] Additional aspects of the present disclosure are illustrated in embodiments E1 to E48 as well as the following embodiments.

[0320] [000348] E1. A sustained release formulation (SRF) for the treatment of BPH by dispensing less than a unit volume of SRF using a needled syringe to a location within the prostate, the SRF comprising a cytostatic or cytotoxic drug, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent capable of dissolving the drug and the copolymer.

[0321] [000349] E2. The SRF of E1 or any embodiment subordinate to E1, wherein the glycolide-based bioabsorbable copolymer is selected from the group consisting of poly(D,L-lactide-co-glycolide) (50:50), poly(D,L-lactide-co-glycolide) (65:35), and poly(D,L-lactide-co-glycolide) (85:15).

[0322] [000350] E3. An SRF according to E1 or any embodiment subordinate to E1, wherein the water-soluble solvent capable of dissolving the drug and copolymer is selected from the group consisting of N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO).

[0323] [000351] E4. An SRF according to E1 or any embodiment subordinate to E1, wherein the cytotoxic agent is selected from the set of paclitaxel, docetaxel, taxanes, protaxel, vincristine, etoposide, nocodazole, indirubin, anthracyclines, daunorubicin, daunomycin, plicamycin, tauromustine, bohumustine and plicamycin, irinotecan and doxorubicin, and combinations thereof.

[0324] [000352] E6. The SRF of E1 or any embodiment subordinate to E1, wherein the glycolide-based bioabsorbable copolymer is selected from the group of poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA.

[0325] [000353] E7. An SRF according to E1 or any embodiment subordinate to E1, wherein the glycolide-based bioabsorbable copolymer has a total concentration of 25-75% by weight, the solvent has a total concentration of 75-25% by weight, and the cytotoxic or cytostatic agent has a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight.

[0326] [000354] E8. The SRF of E1 or any embodiment subordinate to E1, wherein the composition is adapted to release the drug entirely into the prostate over a period of at least 14 days, or over a period of 30 to 90 days, or over a period of 90 to 180 days after injection into the prostate.

[0327] [000355] E9. An SRF according to E1 or any embodiment dependent thereon, wherein the drug has a release rate of not more than 10%-85% over the first month, not more than 25%-95% over the first three months, and / or not more than 50%-100% by weight over the first six months.

[0328] [000356] E10. An SRF of E1 or any embodiment subordinate to E1, wherein the drug has a release rate of 5% to 50% by weight during the first 24 hours following injection of the composition into the prostate.

[0329] [000357] E11. An SRF according to E1 or any embodiment dependent on E1, wherein the viscosity of the glycolide-based bioabsorbable copolymer is 0.2-0.5 dL / g, or 0.2-0.4 dL / g, or 0.2-0.3 dL / g, and the ratio of DL-lactide to glycolide is 50 / 50 to 85 / 15 or less.

[0330] [000358] E12. An SRF according to E1 or any embodiment subordinate to E1, wherein the cytostatic or cytotoxic agent is from 0.1 to a maximum of 10%, 1-15%, or 20-30% by weight of the composition.

[0331] [000359] E13. An SRF according to E1 or any embodiment subordinate to E1, wherein the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

[0332] [000360] E14. An SRF as described in E1 or any embodiment subordinate to E1, wherein the SRF is adapted to release 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.

[0333] [000361] E15. An SRF according to E1 or any embodiment subordinate to E1, wherein the drug is a cytostatic drug consisting of rapamycin, sirolimus, everolimus, temsirolimus or zotarolimus.

[0334] [000362] E16. An SRF according to E1 or any embodiment subordinate to E1, wherein the drug is a cytotoxic drug comprising paclitaxel or docetaxel.

[0335] [000363] E17. The SRF of E1 or any embodiment dependent on E1, wherein when the SRF contacts the prostate, the SRF forms a solid material having one or more shapes of microparticles, nanoparticles, rods, or gels, or any combination thereof.

[0336] [000364] E18. A device for treating a prostate volume PV, comprising: a composition having an absolute viscosity μ and comprising SRF in an amount of at least one unit volume v; and a syringe, the syringe housing the composition in a barrel thereof, the needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition, the syringe holding at least n unit volumes v, n being related to the PV as n=PV / (200×v), and the n unit volumes being equal to a total volume for the treatment of BPH; the device having a KIR of 10-1000, 10-300, or 40-400, the KIR being (μ)×(L) 2 / (vD)×10 (-6) The device is defined as:

[0337] [000365] E19. An apparatus as described in E18 or any claim dependent thereon, wherein μ is between 500 cP and 6000 cP.

[0338] [000366] E19b. The device of E18 or any claim dependent thereon, wherein μ is between 200 cP and 500 cP.

[0339] [000367] E20. An apparatus as described in E18 or any claim dependent thereon, wherein L is 10 to 20 cm.

[0340] [000368] E21. The apparatus of E18 or any claim dependent thereon, wherein the outer barrel has a slenderness ratio of 5-50 or, more specifically, 10-30.

[0341] [000369] E22. The device of E18 or any claim dependent thereon, wherein the needle has a slenderness ratio (L / D) of 200-400 or 250-350.

[0342] [000370] E23. The device of E18 or any claim dependent thereon, wherein the needle has an inner diameter of 0.02 cm to about 0.12 cm, or more precisely 0.06 cm to 0.08 cm.

[0343] [000371] A device described in E18 or any claim dependent thereon, wherein E24.v is 0.05ml to 0.2ml.

[0344] [000372] E25. The device of E18 or any claim dependent thereon, wherein L is 15 to 20 cm, the barrel has a slenderness ratio of about 10 and 30, the needle has an inner diameter of 0.06 cm to about 0.08 cm, v is 0.05 ml to 0.2 ml, and viscosity is 1065 cP to 4000 cP.

[0345] [000373] E26. The device of E18 or any claim dependent thereon, wherein the syringe barrel contains 2 to 10 unit volumes of the composition, excluding dead volume of the composition within the syringe barrel.

[0346] [000374] E27. The device of E18 or any claim dependent thereon, wherein the composition comprises a bioabsorbable polymer in a total concentration of 40-50% by weight, a solvent in a total concentration of 80-20% by weight, 75-25% by weight, 60-40% by weight, and a drug in a total concentration of 0.5% by weight to 30% by weight, 1% by weight to 20% by weight, or 2% by weight to 6% by weight.

[0347] [000375] E28. The device of E18 or any claim dependent thereon, wherein the drug in the SRF has a release rate of 10% to 85% or less over the first month, 25% to 95% or less over the first 3 months, and / or 50% to 100% or less over the first 6 months.

[0348] [000376] E29. The device of E18 or any claim dependent thereon, wherein the drug has a release rate of 5% to 50% during the first 24 hours following injection of the composition into the prostate.

[0349] [000377] E30. The device of E18 or any claim dependent thereon, wherein the SRF comprises no more than 0.1-10%, no more than 10-15%, or no more than 20-30% by weight of the SRF of a cytostatic or cytotoxic agent.

[0350] [000378] E31. The device of E18 or any claim dependent thereon, wherein the drug is sirolimus, docetaxel or paclitaxel.

[0351] [000379] E32. The device of E18 or any claim dependent thereon, wherein the drug comprises an alpha blocker or a 5-alpha reductase inhibitor, an anti-inflammatory drug such as a corticosteroid, and / or a vasodilator.

[0352] [000380] E33. The device of E18 or any claim dependent thereon, wherein the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

[0353] [000381] E34. The device of E18 or any claim dependent thereon, wherein KIR is 40 to 400.

[0354] [000382] E35. An apparatus for treating a prostate volume PV, comprising: a composition comprising SRF having an absolute viscosity μ and in an amount of at least one unit volume v; a syringe containing the composition in a barrel of the syringe, comprising a needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition, the syringe holding at least n unit volumes, n related to the PV as n=PV / (200×v), L is 15-20 cm, the barrel has a slenderness ratio of about 10 and 30, the needle has an inner diameter of 0.06 cm to about 0.08 cm, v is 0.05 ml to 0.1 ml, and μ is 1065 cP to 4000 cP, the apparatus comprising: (μ)×(L) 2 / (vD)×10 (-6) A device having a KIR between 10 and 1000, defined as

[0355] [000383] The device of claim 18, wherein E36.KIR is 40-400.

[0356] [000384] E37. The device of claim 18, wherein the syringe barrel contains 2-10 unit volumes of the composition, excluding dead volume of the composition within the syringe barrel.

[0357] [000385] E38. A method of making comprising combining a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent capable of dissolving the drug and the copolymer to form a composition for treating BPH.

[0358] [000386] E39. A method of making the method of E48 or any claim dependent thereon, wherein the composition, when placed into a needled syringe, forms a device having a KIR of 10-1000.

[0359] [000387] E.40. A method of making the composition described in E48 or any claim dependent thereon, wherein the composition when delivered to the prostate gland provides an effective outcome when delivered as a total volume to the prostate gland.

[0360] [000388] E.41. The method of E48 or any claim dependent thereon, wherein the cytotoxic or cytostatic drug, the glycolide-based bioabsorbable copolymer and the water-soluble solvent are combined when placed in the barrel of a needled syringe.

[0361] In some embodiments, including any of the above, KIR is 10-300, 100-900, 300-600, 10-1000, or 40-400.

[0362] [000389] In some embodiments, including any of the above, the TZUL is between 1.5 cm and 3.5 cm.

[0363] [000390] In some embodiments, including any of the above, TZUL is 2 cm, v is 0.05 ml, and n is 3.

[0364] [000391] In some embodiments, including any of the above, n is 1-10.

[0365] In some embodiments, including any of the above, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0366] [000392] In some embodiments, including any of the above, n is 2-6.

[0367] [000393] In some embodiments, including any of the foregoing, the number n of unit volumes v of the composition is such that n = TZUL / (11 x v).

[0368] [000394] In some embodiments, including any of the foregoing, the number n of unit volumes v of the composition is such that n is related to the prostate volume PV as n=PV / (200×v).

[0369] [000395] In some embodiments, including any of the above, KIR is 10-300, 100-900, 300-600, 10-1000, or 40-400.

[0370] [000396] In some embodiments, including any of the foregoing, the needle syringe has a needle thinness ratio of greater than 300.

[0371] [000397] In some embodiments, including any of the above, the needle syringe has a needle thinness ratio of 300-1100.

[0372] [000398] In some embodiments, including any of the above, the needle is greater than 5 mm long.

[0373] [000399] In some embodiments, including any of the above, the needle can be pivoted 90 degrees.

[0374] [000400] The unit volume delivery system of any one of claims 11 to 35, comprising a handle.

[0375] [000401] The unit volume delivery system of any one of claims 11 to 35 configured as a syringe gun.

[0376] [000402] In some embodiments, including any of the above, dead volume control is also included.

[0377] [000403] In some embodiments, including any of the above, μ is between 1065 cP and 4000 cP.

[0378] [000404] In some embodiments, including any of the above, L is 10 to 20 cm.

[0379] [000405] In some embodiments, including any of the above, L is 15 to 20 cm.

[0380] [000406] In some embodiments, including any of the above, the needle has a length / distance ratio (L / D) of 250-350.

[0381] [000407] In some embodiments, including any of the above, the needle has an inner diameter of between 0.06 cm and 0.08 cm.

[0382] [000408] In some embodiments, including any of the foregoing, the syringe barrel contains 2-10 unit volumes of the composition, excluding any dead volume of the composition within the syringe barrel.

[0383] [000409] In some embodiments, including any of the above, the composition has a release rate of 10% to 85% or less over the first month.

[0384] [000410] In some embodiments, including any of the foregoing, the composition has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

[0385] [000411] In some embodiments, including any of the foregoing, the composition comprises 0.1-10% by weight or less of sirolimus or paclitaxel.

[0386] [000412] In some embodiments, including any of the above, the composition comprises an alpha blocker, a 5-alpha reductase inhibitor, an anti-inflammatory agent, a vasodilator, or a combination thereof.

[0387] [000413] In some embodiments, including any of the above, the concentration of the glycolide-based bioabsorbable copolymer in the composition is 40-50% by weight, the concentration of the solvent is 20-80% by weight, and the concentration of the drug is 0.5% to 30% by weight.

[0388] [000414] In some embodiments, including any of the above, the bioabsorbable polymer is poly(lactide-co-glycolide) (PLGA).

[0389] [000415] In some embodiments, including any of the above, the solvent is N-methyl-pyrrolidone.

[0390] [000416] In some embodiments, including any of the above, the drug is sirolimus or paclitaxel.

[0391] [000417] In some embodiments, including any of the above, PV is 20~80cm 3 and L is 15 to 20 cm. The outer cylinder has a slenderness ratio of about 200 to 400. D is about 0.06 cm to about 0.08 cm, v is between 0.05 ml and 0.1 ml; and μ is between 1065cP and 4000cP.

[0392] [000418] In some embodiments, including any of the above, PV is 20~200cm 3 and L is 15 to 20 cm. The outer cylinder has a slenderness ratio of about 200 to 400. D is about 0.06 cm to about 0.08 cm, v is between 0.05 ml and 0.1 ml; and μ is between 1065cP and 4000cP.

[0393] [000419] In some embodiments, including any of the foregoing, the needled syringe includes a needle capable of creating multiple lesions along the urethral transition zone.

[0394] [000420] In some embodiments, including any of the foregoing, the needle syringe includes up to 20 side holes through which the needle syringe can inject the composition.

[0395] [000421] In some embodiments, including any of the foregoing, the needle syringe includes 10 to 20 side holes through which the needle syringe can inject the composition.

[0396] [000422] In some embodiments, including any of the foregoing, the needle syringe includes 12 side holes through which the needle syringe can inject the composition.

[0397] [000423] In some embodiments, including any of the above, the needle syringe is a large 20 Fr / 6.7 mm OD and 22 cm in length.

[0398] [000424] In some embodiments, including any of the above, the needle is flexible.

[0399] [000425] In some embodiments, including any of the above, the needle is rigid.

[0400] [000426] The unit volume delivery system of any one of claims 11-66, further comprising a luer port for connection to a needle.

[0401] [000427] The unit volume delivery system of any one of claims 11-67, configured to be opened for manual withdrawal of the needle.

[0402] [000428] In some embodiments, including any of the above, the needle length is greater than 5 mm.

[0403] [000429] In some embodiments, including any of the above, the needle length is greater than about 8 mm.

[0404] [000430] In some embodiments, including any of the above, the needle is a transrectal needle.

[0405] [000431] In some embodiments, including any of the above, the needle is a transurethral needle.

[0406] [000432] Some embodiments, including any of the above, also include an 18G needle.

[0407] [000433] Some embodiments, including any of the above, also include a 20G needle.

[0408] [000434] Some embodiments, including any of the above, also include needles smaller than a 20G needle.

[0409] [000435] Some embodiments, including any of the above, also include a 22G needle.

[0410] [000436] Some embodiments, including any of the above, also include a 23G needle.

[0411] [000437] Some embodiments, including any of the above, also include a 25G needle.

[0412] [000438] The unit volume delivery system of any one of claims 11 to 72, wherein the needle is between 1 mm and 35 cm in length.

[0413] [000439] In some embodiments, including any of the above, the needle is between 4 mm and 20 cm in length.

[0414] [000440] Some embodiments, including any of the above, also include a 20G x 20cm transrectal needle.

[0415] [000441] Some embodiments, including any of the above, also include a 20G x 20cm transrectal needle.

[0416] [000442] In some embodiments, including any of the above, the needle is rigid.

[0417] [000443] In some embodiments, including any of the above, the needle is flexible.

[0418] [000444] The unit volume delivery system of any one of claims 11-72, comprising a Cook's 45 cm long needle.

[0419] [000445] The unit volume delivery system of any one of claims 11-72 comprising a 23G 8mm length needle.

[0420] [000446] Some embodiments, including any of the above, also include a Storrs, Olympus, or Ambu flexible cystoscope.

[0421] [000447] Some embodiments, including any of the above, also include a flexible scope.

[0422] [000448] Some embodiments, including any of the above, also include a hollow plastic handle having a button configured to couple to an optical rigid cystoscope.

[0423] [000449] Some embodiments, including any of the above, also include a curved, elongated transurethral needle for reaching the urethra.

[0424] [000450] Some embodiments, including any of the above, also include a luer port for a proximal needle.

[0425] [000451] Some embodiments, including any of the above, also include a plastic syringe support that holds the syringe fixed in place while still allowing the handle to rotate.

[0426] [000452] In some embodiments, including any of the above, the needle is rotatable.

[0427] [000453] In some embodiments, including any of the above, the needle is rotatable via a syringe and a Luer port for additional injections.

[0428] [000454] In some embodiments, including any of the foregoing, the unit volume delivery system is made by injection molding.

[0429] [000455] Some embodiments, including any of the above, also include a long flexible needle that is placed inside the fluid port of a commercially available flexible cystoscope.

[0430] [000456] Some embodiments, including any of the above, also include a curved tip that is 5 mm or longer.

[0431] [000457] Some embodiments, including any of the above, also include a curved tip that is 10 mm or longer in length.

[0432] [000458] Some embodiments, including any of the above, also include a collar coupled to a plunger of the needle syringe, the collar configured to dispense a single unit volume.

[0433] [000459] Some embodiments, including any of the above, also include a collar coupled to a plunger of the needle syringe, the collar configured to dispense the total volume.

[0434] [000460] Some embodiments, including any of the above, also include a ratcheting system that engages the plunger for each unit volume delivered.

[0435] [000461] In some embodiments, including any of the foregoing, provided herein is a method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: [000462] A method is provided that includes providing a unit volume delivery system as provided herein and dispensing a total volume of a composition to the prostate using the unit volume delivery system to produce an effective outcome for the treatment of BPH, comprising dispensing no more than a unit volume of the composition using a needle syringe to a first prostatic location of the prostate.

[0436] [000463] In some embodiments, including any of the foregoing, the method includes placing a needle syringe at a second location within the prostate and dispensing no more than one unit volume of the composition to the second location of the prostate.

[0437] [000464] In some embodiments, including any of the foregoing, the method includes a plurality of volumes, n, not exceeding unit volume v, injected into the prostate to treat the prostate at corresponding n prostate locations, where n=TZUL / (11×v).

[0438] [000465] In some embodiments, including any of the foregoing, the method includes a plurality of volumes, n, not exceeding a unit volume, v, injected into the prostate to treat the prostate at corresponding n prostate locations, where n is related to a prostate volume, PV, as n=PV / (200×v), and the sum of the unit volumes is a total volume for the prostate volume, PV.

[0439] [000466] In some embodiments, including any of the above, the needle syringe includes a barrel that holds at least n unit volumes, where n is an integer from 2 to 10; [000467] When the prostate size is 20 to 40 grams, n is 2 to 4; When the prostate size is 40-60 grams, n is 2-6; n is between 4 and 8 when the prostate size is between 60 and 80 grams, and When the prostate size is 80 grams or more, n is 6 to 10.

[0440] [000468] In some embodiments, including any of the above, the unit volume is 0.05 ml to 0.5 ml, 0.05 ml to 0.1 ml, 0.1 to 0.2 ml, or 0.05 to 0.2 ml.

[0441] [000469] In some embodiments, including any of the above, the composition comprises between 4% and 15% by volume of the cytotoxic or cytostatic agent.

[0442] [000470] In some embodiments, including any of the foregoing, the cytotoxic or cytostatic agent is selected from the group consisting of paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, and temsirolimus.

[0443] [000471] In some embodiments, including any of the above, the cytotoxic agent is docetaxel or paclitaxel.

[0444] [000472] In some embodiments, including any of the foregoing, the cytostatic agent is sirolimus.

[0445] [000473] Some embodiments, including any of the above, also include measuring the TZUL and selecting a total number of unit volumes v of the composition to dispense into the prostate at each of a plurality of locations in the prostate based on the TZUL, where the sum of the unit volumes is approximately equal to the total volume.

[0446] [000474] Some embodiments, including any of the foregoing, also include measuring a prostate size and selecting a total volume of the composition for treating BPH based on the prostate size, wherein selecting includes selecting a number of unit volumes of the composition to dispense into the prostate at each of the multiple locations of the prostate, the sum of the unit volumes approximately equal to the total volume.

[0447] [000475] In some embodiments, including any of the above, the prostate size is prostate volume or prostate weight, and the prostate volume or prostate weight is measured by ultrasound imaging.

[0448] [000476] In some embodiments, including any of the above, the composition further comprises an alpha blocker or a 5 alpha reductase inhibitor, or an anti-inflammatory agent.

[0449] [000477] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer is selected from the set of poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 50:50, poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 65:35, and poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 75:25, and poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 85:15.

[0450] [000478] In some embodiments, including any of the foregoing, the water-soluble solvent capable of dissolving the drug and the copolymer is selected from the set of N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO) and combinations thereof.

[0451] [000479] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer is selected from the set of poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA.

[0452] [000480] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer has a total concentration of 30-50% by weight, the solvent has a total concentration of 50-30% by weight, and the cytotoxic or cytostatic agent has a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight.

[0453] [000481] In some embodiments, including any of the above, the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

[0454] [000482] In some embodiments including any of the above, the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

[0455] [000483] In some embodiments, including any of the above, the unit volume is between 0.05 ml and 0.2 ml.

[0456] [000484] In some embodiments, including any of the above, the multiple unit volumes equal a total volume for treatment of BPH.

[0457] [000485] In some embodiments, including any of the above, the composition has 4% to 15% by volume of a cytotoxic or cytostatic agent, wherein the cytotoxic agent is docetaxel or paclitaxel, and the cytostatic agent is sirolimus.

[0458] [000486] In some embodiments, including any of the above, n is the number of unit volumes of the composition, where n is related to TZUL as n=TZUL / (11 x v).

[0459] [000487] In some embodiments, including any of the above, for the treatment of BPH, the plurality of unit volumes, n, is related to the prostate volume, PV, as n=PV / (200×v).

[0460] [000488] In some embodiments, including any of the above, the anti-inflammatory agent is selected from a corticosteroid, a vasodilator, and combinations thereof.

[0461] [000489] In some embodiments, including any of the above, the following active agents may be administered in combination and are methods, devices and apparatuses described herein.

[0462] [000490] Some embodiments, including any of the foregoing, also include analgesics or pain medications such as, but not limited to, lidocaine, xylocaine, bupipocaine, bupivacaine, cocaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine, trimecaine, carticaine, articaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, and combinations thereof.

[0463] [000491] Some embodiments, including any of the above, also include 5-alpha reductase inhibitors, such as, but not limited to, dutasteride and finasteride.

[0464] [000492] Some embodiments, including any of the foregoing, also include alpha blockers and smooth muscle cell relaxants, such as, but not limited to, doxazosin, prazosin, terazosin, tamsulosin, alfuzosin, silodosin, phenoxybenzamine, vibegron, beta3 adrenergic receptor agonists, mirabegron, and tolterodine.

[0465] [000493] Some embodiments, including any of the foregoing, also include anti-inflammatory agents, such as, but not limited to, fluticasone furoate, mometasone furoate, dexamethasone, prednisone, betamethasone, cortisone, hydrocortisone, methylprednisolone, NSAIDs, aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamic acid, mefenamic acid, and other COX-2 inhibitors, and combinations thereof.

[0466] [000494] Some embodiments, including any of the foregoing, also include anticholinergics, such as, but not limited to, atropine, belladonna alkaloids, benztropine mesylate, clidinium, cyclopentolate, darifenacin, dicyclomine, diphenhydramine, fesoterodine, flavoxate, glycopyrrolate, homatropine hydrobromide, hyoscyamine, ipratropium, orphenadrine, oxybutynin, propantheline, scopolamine, methscopolamine, solifenacin, succinylcholine, tiotropium, tolterodine, trihexyphenidyl, trospium, and vecuronium.

[0467] [000495] In some embodiments, including any of the foregoing, the medicaments include, but are not limited to, amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline, minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, rifampin ... Also included are antifungal, antimicrobial, antibiotic and antibacterial agents such as benzodiazepines, penicillins, aminoglycosides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporins, carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropin-melittin, magainin, dermaseptin, cathelicidin, alpha-defensins and alpha-protegrins.

[0468] [000496] Antifungal agents, in some embodiments, include, but are not limited to, ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifonazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

[0469] [000497] Some embodiments, including any of the foregoing, also include antimuscarinics, such as, but not limited to, tolterodine, solifenacin, darifenacin, propiverine, oxybutynin, trospium and chloride.

[0470] [000498] Some embodiments, including any of the above, also include other drugs, such as, but not limited to, capsaicin and botox.

[0471] [000499] In some embodiments, including any of the above, a single drug may be utilized.

[0472] [000500] In some embodiments, including any of the above, combinations of various drugs may be utilized.

[0473] [000501] Some embodiments, including any of the above, also include drugs such as enzalutamide (a nonsteroidal antiandrogen) and abiraterone acetate (Zytiga).

[0474] In some embodiments, provided herein is a method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: using a needled syringe containing a composition comprising a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and an aqueous solvent capable of dissolving the drug and the copolymer; dispensing a total volume of the composition into the prostate to produce an effective outcome for the treatment of BPH, comprising dispensing a unit volume or less of the composition into a first prostatic location of the prostate using a needle syringe; A method is presented that includes:

[0475] [000502] In some embodiments, including any of the foregoing, the method includes using a device comprising a needle syringe and a composition, wherein the device has a KIR of 10-1000, 10-300, or 40-400.

[0476] [000503] In some embodiments, including any of the foregoing, the step of placing a needle syringe at a second location within the prostate gland and dispensing no more than one unit volume of the composition using the device to the second location of the prostate gland.

[0477] [000504] The method of any one of claims 1 to 3, wherein a plurality n of unit volumes v or less are injected into the prostate to treat the prostate at n corresponding prostate locations, where n is related to the prostate volume PV as n = PV / (200 x v), and the sum of the plurality n of unit volumes is a total volume for the prostate volume PV.

[0478] [000505] In some embodiments, including any of the above, the needle syringe comprises: When the prostate size is 20-40 grams, n is 2-4; When the prostate size is 40-60 grams, n is 2-6; n is 4 to 8 when the prostate size is 60 to 80 grams, and When the prostate size is 80 grams or more, n is 6 to 10 The cylinder includes an outer cylinder that holds at least n unit volumes such that

[0479] [000506] In some embodiments, including any of the above, the unit volume is 0.05 ml to 0.5 ml, 0.05 ml to 0.1 ml, 0.1 to 0.2 ml, or 0.05 to 0.2 ml.

[0480] [000507] In some embodiments, including any of the above, the composition comprises between 4% and 15% by volume of the cytotoxic or cytostatic agent.

[0481] [000508] In some embodiments, including any of the above, the cytotoxic agent is docetaxel or paclitaxel.

[0482] [000509] In some embodiments, including any of the foregoing, the cytostatic drug is sirolimus.

[0483] [000510] In some embodiments, including any of the foregoing, measuring a prostate size and selecting a total volume of a composition for treating BPH based on the prostate size, wherein selecting includes selecting a number of unit volumes of the composition to dispense into the prostate at each of a plurality of locations in the prostate, the sum of the unit volumes approximately equal to the total volume.

[0484] [000511] In some embodiments, including any of the above, prostate volume or weight is measured by ultrasound imaging.

[0485] [000512] In some embodiments, including any of the foregoing, the composition further comprises an anti-inflammatory agent, such as an alpha blocker or a 5-alpha reductase inhibitor, a corticosteroid, and / or a vasodilator.

[0486] [000513] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer is selected from the set of poly(D,L-lactide-co-glycolide) (50:50), poly(D,L-lactide-co-glycolide) (65:35), and poly(D,L-lactide-co-glycolide) (75:25), and poly(D,L-lactide-co-glycolide) (85:15).

[0487] [000514] In some embodiments, including any of the foregoing, the water-soluble solvent capable of dissolving the drug and the copolymer is selected from the set of N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO), and combinations thereof.

[0488] [000515] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer is selected from the set of poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA.

[0489] [000516] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer has a total concentration of 30-50% by weight, the solvent has a total concentration of 50-30% by weight, and the cytotoxic or cytostatic agent has a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight.

[0490] [000517] In some embodiments, including any of the above, the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

[0491] [000518] In some embodiments, including any of the foregoing, the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

[0492] [000519] In some embodiments, provided herein is a method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: [000520] Using a device including a needled syringe containing a composition including a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and an aqueous solvent capable of dissolving the drug and the copolymer, the composition having an absolute viscosity μ, the needled syringe having a needle length L with an inner diameter D; [000521] Dispensing a plurality of unit volumes v of the composition into a respective plurality of different locations in the prostate using a needle syringe; Including, [000522] The unit volume is 0.05 ml to 0.2 ml. [000523] A plurality of unit volumes is equal to a total volume for treatment of BPH, [000524] The device has 10 to 300 or 40 to 400 KIRs, the KIRs being

number

[0493] [000525] In some embodiments, including any of the above, the composition has 4% to 15% by volume of a cytotoxic or cytostatic agent, wherein the cytotoxic agent is docetaxel or paclitaxel, and the cytostatic agent is sirolimus.

[0494] [000526] In some embodiments, including any of the above, for the treatment of BPH, the plurality of unit volumes, n, is related to the prostate volume, PV, as n=PV / (200×v).

[0495] [000527] In some embodiments, provided herein is an apparatus for treating a prostate volume PV, comprising: a composition comprising an SRF having an absolute viscosity μ and in an amount of at least one unit volume v; a syringe containing the composition in a barrel of the syringe, including a needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition; Including, the syringe holds at least n unit volumes, v, where n is related to PV as n=PV / (200×v), and n unit volumes equal the total volume for the treatment of BPH; The device has a KIR of 10-1000, 10-300, or 40-400, where KIR is (μ)×(L) 2 / (vD)×10 (-6) The apparatus is shown as:

[0496] [000528] In some embodiments, including any of the above, μ is between 500 cP and 6000 cP.

[0497] [000529] In some embodiments, including any of the above, L is between 10 and 20 cm.

[0498] [000530] In some embodiments, including any of the above, the barrel has a slenderness ratio of 5-50, or, more specifically, 10-30.

[0499] [000531] In some embodiments, including any of the above, the needle has a length / distance ratio (L / D) of 200-400 or 250-350.

[0500] [000532] [000533] In some embodiments, including any of the above, the needle has an inner diameter of between 0.02 cm and about 0.12 cm, or more specifically, between 0.06 cm and 0.08 cm.

[0501] [000534] [000535] In some embodiments, including any of the above, v is between 0.05 ml and 0.2 ml.

[0502] [000536] In some embodiments, including any of the above, L is 15-20 cm; [000537] The barrel has a slenderness ratio of about 10 and 30; [000538] The needle has an inner diameter of about 0.06 cm to about 0.08 cm. [000539] v is between 0.05 ml and 0.2 ml; and [000540] The viscosity is 1065 cP to 4000 cP.

[0503] [000541] In some embodiments, including any of the foregoing, the syringe barrel contains 2-10 unit volumes of the composition, excluding any dead volume of the composition within the syringe barrel.

[0504] [000542] In some embodiments, including any of the above, the composition comprises: [000543] A bioabsorbable polymer in a total concentration of 40-50% by weight, a solvent in a total concentration of 80-20% by weight, 75-25% by weight, or 60-40% by weight, and a drug in a total concentration of 0.5% by weight to 30% by weight, 1% by weight to 20% by weight, or 2% by weight to 6% by weight. Includes.

[0505] [000544] In some embodiments, including any of the above, the drug in the SRF has a release rate of 10%-85% or less over the first month, 25%-95% or less over the first 3 months, and / or 50%-100% or less over the first 6 months.

[0506] [000545] In some embodiments, including any of the above, the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

[0507] [000546] In some embodiments, including any of the foregoing, the SRF comprises no more than 0.1-10%, no more than 10-15%, or no more than 20-30% cytostatic or cytotoxic agent by weight of the SRF.

[0508] [000547] In some embodiments, including any of the above, the drug is sirolimus, docetaxel, or paclitaxel.

[0509] [000548] In some embodiments, including any of the foregoing, the medication comprises an alpha blocker or a 5-alpha reductase inhibitor, an anti-inflammatory drug such as a corticosteroid, and / or a vasodilator.

[0510] [000549] In some embodiments including any of the above, the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

[0511] [000550] In some embodiments, including any of the above, the KIR is 40-400.

[0512] [000551] In some embodiments, provided herein is an apparatus for treating a prostate volume PV, comprising: [000552] A composition comprising an SRF having an absolute viscosity μ and in an amount of at least 1 unit volume v; [000553] A syringe containing a composition in a syringe barrel, including a needle having a syringe length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition. Including, [000554] The syringe holds at least n unit volumes, where n is related to PV as n=PV / (200×v); L is 15 to 20 cm. The barrel has a slenderness ratio of about 10 and 30; The needle has an inner diameter of about 0.06 cm to about 0.08 cm. v is between 0.05 ml and 0.1 ml; and μ is 1065cP to 4000cP, The device is (μ) × (L) 2 / (vD)×10 (-6) A device is shown having a KIR of 10 to 1000, defined as

[0513] [000555] In some embodiments, including any of the above, the KIR is 40-400.

[0514] [000556] In some embodiments, including any of the foregoing, the syringe barrel contains 2-10 unit volumes of the composition, excluding any dead volume of the composition within the syringe barrel.

[0515] [000557] In some embodiments, there is provided herein a guide for providing incremental dosages from a syringe, the syringe coupled to the guide including a barrel, a finger hook extending from the barrel, and a plunger movable relative to the barrel, the guide comprising: (a) a body extending along a central axis between a first end and a second end and defining an interior space; (1) The exterior wall, (2) an inner wall disposed radially inward of the outer wall; (3) a plurality of detents extending from the inner wall into the interior space, the detents being spaced apart from one another along a central axis of the body; A main body including (b) a finger catch at the second end of the body, the finger catch configured to engage a finger catch of the syringe to prevent the barrel from moving relative to the body. A guide including the following is shown. [000558] Here, when the syringe is provided on the guide, the plunger extends into the interior space of the body, and when the plunger is moved relative to the barrel, a first detent of the plurality of detents is configured to engage the plunger to resist movement of the plunger relative to the barrel, and the plunger is moveable beyond the first detent of the plurality of detents to a second detent of the plurality of detents.

[0516] [000559] In some embodiments, including any of the foregoing, the finger hook clasp portion is provided as an aperture extending through the body between the outer wall and the inner wall, and when a syringe is provided in the guide, the finger hook extends through the aperture and away from the body.

[0517] [000560] In some embodiments, including any of the foregoing, the finger catch portion is provided as wings that extend radially outward from an outer wall of the body and at least partially enclose the finger catch when the syringe is provided in the guide.

[0518] [000561] In some embodiments, including any of the foregoing, the body includes a first portion and a second portion, the second portion movable relative to the first portion to transition the guide between a first state and a second state, the first state allowing relative movement of the barrel with respect to the body, and the second state preventing movement of the barrel with respect to the body.

[0519] [000562] In some embodiments, including any of the above, the first portion and the second portion are connected together by a hinge, and the body includes a snap-on connector to maintain the guide in the second state.

[0520] [000563] In some embodiments, including any of the foregoing, the first portion and the second portion are separate components, the body includes a snap-on connector for securing the second portion to the first portion, and when the second portion is secured to the first portion, the guide is in the second state.

[0521] [000564] In some embodiments, including any of the foregoing, a first distance (LDC) between the first and second detents along a central axis of the body corresponds to one unit volume (v) of the composition contained within the barrel.

[0522] [000565] In some embodiments, including any of the above, the syringe barrel has an inner diameter (d) and a first distance (LDC) proportional to a unit volume (v), the first distance LDC being defined as: [000566] LDC = [4 / (πd 2 )]v. In some embodiments, including any of the above, the detent is configured to provide tactile feedback to inform a user that the plunger has moved the first distance.

[0523] [000567] In some embodiments, including any of the above, the detent is configured to provide audio feedback to inform a user that the plunger has moved the first distance.

[0524] [000568] In some embodiments, including any of the foregoing, the plunger includes a head, and the plurality of detents includes a third detent located between the first detent and the second detent, a second distance between the first detent and the third detent along the central axis of the body and a third distance between the third detent and the first detent along the central axis of the body are both equal to a thickness of the head, and optionally the distances are such that the head is retained between the detents, and when moved from either the upper or lower detent, there is a tactile or audible sound indicating that the head has moved from its position between the detents.

[0525] [000569] In some embodiments, including any of the foregoing, the inner wall has a first circumscribing area and the plunger includes a head having a second circumscribing area, the second circumscribing area being smaller than the first circumscribing area.

[0526] [000570] In some embodiments, including any of the foregoing, the inner wall has a first circumscribing area and the plunger includes a head having a second circumscribing area, the second circumscribing area being smaller than the first second circumscribing area.

[0527] [000571] A guide as claimed in any one of claims 42 to 52, wherein resistance to movement of the plunger relative to the barrel is provided by engagement between a detent and a head of the plunger.

[0528] [000572] In some embodiments, including any of the above, the plunger includes a head, the head having a rounded rectangular configuration, and a cross-section of the inner wall of the body approximates at least a portion of the rounded rectangular configuration of the head of the plunger.

[0529] [000573] In some embodiments, including any of the foregoing, the detents are provided only on at least a portion of the rounded rectangular configuration, optionally only on the curved portion of the inner wall of the body.

[0530] [000574] In some embodiments, including any of the foregoing, the body includes a weakened portion configured to deflect the body away from the plunger head when the plunger head is forced to move between the detents.

[0531] [000575] In some embodiments, including any of the foregoing, the weakened portion is provided as a slot extending through the body between the outer wall and the inner wall, the slot being positioned to weaken the resistance of the body to outward pressure applied when the plunger head is forced to move between the detents.

[0532] [000576] In some embodiments, including any of the above, the weakened portion is provided as a portion of reduced thickness that does not extend through the body.

[0533] [000577] In some embodiments, including any of the above, the portion of reduced thickness extends substantially parallel to a central axis of the body.

[0534] [000578] In some embodiments, including any of the foregoing, the body includes a cut-out portion extending from the terminal end toward the first end of the body, the cut-out portion configured to provide clearance for a finger of a user manipulating the syringe to move the plunger head toward the barrel when dispensing a unit volume.

[0535] [000579] In some embodiments, including any of the above, a syringe is provided in the guide and a portion of the barrel of the syringe is disposed in the body.

[0536] [000580] In some embodiments, including any of the foregoing, the body further includes a plurality of bumpers extending from the inner wall into the interior space, the bumpers configured to engage a portion of a barrel of a syringe disposed on the body to prevent the barrel from moving relative to the body.

[0537] [000581] In some embodiments, including any of the above, the guide is a unitary assembly securable over a syringe barrel of the needle syringe assembly.

[0538] [000582] In some embodiments, including any of the foregoing, the guide comprises a plurality of n unit volumes v of the composition, where n is related to TZUL as n=TZUL / (11×v), and the composition comprises a cytotoxic or cytostatic drug powder, a glycolide-based bioabsorbable copolymer, and a water soluble solvent.

[0539] [000583] In some embodiments, including any of the foregoing, the guide comprises a plurality of number n of unit volumes of the composition, where n is related to the prostate volume PV as n=PV / (200×v), and the composition comprises a cytotoxic or cytostatic drug powder, a glycolide-based bioabsorbable copolymer, and a water soluble solvent.

[0540] [000584] In some embodiments, including any of the above, the TZUL is between 1.5 cm and 3.5 cm.

[0541] [000585] In some embodiments, including any of the above, TZUL is 2 cm, v is 0.05 ml, and n is 3.

[0542] [000586] In some embodiments, including any of the above, the guide includes a dead volume control.

[0543] [000587] In some embodiments, provided herein is a delivery device configured to mix a first composition with a second composition, comprising: a barrel extending between a first end and a second end, the first end of the barrel adapted for attachment to a needle; a septum disposed within the barrel, the septum dividing the barrel into a first chamber and a second chamber, the first chamber receiving the first composition and the second chamber receiving the second composition; a plunger extending from the second end of the barrel, the plunger being movable relative to the barrel and configured to break the septum to allow the first composition to mix with the second composition to form a mixture and to force the mixture from the first end of the barrel and into the needle; A delivery device is shown that includes:

[0544] [000588] In some embodiments, including any of the above, the guide includes a piercing member disposed within the barrel, the piercing member configured to break the septum.

[0545] [000589] In some embodiments, including any of the above, the plunger engages the piercing member to move the piercing member relative to the barrel to break the septum.

[0546] [000590] In some embodiments, including any of the foregoing, the plunger includes a shaft portion extending between a first end and a second end, a piston provided at the first end of the shaft portion, the piston in sealing engagement with an inner surface of the barrel.

[0547] [000591] In some embodiments, including any of the above, the piston engages and breaks the septum.

[0548] [000592] In some embodiments, including any of the foregoing, the guide includes a piercing member disposed within the barrel, the piercing member configured to break the septum, and the piston engages the piercing member to move the piercing member relative to the barrel to break the septum.

[0549] [000593] In some embodiments, including any of the foregoing, a head is provided at a second end of the shaft portion, the head having a first circumscribed diameter and the shaft portion having a second circumscribed diameter, the first circumscribed diameter being greater than the second circumscribed diameter.

[0550] [000594] In some embodiments, including any of the foregoing, the guide includes a finger loop, the finger loop extending from an outer surface of the barrel and extending along a first axis transverse to a central axis of the barrel.

[0551] [000595] In some embodiments, including any of the foregoing, the first composition comprises a cytotoxic or cytostatic agent powder and the second composition comprises a glycolide-based bioabsorbable copolymer and a water soluble solvent.

[0552] [000596] In some embodiments, including any of the foregoing, the cytotoxic or cytostatic powder is paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, or temsirolimus.

[0553] [000597] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer and the water soluble solvent are PLGA and N-methylpyrrolidone (NMP).

[0554] [000598] In some embodiments, including any of the foregoing, the cytotoxic or cytostatic agent is paclitaxel, the glycolide-based bioabsorbable copolymer is PLGA8515, and the water soluble solvent is NMP.

[0555] [000599] In some embodiments, the present specification provides a kit including a guide as described in any one of claims 42-70 or a delivery device as described in any one of claims 71-82, together with instructions for use thereof.

[0556] [000600] In some embodiments, provided herein is a kit comprising at least two or more pre-filled syringes, at least one of the at least two or more pre-filled syringes comprising a composition comprising a cytotoxic or cytostatic drug powder, and at least one of the at least two or more pre-filled syringes comprising a composition comprising a glycolide-based bioabsorbable copolymer and a water-soluble solvent, and instructions for mixing the pre-filled syringes.

[0557] [000601] In some embodiments, including any of the foregoing, the prefilled syringe mixing instructions direct how to provide a needled syringe assembly containing at least one unit volume v or more of a composition, the composition comprising a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and a water soluble solvent, the needled syringe assembly having a KIR of 15 to 1200, the KIR being:

number

[0558] [000602] In some embodiments, including any of the foregoing, one of the cytotoxic or cytostatic agents is selected from paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, or temsirolimus.

[0559] [000603] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer and the water soluble solvent comprise PLGA and NMP.

[0560] [000604] In some embodiments, including any of the foregoing, the kit includes instructions for dispensing at least one or more unit volumes v of the composition into the prostate to provide an outcome effective for treating BPH, including dispensing no more than a unit volume of the composition into a first prostatic location of the prostate using a needled syringe.

[0561] [000605] In some embodiments, including any of the above, the kit includes an adapter for joining two of the at least two or more pre-filled syringes.

[0562] [000606] In some embodiments, including any of the above, at least one of the two or more pre-filled syringes contains paclitaxel.

[0563] [000607] In some embodiments, including any of the above, at least one of the two or more pre-filled syringes contains docetaxel.

[0564] [000608] In some embodiments, including any of the above, at least one of the two or more pre-filled syringes contains sirolimus.

[0565] [000609] In some embodiments, including any of the above, at least one of the two or more pre-filled syringes comprises (NMP) and PLGA.

[0566] [000610] In some embodiments, including any of the above, the kit comprises a transrectal needle.

[0567] [000611] In some embodiments, including any of the above, the kit comprises a transurethral needle.

[0568] [000612] In some embodiments, including any of the above, the kit comprises an 18G needle.

[0569] [000613] In some embodiments, including any of the above, the kit comprises a 20G needle.

[0570] [000614] In some embodiments, including any of the above, the kit comprises a 22G needle.

[0571] [000615] In some embodiments, including any of the above, the kit comprises a 23G needle.

[0572] [000616] In some embodiments, including any of the above, the kit includes a 25G needle.

[0573] [000617] In some embodiments, including any of the above, the needle is between 10 cm and 70 cm in length.

[0574] [000618] In some embodiments, including any of the above, the needle is between 10 cm and 20 cm in length.

[0575] [000619] In some embodiments, including any of the above, the kit comprises a 20G x 20cm transrectal needle.

[0576] [000620] In some embodiments, including any of the above, the kit comprises a 23G x 70 cm transurethral needle.

[0577] [000621] In some embodiments, including any of the above, the kit comprises a commercially available transurethral needle, 23G x 45 cm.

[0578] [000622] In some embodiments, including any of the above, the kit includes an adapter for coupling one of the at least two or more pre-filled syringes to a cystoscope.

[0579] [000623] In some embodiments, including any of the above, the adapter is a hub for coupling one of at least two or more pre-filled syringes to a cystoscope.

[0580] [000624] In some embodiments, including any of the above, the adapter is a luer lock capable of coupling to a flexible cystoscope.

[0581] [000625] In some embodiments, including any of the above, the kit comprises a Tuehy-Borst type value.

[0582] [000626] In some embodiments, including any of the above, the kit comprises a 50 μL unit dose.

[0583] [000627] In some embodiments, including any of the above, the kit comprises a 100 μL unit dose.

[0584] [000628] In some embodiments, including any of the above, the kit comprises paclitaxel, NMP, and PLGA8515.

[0585] [000629] In some embodiments, including any of the foregoing, the kit comprises a 50% solution of PLGA 5002A polymer in NMP.

[0586] [000630] In some embodiments, including any of the foregoing, the kit includes at least one dosage administration guide for providing incremental dosages from one of the at least two or more pre-filled syringes.

[0587] [000631] In some embodiments, including any of the foregoing, the kit includes at least one dosing guide for providing two to three incremental doses per patient from one of at least two or more prefilled syringes.

[0588] [000632] In some embodiments, including any of the foregoing, the kit includes at least one dosage administration guide for providing incremental dosage amounts in unit volumes of 0.05 mL to 0.1 mL from one of the at least two or more prefilled syringes.

[0589] [000633] In some embodiments, including any of the foregoing, the kit includes at least one dosage administration guide for providing incremental dosages in unit volumes of 0.1 mL to 0.2 mL from one of the at least two or more prefilled syringes.

[0590] [000634] In some embodiments, including any of the foregoing, the kit includes at least one dosage administration guide for providing 4-8 unit volumes of incremental dosages from one of the at least two or more prefilled syringes.

[0591] [000635] In some embodiments, including any of the above, KIR is 15-300, 100-900, 300-600, 15-1000, or 40-400.

[0592] [000636] In some embodiments, including any of the above, the kit comprises at least n number of unit volumes, where n is related to the prostate volume PV as n=PV / (200×v).

[0593] [000637] In some embodiments, including any of the above, the kit comprises at least n number of unit volumes, where TZUL is the BPH transition zone urethral length, and n=TZUL / (11 x v).

[0594] [000638] In some embodiments, including any of the above, the TZUL is between 1.5 cm and 3.5 cm.

[0595] [000639] In some embodiments, including any of the above, TZUL is 2 cm, v is 0.05 ml, and n is 3.

[0596] [000640] In some embodiments, including any of the above, n is 1-10.

[0597] [000641] In some embodiments, including any of the above, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0598] [000642] In some embodiments, including any of the foregoing, the needle syringe has a needle thinness ratio of greater than 300.

[0599] [000643] In some embodiments, including any of the above, the needle syringe has a needle thinness ratio of 300-1200.

[0600] [000644] In some embodiments, including any of the above, μ is between 250 cP and 4000 cP.

[0601] [000645] In some embodiments, including any of the above, μ is between 250 cP and 1100 cP.

[0602] [000646] In some embodiments, including any of the above, the height of the dose administration guide is proportional to the delivery volume in the needle syringe.

[0603] [000647] In some embodiments, including any of the above, L is between 10 and 20 cm.

[0604] [000648] In some embodiments, including any of the above, L is 15-20 cm.

[0605] [000649] In some embodiments, including any of the above, the needle has a length / distance ratio (L / D) of 300-1200.

[0606] [000650] In some embodiments, including any of the above, the needle has a length / distance ratio (L / D) of 250-350.

[0607] [000651] In some embodiments, including any of the above, the needle has an inner diameter of between 0.06 cm and 0.08 cm.

[0608] [000652] In some embodiments, including any of the foregoing, the syringe barrel contains between 2 and 10 unit volumes of the composition, excluding any dead volume of the composition within the syringe barrel.

[0609] [000653] In some embodiments, including any of the above, PV is 20~80cm 3 and L is 15 to 20 cm. The outer cylinder has a slenderness ratio of 5 to 20. D is about 0.06 cm to about 0.08 cm, v is between 0.05 ml and 0.1 ml; and μ is 250cP to 1100cP.

[0610] [000654] In some embodiments, including any of the foregoing, the needled syringe includes a needle configured to create multiple lesions along the urethral transition zone.

[0611] [000655] In some embodiments, including any of the foregoing, the needle syringe includes up to 20 side holes through which the needle syringe can inject the composition.

[0612] [000656] In some embodiments, including any of the foregoing, the needle syringe includes 10 to 20 side holes through which the needle syringe can inject the composition.

[0613] [000657] In some embodiments, including any of the foregoing, the needle syringe includes 12 side holes through which the needle syringe can inject the composition.

[0614] [000658] In some embodiments, including any of the above, the needle syringe is a large 20 Fr / 6.7 mm OD and 22 cm in length.

[0615] [000659] In some embodiments, including any of the above, the delivery system shaft or sheath is flexible.

[0616] [000660] In some embodiments, including any of the above, the delivery system or sheath is rigid.

[0617] [000661] In some embodiments, including any of the above, the barrel includes a luer port for connecting to a needle.

[0618] [000662] In some embodiments, including any of the above, the guide is configured to open for manual withdrawal of the needle.

[0619] [000663] In some embodiments, including any of the above, the retractable needle length for tissue penetration is greater than 5 mm.

[0620] [000664] In some embodiments, including any of the above, the kit includes a length of retractable needle for tissue penetration that is greater than about 8 mm.

[0621] [000665] In some embodiments, provided herein is a method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: Providing a guide according to any one of claims 1 to 29, a delivery device according to any one of claims 30 to 41 or a kit according to any one of claims 42 to 103; dispensing a total volume of the composition into the prostate to produce an effective outcome for the treatment of BPH, comprising dispensing a unit volume or less of the composition into a first prostatic location of the prostate using a needle syringe; A method is presented that includes:

[0622] [000666] In some embodiments, including any of the foregoing, the method includes using ultrasound imaging in conjunction with a transrectal needle or using cystoscopic imaging in conjunction with a transurethral needle.

[0623] [000667] In some embodiments, including any of the foregoing, the method includes placing a needle syringe at a second location within the prostate and dispensing no more than one unit volume of the composition to the second location of the prostate.

[0624] [000668] In some embodiments, including any of the foregoing, a multiple n of unit volumes v or less are injected into the prostate to treat the prostate at corresponding n prostate locations, where n=TZUL / (11×v).

[0625] [000669] In some embodiments, including any of the foregoing, a plurality of n unit volumes v or less are injected into the prostate to treat the prostate at n corresponding prostate locations, where n is related to the prostate volume PV as n=PV / (200×v), and the sum of the unit volumes is the total volume for the prostate volume PV.

[0626] [000670] In some embodiments, including any of the above, the needle syringe includes a barrel that holds at least n unit volumes, where n is an integer from 2 to 10; When the prostate size is 20-40 grams, n is 2-4. When the prostate size is 40-60 grams, n is 2-6; n is between 4 and 8 when the prostate size is between 60 and 80 grams, and When the prostate size is 80 grams or more, n is 6 to 10.

[0627] [000671] In some embodiments, including any of the above, the unit volume is 0.05 ml to 0.5 ml, 0.05 ml to 0.1 ml, 0.1 to 0.2 ml, or 0.05 to 0.2 ml.

[0628] [000672] In some embodiments, including any of the above, the composition comprises between 4% and 15% by volume of the cytotoxic or cytostatic agent.

[0629] [000673] In some embodiments, including any of the foregoing, the cytotoxic or cytostatic agent is selected from the group consisting of paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, and temsirolimus.

[0630] [000674] In some embodiments, including any of the above, the cytotoxic agent is docetaxel or paclitaxel.

[0631] [000675] In some embodiments, including any of the foregoing, the cytostatic agent is sirolimus.

[0632] [000676] In some embodiments, including any of the foregoing, the method includes measuring the TZUL and selecting a total number of unit volumes v of the composition to dispense into the prostate at each of a plurality of locations in the prostate based on the TZUL, wherein the sum of the unit volumes is approximately equal to the total volume.

[0633] [000677] In some embodiments, including any of the foregoing, the method includes measuring a prostate size and selecting a total volume of a composition for treating BPH based on the prostate size, wherein the selecting includes selecting a number of unit volumes of the composition to dispense into the prostate at each of a plurality of locations in the prostate, wherein the sum of the unit volumes is approximately equal to the total volume.

[0634] [000678] In some embodiments, including any of the above, the prostate size is prostate volume or prostate weight, and the prostate volume or prostate weight is measured by ultrasound imaging.

[0635] [000679] In some embodiments, including any of the above, the composition further comprises an alpha blocker or a 5 alpha reductase inhibitor, or an anti-inflammatory agent.

[0636] [000680] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer is selected from the set of poly(D,L-lactide-co-glycolide) having a 50:50 molar ratio of lactide to glycolide, poly(D,L-lactide-co-glycolide) having a 65:35 molar ratio of lactide to glycolide, and poly(D,L-lactide-co-glycolide) having a 75:25 molar ratio of lactide to glycolide, and poly(D,L-lactide-co-glycolide) having a 85:15 molar ratio of lactide to glycolide.

[0637] [000681] In some embodiments, including any of the foregoing, the water-soluble solvent capable of dissolving the drug and the copolymer is selected from the set of N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO), and combinations thereof.

[0638] [000682] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer is selected from the set of poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA.

[0639] [000683] In some embodiments, including any of the foregoing, the glycolide-based bioabsorbable copolymer has a total concentration of 30-55% by weight, the solvent has a total concentration of 69.5-40% by weight, and the cytotoxic or cytostatic agent has a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight.

[0640] [000684] In some embodiments, including any of the above, the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

[0641] [000685] In some embodiments including any of the above, the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

[0642] [000686] In some embodiments, including any of the above, the unit volume is between 0.05 ml and 0.2 ml.

[0643] [000687] In some embodiments, including any of the above, the multiple unit volumes equal a total volume for treatment of BPH.

[0644] [000688] In some embodiments, including any of the above, the composition has 4% to 15% by volume of a cytotoxic or cytostatic agent, wherein the cytotoxic agent is docetaxel or paclitaxel, and the cytostatic agent is sirolimus.

[0645] [000689] In some embodiments, including any of the above, n is the number of unit volumes of the composition, where n is related to TZUL as n=TZUL / (11×v).

[0646] [000690] In some embodiments, including any of the above, for the treatment of BPH, the plurality of unit volumes, n, is related to the prostate volume, PV, as n=PV / (200×v).

[0647] [000691] In some embodiments, including any of the above, the anti-inflammatory agent is selected from a corticosteroid, a vasodilator, and combinations thereof.

[0648] [000692] In some embodiments, including any of the foregoing, the method includes forcing the plunger head through the unit volume delivery system until the plunger head traverses each unit volume distance (LDC).

[0649] [000693] In some embodiments, including any of the above, the unit volume is as shown in any one of Figures 3A, 3B, 14A or 14B. In some embodiments, including any of the above, the unit volume is 0.05 ml, 0.1 ml, 0.25 ml, 0.5 ml.

[0650] [000694] In some embodiments, including any of the above, the SRF viscosity is as shown in any one of Figures 3A, 3B, 14A, or 14B. In some embodiments, including any of the above, the viscosity (cP) is in the range of 267-10,000. In some embodiments, including any of the above, the viscosity (cP) is in the range of 267-1,000.

[0651] [000695] In some embodiments, including any of the above, the needle length is as shown in any one of Figures 3A, 3B, 14A, or 14B. In some embodiments, including any of the above, the needle length is in the range of 35 cm to 75 cm.

[0652] [000696] In some embodiments, including any of the above, the needle inner diameter is as shown in any one of Figures 3A, 3B, 14A, or 14B. In some embodiments, including any of the above, the needle inner diameter is in the range of 0.0413 cm to 0.026.

[0653] [000697] In some embodiments, including any of the foregoing, the bioabsorbable polymer is present in a total concentration as shown in any one of FIG. 2 or FIG. 4A. In some embodiments, including any of the foregoing, the bioabsorbable polymer is PLGA8515. In some embodiments, including any of the foregoing, the bioabsorbable polymer is PLGA7525. In some embodiments, including any of the foregoing, the bioabsorbable polymer is PLGA7525. In some embodiments, including any of the foregoing, the bioabsorbable polymer is PLGA5050. In some embodiments, including any of the foregoing, the bioabsorbable polymer is present in a concentration ranging from 35% to 48% by weight. In some embodiments, including any of the foregoing, the bioabsorbable polymer is present in a concentration ranging from 35% to 40% by weight. In some embodiments, including any of the foregoing, the bioabsorbable polymer is present in a concentration ranging from 37% to 40% by weight. In some embodiments, including any of the foregoing, the bioabsorbable polymer is present in a concentration ranging from 37% to 45% by weight. In some embodiments, including any of the foregoing, the bioabsorbable polymer is present in a concentration ranging from 37% to 48% by weight.

[0654] [000698] In some embodiments, including any of the above, the solvent is present as in any one of Figures 2 or 4A. In some embodiments, including any of the above, the solvent is NMP.

[0655] [000699] In some embodiments, including any of the foregoing, the drug is present at a total concentration shown in any one of Figures 2 or 4A. In some embodiments, including any of the foregoing, the drug is sirolimus. In some embodiments, including any of the foregoing, the drug is paclitaxel. In some embodiments, including any of the foregoing, the drug is everolimus. In some embodiments, including any of the foregoing, the drug is docetaxel. In some embodiments, including any of the foregoing, the drug is carmustine. In some embodiments, including any of the foregoing, the drug is mitomycin. In some embodiments, including any of the foregoing, the drug is temsirolimus. In some embodiments, including any of the foregoing, the drug is present at a concentration ranging from 3% to 12% by weight.

[0656] [000700] The embodiments of the present disclosure presented above and in the figures relate to specific embodiments. Those skilled in the art will understand that alternatives may be made without departing from the spirit and scope of the appended claims herein. Different variations of the embodiments may exist in different forms, and other embodiments are all contemplated to fall within the spirit and scope of the appended claims.

Claims

1. 1. A method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: using a needled syringe containing a composition comprising a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and an aqueous solvent capable of dissolving the drug and the copolymer; dispensing a total volume of the composition into the prostate to produce an outcome effective in treating BPH, comprising dispensing a unit volume or less of the composition into a first prostatic location of the prostate using the needle syringe; The method includes:

2. The method further comprises using a device comprising the needle syringe and the composition, the device having a KIR of 10-1000, 10-300, or 40-400, the KIR being: [0010] The method of claim 1 , wherein the

3. 3. The method of claim 1 or 2, further comprising the steps of placing the needle syringe at a second location within the prostate and dispensing, using the device, no more than one unit volume of the composition to the second location of the prostate.

4. 4. The method of any one of claims 1 to 3, wherein a plurality of n unit volumes v or less are injected into the prostate to treat the prostate at corresponding n prostate locations, where n is related to a prostate volume PV as n=PV / (200×v), and the sum of the plurality of n unit volumes is a total volume for the prostate volume PV.

5. The needle syringe includes: When the prostate size is 20-40 grams, n is 2-4; n is 2 to 6 when the prostate size is 40 to 60 grams; n is 4 to 8 when the prostate size is 60 to 80 grams; and When the prostate size is 80 grams or more, n is 6 to 10.

5. The method of claim 4, further comprising: an outer cylinder for holding at least n said unit volumes such that

6. The needle syringe includes: n is 4 when the prostate size is between 20 and 40 grams; n is 4 to 6 when the prostate size is 40 to 60 grams; n is 4 to 8 when the prostate size is 60 to 80 grams; and When the prostate size is 80 grams or more, n is 6 to 10.

5. The method of claim 4, further comprising: an outer cylinder for holding at least n said unit volumes such that

7. 7. The method of any one of claims 1 to 6, wherein the unit volume is between 0.05 ml and 0.5 ml, between 0.05 ml and 0.1 ml, between 0.1 and 0.2 ml, or between 0.05 and 0.2 ml.

8. The method of any one of claims 1 to 7, wherein the composition comprises 4% to 15% by volume of the cytotoxic or cytostatic agent.

9. 9. The method of claim 8, wherein the cytotoxic drug is docetaxel or paclitaxel.

10. The method of claim 8 , wherein the cytostatic drug is sirolimus.

11. 11. The method of any one of claims 1 to 10, further comprising the steps of measuring a prostate size and selecting a total volume of the composition for treating BPH based on the prostate size, said selecting comprising selecting a number of unit volumes of the composition for dispensing into the prostate at each of a plurality of locations of the prostate, wherein the sum of the unit volumes is approximately equal to the total volume.

12. The method of claim 11 , wherein the prostate volume or weight is measured by ultrasound imaging.

13. The method of any one of claims 1 to 12, wherein the composition further comprises an anti-inflammatory agent, such as an alpha blocker or a 5-alpha reductase inhibitor, a corticosteroid, and / or a vasodilator.

14. 14. The method according to any one of claims 1 to 13, wherein the glycolide-based bioabsorbable copolymer is selected from the group consisting of poly(D,L-lactide-co-glycolide) (50:50), poly(D,L-lactide-co-glycolide) (65:35), and poly(D,L-lactide-co-glycolide) (75:25), and poly(D,L-lactide-co-glycolide) (85:15).

15. The method according to any one of claims 1 to 14, wherein the water-soluble solvent capable of dissolving the drug and the copolymer is selected from the group consisting of N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO) and combinations thereof.

16. The method according to any one of claims 1 to 15, wherein the glycolide-based bioabsorbable copolymer is selected from the group poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA.

17. The method according to any one of claims 1 to 16, wherein the glycolide-based bioabsorbable copolymer comprises PEG groups.

18. 18. The method of any one of claims 1 to 17, wherein the glycolide-based bioabsorbable copolymer has a total concentration of 30 to 50% by weight, the solvent has a total concentration of 50 to 30% by weight, and the cytotoxic or cytostatic drug has a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight.

19. 19. The method of any one of claims 1 to 18, wherein the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

20. The method of any one of claims 1 to 19, wherein the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

21. 1. A method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: using a device including a needled syringe containing a composition including a cytotoxic or cytostatic drug, a glycolide-based bioabsorbable copolymer, and an aqueous solvent capable of dissolving the drug and the copolymer, the composition having an absolute viscosity μ, and the needled syringe having a needle length L with an inner diameter D; dispensing a plurality of unit volumes v of said composition into a respective plurality of different locations in the prostate using said needle syringe; Including, The unit volume is 0.05 ml to 0.2 ml. said plurality of unit volumes being equal to a total volume for the treatment of BPH; The device has 10-300 or 40-400 KIRs, and the KIRs [0025] The method is defined as:

22. 22. The method of claim 21, wherein the composition has 4% to 15% by volume of the cytotoxic or cytostatic drug, and the cytotoxic drug is docetaxel or paclitaxel and the cytostatic drug is sirolimus.

23. 22. The method of claim 21, wherein the plurality of n unit volumes is related to a prostate volume PV for the treatment of BPH as n=PV / (200×v).

24. 1. An apparatus for treating a prostate volume (PV), comprising: a composition having an absolute viscosity μ and comprising an SRF in an amount of at least one unit volume v; a syringe containing the composition in a barrel of the syringe, including a needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition; Including, said syringe holds at least n of said unit volumes v, where n is related to PV as n=PV / (200×v), and said n unit volumes are equal to a total volume for treatment of BPH; The device has a KIR of 10-1000, 10-300, or 40-400, and the KIR is (μ)×(L) ２ / (vD) × 10 （－６） The device is defined as:

25. 25. The apparatus of claim 24, wherein μ is between 267 cP and 500 cP.

26. 25. The apparatus of claim 24, wherein μ is between 500 cP and 6000 cP.

27. 27. Apparatus according to any one of claims 24 to 26, wherein L is between 15 and 20 cm.

28. 28. Apparatus according to any one of claims 24 to 27, wherein the barrel has a slenderness ratio of 5 to 50 or more precisely 10 to 30.

29. 29. The device according to any one of claims 24 to 28, wherein the needle has a slenderness ratio (L / D) of 200 to 400 or 250 to 350.

30. 30. The device of claim 29, wherein the needle has an inner diameter of 0.02 cm to about 0.12 cm, or more narrowly 0.06 cm to 0.08 cm.

31. 31. A device according to any one of claims 24 to 30, wherein v is between 0.05ml and 0.2ml.

32. L is 15 cm to 20 cm, the barrel has a slenderness ratio of 5 to 50 or 10 to 30; the needle has an inner diameter of 0.06 cm to about 0.08 cm; v is between 0.05 ml and 0.2 ml; and 32. The device of any one of claims 24 to 31, wherein the viscosity is between 1065 cP and 4000 cP.

33. L is 35 cm to 75 cm, the barrel has a slenderness ratio of 5 to 50 or 10 to 30; the needle has an inner diameter of 0.03 cm to about 0.04 cm; v is between 0.05 ml and 0.2 ml; and 33. The device of any one of claims 24 to 32, wherein the viscosity is between 250 cP and 1100 cP.

34. 34. The device of any one of claims 24 to 33, wherein the syringe barrel contains 2 to 10 unit volumes of the composition, excluding any dead volume of composition within the syringe barrel.

35. The composition comprises: Bioabsorbable polymer at a total concentration of 40-50% by weight, solvent at a total concentration of 80-20% by weight, 75-25% by weight, 60-40% by weight, and drug at a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight. The apparatus according to any one of claims 24 to 34, comprising:

36. 36. The device of any one of claims 24 to 35, wherein the SRF drug has a release rate of 10% to 85% or less over the first month, 25% to 95% or less over the first three months, and / or 50% to 100% or less over the first six months.

37. 37. The device of any one of claims 24 to 36, wherein the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

38. 38. The device of any one of claims 24 to 37, wherein the SRF comprises up to 0.1-10%, 10-15% or 20-30% by weight of the SRF of a cytostatic or cytotoxic drug.

39. The device of any one of claims 24 to 38, wherein the drug is sirolimus, docetaxel or paclitaxel.

40. 40. A device according to any one of claims 24 to 39, wherein the drug comprises an anti-inflammatory drug such as an alpha blocker or a 5-alpha reductase inhibitor, a corticosteroid and / or a vasodilator.

41. The device of any one of claims 24 to 40, wherein the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

42. The device according to any one of claims 24 to 41, wherein the KIR is between 40 and 400.

43. 1. An apparatus for treating a prostate volume (PV), comprising: a composition having an absolute viscosity μ and comprising an SRF in an amount of at least one unit volume v; a syringe containing the composition in a barrel of the syringe, including a needle having a length L and a lumen diameter D, and adapted to be placed in fluid communication with the composition; Including, said syringe holds at least n said unit volumes, and n is related to PV as n=PV / (200×v); L is 15 cm to 20 cm or 35 cm to 70 cm, the barrel having a slenderness ratio of about 10 and 30; the needle has an inner diameter of 0.06 cm to about 0.08 cm or 0.03 cm to about 0.04 cm; v is between 0.05 ml and 0.1 ml; and μ is between 1065 cP and 4000 cP or between 250 cP and 1100 cP; The device has (μ)×(L) ２ / (vD) × 10 （－６） A device having a KIR of 10-1000, defined as:

44. The device of claim 43, wherein the KIR is between 40 and 400.

45. 44. The device of claim 43, wherein the syringe barrel contains between 2 and 10 unit volumes of the composition, excluding any dead volume of composition within the syringe barrel.

46. 1. A guide for providing incremental dosages of an SRF from a syringe coupled to the guide, the syringe including a barrel, a finger hook extending from the barrel, and a plunger movable relative to the barrel, the guide comprising: (c) a body extending along a central axis between a first end and a second end, the body defining an interior space; (4) an exterior wall; (5) an inner wall disposed radially inward of the outer wall; (6) a plurality of detents extending from the inner wall into the interior space, the detents being spaced apart from one another along the central axis of the body; A main body including (d) a finger catch at the second end of the body, the finger catch configured to engage the finger catch of the syringe to prevent the barrel from moving relative to the body. when the syringe is provided to the guide, the plunger extends into the interior space of the body, when the plunger is moved relative to the barrel, a first detent of the plurality of detents is configured to engage the plunger to resist movement of the plunger relative to the barrel, and the plunger is movable beyond the first detent of the plurality of detents to a second detent of the plurality of detents.

47. 47. The guide of claim 46, wherein the finger restraint portion is provided as an aperture extending through the body between the outer wall and the inner wall, and wherein when the syringe is provided in the guide, the finger rest extends through the aperture and away from the body.

48. 48. A guide as claimed in claim 46 or 47, wherein the finger restraining portion is provided as wings extending radially outward from the outer wall of the body, the wings at least partially enclosing the finger rest when the syringe is provided on the guide.

49. 49. The guide of any one of claims 46 to 48, wherein the body includes a first portion and a second portion, the second portion being movable relative to the first portion to transition the guide between a first state and a second state, the first state allowing movement of the outer tube relative to the body and the second state preventing movement of the outer tube relative to the body.

50. 50. The guide of claim 49, wherein the first and second portions are connected together by a hinge, and the body includes a snap-fit ​​connector for maintaining the guide in the second state.

51. 51. The guide of claim 50, wherein the first portion and the second portion are separate components, the body includes a snap-fit ​​connector for securing the second portion to the first portion, and the guide is in the second state when the second portion is secured to the first portion.

52. 52. The guide of any one of claims 46-51, wherein a first distance (LDC) between the first and second detents along the central axis of the body corresponds to one unit volume (v) of composition contained within the barrel.

53. The barrel of the syringe has an inner diameter (d), and the first distance (LDC) is proportional to the unit volume (v), and the first distance LDC is: LDC=[4 / (πd ２ )]v 53. The guide of claim 52, defined as:

54. A guide according to any one of claims 46 to 53, wherein the detent is configured to provide tactile feedback to inform a user that the plunger has travelled the first distance.

55. A guide according to any one of claims 46 to 54, wherein the detent is configured to provide acoustic feedback to inform a user that the plunger has travelled the first distance.

56. 56. A guide as described in any one of claims 46 to 55, wherein the plunger includes a head, the plurality of detents includes a third detent located between the first detent and the second detent, and a second distance between the first detent and the third detent along the central axis of the body and a third distance between the third detent and the first detent along the central axis of the body are both equal to a thickness of the head.

57. 57. A guide as claimed in any one of claims 46 to 56, wherein the inner wall has a first circumscribing area and the plunger includes a head having a second circumscribing area, the second circumscribing area being smaller than the first second circumscribing area.

58. A guide as claimed in any one of claims 46 to 57, wherein the inner wall has a first circumscribing area and the plunger includes a head having a second circumscribing area, the second circumscribing area being smaller than the first second circumscribing diameter.

59. A guide according to any one of claims 46 to 58, wherein resistance to movement of the plunger relative to the barrel is provided by engagement between the detent and the head of the plunger.

60. 60. A guide as claimed in any one of claims 46 to 59, wherein the plunger includes a head having a rounded rectangular configuration, and a cross-section of the inner wall of the body approximates at least a portion of the rounded rectangular configuration of the head of the plunger.

61. 61. The guide of claim 60, wherein the detents are provided only on the at least a portion of the rounded rectangular configuration, optionally only on a curved portion of the inner wall of the body.

62. A guide as claimed in any one of claims 46 to 61, wherein the body includes separate parts which are cantilevered from a weakened portion or base of the guide and which together form the interior of the body for passage of the plunger head.

63. 63. The guide of claim 62, wherein the weakened portion is provided as a slot extending through the body between the outer wall and the inner wall, the slot being positioned to weaken the resistance of the body to outward pressure applied when the plunger head is forcibly moved between detents.

64. 64. The guide of claim 63, wherein the weakened portion is provided as a portion of reduced thickness that does not extend through the body.

65. 65. The guide of claim 64, wherein the reduced thickness portion extends substantially parallel to the central axis of the body.

66. 66. The guide of any one of claims 46-65, wherein the body includes a cutout portion extending from a terminal end of the body toward the first end, the cutout portion configured to provide clearance for a finger of a user manipulating the syringe to move the plunger head toward the barrel when dispensing a unit volume.

67. A guide according to any one of claims 46 to 66, wherein when the syringe is provided to the guide, a portion of the barrel of the syringe is disposed in the body.

68. 68. The guide of claim 67, wherein the body further includes a plurality of bumpers extending from the inner wall into the interior space, the bumpers configured to engage the portion of the barrel of the syringe disposed in the body to prevent the barrel from moving relative to the body.

69. A guide according to any one of claims 46 to 68, which is a unitary assembly securable onto a syringe barrel of the needle syringe assembly.

70. 70. The guide of any one of claims 46-69, comprising a plurality of number n of unit volumes v of a composition, where n is related to TZUL as n=TZUL / (11×v), the composition comprising a cytotoxic or cytostatic drug powder, a glycolide-based bioabsorbable copolymer, and a water soluble solvent.

71. 71. The guide of any one of claims 46-70, comprising a plurality of number n of unit volumes of a composition, n being related to a prostate volume PV as n=PV / (200×v), the composition comprising a cytotoxic or cytostatic drug powder, a glycolide-based bioabsorbable copolymer, and a water-soluble solvent.

72. 72. The guide of claim 70 or 71, wherein the TZUL is between 1.5 cm and 3.5 cm.

73. 72. The guide of claim 70 or 71, wherein TZUL is 2 cm, v is 0.05 ml, and n is 3.

74. A guide according to any one of claims 46 to 73, comprising dead volume control.

75. A delivery device configured to mix a first composition with a second composition, comprising: a barrel extending between a first end and a second end, the first end of the barrel adapted for attachment to a needle; a septum disposed within the barrel, the septum dividing the barrel into a first chamber and a second chamber, the first chamber receiving the first composition and the second chamber receiving the second composition; a plunger extending from the second end of the barrel, the plunger being movable relative to the barrel and configured to break the septum to allow the first composition to mix with the second composition to form a mixture, and to force the mixture from the first end of the barrel into the needle; A delivery device comprising:

76. 76. The delivery device of claim 75, further comprising a piercing member disposed within the barrel, the piercing member configured to break the septum.

77. 77. The delivery device of claim 76, wherein the plunger engages the piercing member to move the piercing member relative to the barrel to break the septum.

78. 77. The delivery device of claim 76, wherein the plunger includes a shaft portion extending between a first end and a second end, a piston provided at the first end of the shaft portion, the piston in sealing engagement with an inner surface of the barrel.

79. 80. The delivery device of claim 78, wherein the piston engages and breaks the septum.

80. 77. The delivery device of claim 76, further comprising a piercing member disposed within the barrel and configured to break the septum, wherein the piston engages the piercing member to move the piercing member relative to the barrel to break the septum.

81. 81. A delivery device according to any one of claims 75 to 80, wherein a head is provided at the second end of the shaft portion, the head having a first circumscribed diameter and the shaft portion having a second circumscribed diameter, the first circumscribed diameter being greater than the second circumscribed diameter.

82. 82. The delivery device of any one of claims 75 to 81, further comprising a finger hook extending from an outer surface of the barrel and extending along a first axis transverse to a central axis of the barrel.

83. 83. The delivery device of any one of claims 75 to 82, wherein the first composition comprises a cytotoxic or cytostatic drug powder and the second composition comprises a glycolide-based bioabsorbable copolymer and a water soluble solvent.

84. 84. The delivery device of claim 83, wherein the cytotoxic or cytostatic drug powder is paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, or temsirolimus.

85. 84. The delivery device of claim 82 or 83, wherein the glycolide-based bioabsorbable copolymer and water-soluble solvent are PLGA and N-methylpyrrolidone (NMP).

86. 86. The delivery device of claim 85, wherein the cytotoxic or cytostatic drug is paclitaxel, the glycolide-based bioabsorbable copolymer is PLGA8515, and the water soluble solvent is NMP.

87. A kit comprising a guide according to any one of claims 46 to 74 or a delivery device according to any one of claims 75 to 86, together with instructions for use thereof.

88. At least two or more prefilled syringes, one of the at least two or more pre-filled syringes contains a composition comprising a cytotoxic or cytostatic drug powder; At least two or more pre-filled syringes, one of which contains a composition comprising a glycolide-based bioabsorbable copolymer and a water-soluble solvent; instructions for mixing said prefilled syringe; Kit including:

89. at least one syringe containing a composition comprising a cytotoxic or cytostatic drug powder, a composition comprising a glycolide-based bioabsorbable copolymer, and a water-soluble solvent; instructions for administration of said composition; Kit including:

90. The instructions for mixing the prefilled syringe direct a method of providing a needle syringe assembly containing at least one unit volume v or more of a composition, the composition comprising: said cytotoxic or cytostatic drug; The glycolide-based bioabsorbable copolymer; The water-soluble solvent. Including, the needle-syringe assembly has a K Injection Ratio (KIR) of 15 to 1200; K.I.R. [0030] is defined as The needle syringe has a needle length L and a tube diameter D, 89. The kit of claim 88, wherein μ is the absolute viscosity of the composition.

91. 90. The kit of claim 88 or 89, wherein the one of the cytotoxic or cytostatic drugs is selected from paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, or temsirolimus.

92. The kit of any one of claims 88 to 91, wherein the glycolide-based bioabsorbable copolymer and water-soluble solvent comprise PLGA and NMP.

93. 88. The kit of claim 87, further comprising instructions for dispensing at least one unit volume v or more of the composition into the prostate to provide an effective outcome for the treatment of BPH, comprising dispensing no more than a unit volume of the composition into a first prostatic location of the prostate using the needle syringe.

94. The kit of any one of claims 88 to 92, further comprising an adapter for joining two of the at least two or more pre-filled syringes.

95. The kit of any one of claims 88 to 93, wherein one of the at least two or more prefilled syringes contains paclitaxel.

96. The kit of any one of claims 88 to 94, wherein one of the at least two or more pre-filled syringes contains docetaxel.

97. The kit of any one of claims 88 to 95, wherein one of the at least two or more pre-filled syringes contains sirolimus.

98. The kit of any one of claims 84 to 96, wherein one of the at least two or more pre-filled syringes comprises (NMP) and PLGA.

99. The kit of any one of claims 84 to 97, further comprising a transrectal needle.

100. The kit of any one of claims 84 to 98, further comprising a transurethral needle.

101. The kit of any one of claims 84 to 98, further comprising an 18G needle.

102. The kit of any one of claims 84 to 98, further comprising a 20G needle.

103. The kit of any one of claims 84 to 98, further comprising a 22G needle.

104. The kit of any one of claims 84 to 98, further comprising a 23G needle.

105. The kit of any one of claims 84 to 98, further comprising a 25G needle.

106. The kit of any one of claims 84 to 100, wherein the needle is between 10 cm and 70 cm in length.

107. The kit of any one of claims 84 to 100, wherein the needle is between 10 cm and 20 cm in length.

108. The kit of any one of claims 84 to 100, further comprising a 20G x 20cm transrectal needle.

109. The kit of any one of claims 84 to 100, further comprising a 23G x 70cm transurethral needle.

110. The kit according to any one of claims 84 to 100, comprising a commercially available transurethral needle of 23G x 45cm.

111. The kit of any one of claims 84 to 1110, further comprising an adapter for connecting one of the at least two or more pre-filled syringes to a cystoscope.

112. 112. The kit of claim 111, wherein the adapter is a hub for connecting one of the at least two or more pre-filled syringes to a cystoscope.

113. The kit of any one of claims 105 to 1112, wherein the adapter is a luer lock capable of being coupled to a flexible cystoscope.

114. The kit of any one of claims 105 to 113, further comprising a Tuehy-Borst type value.

115. The kit of any one of claims 84 to 114, comprising a unit dose of 50 μL.

116. 115. The kit of any one of claims 84 to 114, comprising a unit dose of 100 μL.

117. The kit of any one of claims 84 to 116, comprising paclitaxel, NMP and PLGA8515.

118. 118. The kit of any one of claims 84 to 117, comprising a 50% solution of PLGA 5002A polymer in NMP.

119. The kit of any one of claims 84 to 118, further comprising at least one dosage administration guide for providing incremental dosages from one of the at least two or more pre-filled syringes.

120. The kit of any one of claims 84 to 119, further comprising at least one dosage administration guide for providing 2-3 incremental doses per patient from one of the at least two or more pre-filled syringes.

121. The kit of any one of claims 84 to 120, further comprising at least one dosage administration guide for providing incremental dosages of unit volumes of 0.05 mL to 0.1 mL from one of the at least two or more pre-filled syringes.

122. The kit of any one of claims 84 to 121, further comprising at least one dosage administration guide for providing incremental dosages of unit volumes of 0.1 mL to 0.2 mL from one of the at least two or more prefilled syringes.

123. The kit of any one of claims 84 to 122, further comprising at least one dosage administration guide for providing 4 to 8 unit volumes of incremental dosage from one of the at least two or more prefilled syringes.

124. The kit of any one of claims 88 to 123, wherein the KIR is 15 to 300, 100 to 900, 300 to 600, 15 to 1000, or 40 to 400.

125. 125. The kit of any one of claims 88 to 124, comprising at least n number of unit volumes, where n is related to the prostate volume PV as n=PV / (200×v).

126. 126. The kit of any one of claims 88 to 125, comprising at least n number of unit volumes, TZUL being the BPH transition zone urethral length, and n=TZUL / (11 x v).

127. The kit of claim 126, wherein the TZUL is between 1.5 cm and 3.5 cm.

128. 128. The kit of claim 126 or 127, wherein TZUL is 2 cm, v is 0.05 ml, and n is 3.

129. The kit according to any one of claims 125 to 128, wherein n is 1 to 10.

130. The kit of any one of claims 125 to 129, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

131. The kit according to any one of claims 88 to 129, wherein the needled syringe has a needle thinness ratio of greater than 300.

132. The kit according to any one of claims 88 to 129, wherein the needled syringe has a needle thinness ratio of 300 to 1200.

133. The kit according to any one of claims 88 to 131, wherein μ is between 250 cP and 4000 cP.

134. The kit according to any one of claims 88 to 132, wherein μ is between 250 cp and 1100 cP.

135. The kit of any one of claims 88 to 134, wherein the height of the dosage guide is proportional to the delivery volume in the needle syringe.

136. The kit according to any one of claims 88 to 135, wherein L is 10 to 20 cm.

137. The kit according to any one of claims 88 to 135, wherein L is 15 to 20 cm.

138. The kit of any one of claims 88 to 137, wherein the needle has a slenderness ratio (L / D) of 300 to 1200.

139. The kit of any one of claims 88 to 138, wherein the needle has a length / distance ratio (L / D) of 250 to 350.

140. The kit of any one of claims 88 to 138, wherein the needle has an inner diameter of between 0.06 cm and 0.08 cm.

141. 139. The kit of any one of claims 88 to 138, wherein the syringe barrel contains 2 to 10 unit volumes of the composition, excluding dead volume of the composition within the syringe barrel.

142. PV is 20 to 200 cm ３ and L is 15 to 20 cm; the barrel has a slenderness ratio of 5 to 20; D is about 0.06 cm to about 0.08 cm; v is between 0.05 ml and 0.1 ml; and The kit according to any one of claims 88 to 141, wherein μ is between 250 cP and 1100 cP.

143. 143. The kit of any one of claims 88-142, wherein the needled syringe includes a needle configured to create multiple lesions along the urethral transition zone.

144. The kit of any one of claims 88 to 143, wherein the needle syringe comprises up to 20 side holes through which the needle syringe can inject the composition.

145. 145. The kit of any one of claims 88 to 144, wherein the needle syringe comprises 10 to 20 side holes through which the needle syringe can inject the composition.

146. 146. The kit of any one of claims 88 to 145, wherein the needle syringe includes 12 side holes through which the needle syringe can inject the composition.

147. The kit of any one of claims 88 to 146, wherein the needle syringe is large 20 Fr / 6.7 mm OD and 22 cm long.

148. The kit of any one of claims 88 to 147, wherein the delivery system shaft or sheath is flexible.

149. The kit of any one of claims 88 to 148, wherein the delivery system or sheath is rigid.

150. The kit of any one of claims 88 to 149, wherein the barrel includes a luer port for connection to the needle.

151. The kit of any one of claims 88 to 150, wherein the extendable needle length for tissue penetration is greater than 2.5 mm.

152. The kit of any one of claims 88 to 151, wherein the extendable needle length for tissue penetration is at least 5 mm.

153. 1. A method of treating benign prostatic hyperplasia (BPH) in a subject in need thereof, comprising: Providing a guide according to any one of claims 1 to 29, a delivery device according to any one of claims 30 to 41 or a kit according to any one of claims 42 to 103; dispensing a total volume of the composition into the prostate to produce an effective outcome in treating BPH, comprising dispensing a unit volume or less of the composition into a first prostatic location of the prostate using the needle syringe; The method includes:

154. 154. The method of claim 153, further comprising using ultrasound imaging in conjunction with a transrectal needle or using cystoscopic imaging in conjunction with a transurethral needle.

155. 155. The method of claim 153 or 154, further comprising the step of placing the needle syringe at a second location within the prostate and dispensing no more than one unit volume of the composition to the second location of the prostate.

156. 156. The method of any one of claims 153-155, wherein a plurality n of unit volumes v or less are injected into the prostate to treat the prostate at corresponding n prostate locations, where n=TZUL / (11×v).

157. 157. The method of any one of claims 153-156, wherein a plurality n of unit volumes v or less are injected into the prostate to treat the prostate at a corresponding n prostate locations, where n is related to a prostate volume PV as n=PV / (200×v), and the sum of the unit volumes is a total volume for the prostate volume PV.

158. the needle syringe includes a barrel that holds at least n of the unit volumes, where n is an integer from 2 to 10; When the prostate size is between 20 and 40 grams, n is between 2 and 4; when the prostate size is between 40 and 60 grams, n is between 2 and 6; When the prostate size is between 60 and 80 grams, n is between 4 and 8; and 158. The method of any one of claims 153 to 157, wherein n is between 6 and 10 when the prostate size is 80 grams or greater.

159. 159. The method of claim 158, wherein the unit volume is between 0.05 ml and 0.5 ml, between 0.05 ml and 0.1 ml, between 0.1 and 0.2 ml, or between 0.05 and 0.2 ml.

160. 160. The method of claim 158 or 159, wherein the composition comprises 4% to 15% by volume of the cytotoxic or cytostatic agent.

161. 160. The method of claim 158 or 159, wherein the composition comprises 4% to 15% by weight of the cytotoxic or cytostatic agent.

162. 162. The method of any one of claims 158-161, wherein the cytotoxic or cytostatic agent is selected from the group consisting of paclitaxel, sirolimus, docetaxel, everolimus, carmustine, mitomycin, tacrolimus, and temsirolimus.

163. 163. The method of any one of claims 158 to 162, wherein the cytotoxic agent is docetaxel or paclitaxel.

164. 164. The method of any one of claims 158 to 163, wherein the cytostatic drug is sirolimus.

165. 165. The method of any one of claims 158 to 164, further comprising the steps of measuring the TZUL and selecting a total number of unit volumes v of the composition to dispense into the prostate at each of a plurality of locations in the prostate based on the TZUL, wherein the sum of the unit volumes is approximately equal to the total volume.

166. 166. The method of any one of claims 158 to 165, further comprising the steps of measuring a prostate size and selecting a total volume of the composition for treating BPH based on the prostate size, said selecting comprising selecting a number of unit volumes of the composition to dispense into the prostate at each of a plurality of locations of the prostate, wherein the sum of the unit volumes is approximately equal to the total volume.

167. 167. A method according to any one of claims 158 to 166, wherein the prostate size is prostate volume or prostate weight, and the prostate volume or prostate weight is measured by ultrasound imaging.

168. The method of any one of claims 158 to 167, wherein the composition further comprises an alpha blocker or a 5 alpha reductase inhibitor or an anti-inflammatory agent.

169. 169. The method of any one of claims 158 to 168, wherein the glycolide-based bioabsorbable copolymer is selected from the group consisting of poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 50:50, poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 65:35, and poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 75:25, and poly(D,L-lactide-co-glycolide) having a molar ratio of lactide to glycolide of 85:

15.

170. The method of any one of claims 158 to 169, wherein the water-soluble solvent capable of dissolving the drug and copolymer is selected from the group consisting of N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO) and combinations thereof.

171. 171. The method of any one of claims 158 to 170, wherein the glycolide-based bioabsorbable copolymer is selected from the group poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-PEG-PLGA.

172. 172. The method of any one of claims 158 to 171, wherein the glycolide-based bioabsorbable copolymer has a total concentration of 30 to 55% by weight, the solvent has a total concentration of 69.5 to 40% by weight, and the cytotoxic or cytostatic drug has a total concentration of 0.5% to 30% by weight, 1% to 20% by weight, or 2% to 6% by weight.

173. 173. The method of any one of claims 158 to 172, wherein the drug has a release rate of 5% to 50% during the first 24 hours after injection of the composition into the prostate.

174. 174. The method of any one of claims 158 to 173, wherein the solvent comprises N-methyl-pyrrolidone, the drug is paclitaxel, and the polymer is PLGA.

175. The method of any one of claims 158 to 174, wherein the unit volume is between 0.05 ml and 0.2 ml.

176. 176. The method of any one of claims 158 to 175, wherein the multiple unit volumes are equal to a total volume for the treatment of BPH.

177. 177. The method of any one of claims 158 to 176, wherein the composition has 4% to 15% by volume of the cytotoxic or cytostatic agent, the cytotoxic agent being docetaxel or paclitaxel, and the cytostatic agent being sirolimus.

178. 178. The method of any one of claims 158 to 177, wherein the n number is the number of unit volumes of the composition, and n is related to TZUL as n=TZUL / (11×v).

179. 179. The method of any one of claims 158 to 178, wherein the plurality n of unit volumes is related to a prostate volume PV for the treatment of BPH as n=PV / (200×v).

180. 180. The method of any one of claims 159 to 179, wherein the anti-inflammatory agent is selected from corticosteroids, vasodilators, and combinations thereof.

181. 181. The method of any one of claims 158-180, further comprising forcing the plunger head through the unit volume delivery system until the plunger head traverses the distance of each unit volume (LDC).

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