WO2022219179A1

WO2022219179A1 - Drug-release implant for soft tissue surgery

Info

Publication number: WO2022219179A1
Application number: PCT/EP2022/060171
Authority: WO
Inventors: Gwendolyn NIEBLER; Alexandra DIETRICH; Louis Pascarella
Original assignee: Innocoll Pharmaceuticals Limited
Priority date: 2021-04-15
Filing date: 2022-04-15
Publication date: 2022-10-20

Abstract

A method of performing a soft tissue surgery procedure in a subject in need thereof, may include placing a drug delivery device comprising an analgesic or anesthetic drug substance at a surgical site, for controlled and/or sustained release of the drug substance.

Description

DRUG-RELEASE IMPLANT FOR SOFT TISSUE SURGERY

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application is an International Application which claims priority to U.S. Provisional Application No. 63/175,341, filed April 15, 2021, incorporated herein in its entirety.

BACKGROUND

Field

[0002] The present disclosure relates generally to the implants for controlled drug release, in particular, to implants for controlled drug release that are adapted for implantation during soft tissue surgery.

Background

[0003] Management of acute pain is a significant concern in the postsurgical period, with nearly 90% of patients experiencing acute postsurgical pain as reported in a retrospective study (Gan, et al., 2014). In general, if acute postsurgical pain is not appropriately managed, it can lead to physiologic dysfunction across many organ systems including the central nervous, cardiopulmonary, and immune systems. Inadequately managed acute postsurgical pain can also promote the development of chronic postoperative pain (Gan., 2017), which can place a significant burden on the health care system.

[0004] Recent efforts to improve acute postsurgical pain management have focused on limiting the use of opioids to reduce the risk for opioid-related adverse events and the risk of developing an opioid addiction. Instead, a multimodal approach to analgesia is used which involves the administration of drugs with a variety of mechanisms of action to improve the effectiveness of analgesia (Chou, et al., 2016). Infiltration of local anesthetics, such as bupivacaine, at the surgical site has become a common component of multimodal analgesic strategies. However, locally injected bupivacaine hydrochloride (HC1) injection has a short duration of action (48 hours) (McGee, 2010) that is insufficient to manage acute postoperative pain, which can last for several days depending on the surgery (Svensson, et al., 2000, Scully, et al, 2018). In addition, administration of liquid forms of bupivacaine increases the risk for accidental intravascular injection, which can result in local anesthetic systemic toxicity (LAST) which is associated with significant morbidity and mortality (Goyal and Shukla, 2012). Therefore, there is an unmet medical need for non-liquid formulations of bupivacaine that can deliver drug overtime into a surgical site postoperatively.

SUMMARY

[0005] The disclosure provides a method of performing a soft tissue surgery procedure in a subject in need thereof, comprising placing a drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising a type I fibrillar collagen matrix and about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day. In some embodiments, the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat. In some embodiments, the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure. In some embodiments, the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intrap eritoneal placement. In some embodiments, the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices. In some embodiments, the surgery procedure is open ventral hernia repair comprising onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath. In some embodiments, the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision. In some embodiments, the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision. In some embodiments, the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets. In some embodiments, the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen. In some embodiments, the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride. In some embodiments, the method further comprising partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently. In some embodiments, the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm. In some embodiments, the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device. In some embodiments, the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profde of the unpartitioned drug delivery device.

[0006] The disclosure also provides for the use of a type I fibrillar collagen matrix and bupivacaine hydrochloride for the manufacture of drug delivery device for a soft tissue surgery procedure in a subject in need thereof, the procedure comprising placing the drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day. In some embodiments, the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat. In some embodiments, the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure. In some embodiments, the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement. In some embodiments, the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices. In some embodiments, the surgery procedure is open ventral hernia repair comprising onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath. In some embodiments, the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision. In some embodiments, the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision. In some embodiments, the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets. In some embodiments, the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen. In some embodiments, the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride. In some embodiments, the use further comprising partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently. In some embodiments, the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm. In some embodiments, the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device. In some embodiments, the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

[0007] The disclosure also provides a kit for performing a soft tissue surgery procedure in a subject in need thereof, the kit comprising a drug delivery device and instructions for placement of the drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising a type I fibrillar collagen matrix and about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day. In some embodiments, the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat. In some embodiments, the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure. In some embodiments, the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement. In some embodiments, the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices. In some embodiments, the surgery procedure is open ventral hernia repair comprising mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath. In some embodiments, the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision. In some embodiments, the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision. In some embodiments, the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets. In some embodiments, the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen. In some embodiments, the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride. In some embodiments, the kit further comprising instructions for partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently. In some embodiments, the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm. In some embodiments, the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profde of the unpartitioned drug delivery device. In some embodiments, the release dissolution profde of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

BRIEF DESCRIPTION OF THE DRAWINGS [0008] Various features of illustrative embodiments of the present disclosure are described below with reference to the drawings. The illustrated embodiments are intended to illustrate, but not to limit, the present disclosure. The drawings contain the following figures: [0009] Figs. 1A and IB illustrate the Mean Plasma Bupivacaine Concentration- Time Profiles; Mean (±SD) Plasma Bupivacaine Concentrations by Surgery Type on Linear (Fig. 1A) and Semi-Logarithmic Scale (Fig. IB) -PK Analysis Set.

[0010] Figs. 2A and 2B illustrate the Mean Plasma Bupivacaine Concentration- Time Profiles; Mean (±SD) Plasma Bupivacaine Concentrations by Surgery Type on Linear (Fig. 2A) and Semi-Logarithmic Scale (Fig. 2B) (0-6 Hours) - PK Analysis Set.

[0011] Figs. 3A and 3B illustrate the Mean Plasma Bupivacaine Concentration- Time Profiles; Mean (±SE) Plasma Bupivacaine Concentrations by Surgery Type on Linear (Fig. 3A) and Semi-Logarithmic Scale (Fig. 3B) - PK Analysis Set.

[0012] Figs. 4A and 4B illustrate Box Plots of Plasma Bupivacaine Pharmacokinetic Parameters; Fig. 4A: Box Plots of Plasma Bupivacaine C_max by Surgery Type on Linear Scale- PK Analysis Set; the dashed line is the median; the solid line is the arithmetic mean. The ends of the “box” are the 25th and 75th percentiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile, where IQR is the interquartile range. Data values that do not fall between the whiskers are plotted as outliers; Fig. 4B: Box Plot of Plasma Bupivacaine AUCo-_¥ by Surgery Type on Linear Scale- PK Analysis Set; The dashed line is the median; the solid line is the arithmetic mean. The ends of the “box” are the 25th and 75th percentiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile, where IQR is the interquartile range. Data values that do not fall between the whiskers are plotted as outliers.

[0013] Fig. 5 illustrates the comparison of time to first opioid use between treatment groups, and the difference in percentage of patients that stay opioid free on the drug delivery device described herein, compared to placebo implant.

DETAILED DESCRIPTION

[0014] The embodiments disclosed herein stem from the realization that an implant for controlled, sustained release of bupivacaine may address the unmet medical need for nonliquid formulations of bupivacaine that can deliver drug overtime into a surgical site postoperatively. A collagen-based implant for controlled, sustained release of bupivacaine HC1, also referred to herein as INL-001, has received marketing approval from the United States (US) Food and Drug Administration (FDA) for use in open inguinal hernia repair and a development program in order to obtain FDA approval to expand the approved indication for INL-001 to use in soft-tissue surgeries beyond inguinal hernia repair is underway. Additional efficacy and safety studies with INL-001 in 5 different soft-tissue surgeries is being conducted, which when combined with data from inguinal hernia repair, will serve to describe a range of soft-tissue surgeries for which INL-001 use would be effective and safe.

[0015] Additional features and advantages of the subject technology will be set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subject technology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the written description and embodiments hereof as well as the appended drawings.

[0016] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology.

[0017] In the following detailed description, numerous specific details are set forth to provide a full understanding of the subject technology. It should be understood that the subject technology may be practiced without some of these specific details. In other instances, well-known structures and techniques have not been shown in detail so as not to obscure the subject technology.

[0018] Further, while the present description sets forth specific details of various embodiments, it will be appreciated that the description is illustrative only and should not be construed in any way as limiting. Additionally, it is contemplated that although particular embodiments of the present disclosure may be disclosed or shown in the context of certain soft-tissue surgeries, such embodiments may also be used with other types of soft-tissue surgeries. Furthermore, various applications of such embodiments and modifications thereto, which may occur to those who are skilled in the art, are also encompassed by the general concepts described herein.

[0019] The safety and efficacy of a bupivacaine-collagen implant for postoperative analgesia in patients undergoing open inguinal hernioplasty and open gynecological surgery have recently been reported. The results indicate that the bupivacaine-collagen implant implanted intraoperatively was able to target and control visceral pain more efficiently than continuous perfusion of the surgical wound with bupivacaine for 72 hours postoperatively. Hence, the bupivacaine-collagen implant may be of particular benefit for reducing the postoperative pain following soft-tissue surgeries such as open ventral hernia repair, abdominoplasty, open abdominal hysterectomy, laparoscopic-assisted colectomy, or reduction mammoplasty.

[0020] Abdominoplasty was chosen as the one of the models for soft-tissue surgery for several reasons. Surgical procedures of the abdominal region have been identified as among the most painful soft-tissue surgical procedures, and this pain is often related to the length of the incision site (Chung, et al., 1997, Chia, et al., 2002). Abdominoplasty is a common abdominal surgery and has one of the longest incisions among surgical procedures, going from one anterior superior iliac crest to the contralateral anterior superior iliac crest.

[0021] In addition, abdominoplasty is a well-established acute pain model that has been demonstrated to be sensitive to demonstrating a drug effect. The open surgical approach and large size of the surgical field with abdominoplasty lends itself to use of a drug-device combination like INL-001. Abdominoplasty was also chosen to study because it is considered a more vascular surgery than inguinal hernia repair (O’Dey, et al., 2004). Vascularity of a surgical site is thought to influence the potential for systemic absorption of bupivacaine, which can have safety implications. There is a desire to assess safety as related to potential systemic bupivacaine absorption after release of bupivacaine from INL-001. The study in abdominoplasty allows for an evaluation of the safety of INL-001 in a more vascular soft- tissue surgery.

[0022] A collagen-bupivacaine HC1 implant, INL-001 received marketing approval from the FDA in August 2020. INL-001 [registered as XARACOLL® (bupivacaine hydrochloride) implant] is a single application drug device combination product that is comprised of a collagen drug delivery vehicle and the active ingredient, an amide local anesthetic (i.e., bupivacaine HC1). It is indicated for use in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. The approved dose is 300 mg (three 100 mg implants).

[0023] The active pharmaceutical ingredient in INL-001, bupivacaine, blocks the generation and the conduction of nerve impulses by increasing the threshold for electrical excitation in the nerve by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential (XARACOLL Prescribing Information 2020, Innocoll Pharmaceuticals Limited).

[0024] INL-001 utilizes a proprietary collagen -matrix technology composed of a sterile, resorbable, and biodegradable Type I purified bovine collagen-matrix (Angele, et al, 2004, as well as US Patent No. 8,034,368) and the active ingredient, bupivacaine HC1. The Type I collagen in INL-001 is extracted from bovine Achilles tendons obtained exclusively from closed herds in New Zealand that have been certified as transmissible spongiform encephalopathy (TSE) free and negligible for the risk of bovine spongiform encephalopathy (BSE) in accordance with Regulation European Community (EC) No. 999/200 (Ministry for Primary Industries/Biosecurity New Zealand 2019).

[0025] INL 001 is formulated using 75 mg of Type I collagen with 100 mg of bupivacaine HC1 (equivalent to 88.8 mg of bupivacaine) in an approximately 5 x 5 x 0.5-cm implant. The dose of INL-001 to be evaluated in this study is three 100-mg implants for a total dose of 300 mg.

[0026] A clinical development program for the purpose of evaluating the use of INL-001 in soft tissue surgeries is underway. The purpose of this study is to evaluate the safety, tolerability, and bupivacaine systemic pharmacokinetics of INL 001 in patients following 5 different soft tissue surgeries: open ventral hernia repair, abdominoplasty, open abdominal hysterectomy, laparoscopic-assisted colectomy, and reduction mammoplasty (herein together also referred to as study surgery). These soft tissue surgical procedures were chosen because they result in significant acute postoperative pain, they lend themselves to use of INL 001, and represents a diversity of surgical characteristics seen with soft-tissue surgical procedures. The chosen surgeries represent different anatomic regions of the body (abdominal versus thoracic), incision lengths with involvement of a variety of anatomic layers including fascia and muscle, and surgical site vascularity (O’Dey, et al, 2004). Surgical incision size has been established as a major contributor to postoperative pain (Chung, et al. , 1997, Chia, et al, 2002). Vascularity and extent of anatomic layers involved in a surgical site is thought to influence the potential for systemic absorption of bupivacaine, which can impact safety. In addition, the different surgery types allow for assessment of a variety of placement for INL-001 (single versus at multiple layers in the surgical site). [0027] Accordingly, embodiments of the present disclosure provide a method for implanting drug delivery devices such as, for example, an implant for delivering an analgesic for postoperative pain management following a soft-tissue surgery procedure. In some embodiments, the drug delivery device may deliver drugs such as, for example, Bupivacaine, Levobupivacaine, Lidocaine, Mepivacaine, Prilocaine, Ropivacaine, Articaine, Trimecaine and their salts and prodrugs. In some embodiments, the implant may be a bupivacaine-collagen implant. The methods, devices and kits disclosed herein can be suitably modified for delivery of other drugs are contemplated within the scope of this disclosure.

[0028] The following disclosure describes the methods, systems, devices and kits for controlled, sustained release of analgesic for postoperative pain management following a soft-tissue surgery procedure. However, those of skill in the art, upon understanding of the present disclosure, will be able to suitably modify the methods, systems, devices and kits disclosed herein for implanting other types of implants designed for controlled release of drugs upon implantation during or following other procedures.

[0029] Examples of bupivacaine-collagen implants are described in US Patent No.

8,034,368, which is incorporated herein by reference in its entirety for all purposes. Formulations for and methods of obtaining collagen that can be used in bupivacaine-collagen implants are described in US Patent No. 10,487, 134, which is incorporated herein by reference in its entirety for all purposes. Other examples of drug delivery implants for controlled, sustained drug delivery are described in International Patent Application Publication Nos. WO 2019/071243 , WO 2019/071245 , WO 2019071246, WO 2019/136490, WO 2019/221853 , WO 2020/047013, and WO 2020/046973; US Patent Application Publication Nos. US 2020/0246255, US 2021/0069101, and US 2020/0368398; and Chinese Patent Application Publication Nos. CN 111432807, CN 111655303, and CN 112367980, each of which is incorporated herein by reference in its entirety for all purposes.

[0030] The bupivacaine-collagen implants described in US Patent No. 8,034,368 is typically used for incisional anesthesia in herniotomy surgery. In some embodiments, the bupivacaine-collagen implant may be XaraColl. The typical size of a clinically used bupivacaine-collagen implant, such as XaraColl, is 5 cm x 5 cm (x 0.5 cm thick). In a typical clinical procedure, patients received three 5 cm x 5 cm (x 0.5 cm thick) sponges; one sponge divided between areas adjacent the surgical site (in this case, adjacent the location of the now- removed uterus), one sponge divided and placed across the incision in the wall of the body cavity (in this case, the peritoneum) and the final sponge divided and placed between the sheath and skin around the incision. Each sponge contained 50 mg of bupivacaine hydrochloride, giving a total dose of 150 mg per patient.

[0031] XaraColl contains bupivacaine, an amide local anesthetic, as the active pharmaceutical ingredient. Each XaraColl collagen implant (5 cm x 5 cm x 0.5 cm) contains 100 mg bupivacaine HC1 (equivalent to 88.8 mg bupivacaine) and 75 mg purified Type I collagen. Each implant is individually packaged in sterile blister packaging. Three implants are packaged in a single-use sterile pouch, for a total of 300 mg bupivacaine HC1 (equivalent to 266.4 mg bupivacaine) and 225 mg purified Type I collagen. The resorbable and biodegradable collagen component of the product serves as an inert delivery system and releases bupivacaine through diffusion from the porous collagen implant, which dissolves over time.

[0032] XaraColl is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair (product label: accessdata.fda.gov/dmgsatfda_docs/label/2020/20951 ls0001bl.pdf). XaraColl is supplied as a sterile product that should be handled using aseptic technique. XaraColl is designed as a ready -to-use product and requires no preparation other than cutting the individual implants as needed to accommodate the surgical space.

[0033] XaraColl should be stored at 20 °C to 25 °C (68 °F to 77 °F), excursions permitted between 15 °C and 30 °C (between 59 °F and 86 °F). Brief exposure to temperatures up to 40 °C (104 °F) may be tolerated provided the mean kinetic temperature does not exceed 25 °C (77 °F); however, such exposure should be minimized.

Placement instructions

[0034] Each single-dose package (pouch) of XaraColl contains three implants comprising the total dose of 300 mg bupivacaine HC1. Inspect the outer pouch and inner blister packaging prior to use. Do not use XaraColl if the packaging has been compromised. XaraColl is white to off-white in color, has uniform thickness, and is approximately 5 cm x 5 cm x 0.5 cm in size. Do not use XaraColl if it appears discolored, contains foreign particulates, or is collapsed, compressed, or misshapen. Avoid excessive handling and compression of XaraColl. Avoid contact of XaraColl with liquids prior to placement. Place the XaraColl implant into the surgical site dry. Pre-moistening may result in premature release of bupivacaine from XaraColl. XaraColl is intended for single-dose administration. The recommended dose of XaraColl is 300 mg (3 x 100 mg implants). Doses of XaraColl above 300 mg (3 x 100 mg implants) per patient have not been studied in clinical trials. Each XaraColl implant contains 100 mg bupivacaine HC1 (equivalent to 88.8 mg bupivacaine) and is white to off-white in color. Each implant is approximately 5 cm x 5 cm x 0.5 cm in size

[0035] Both the outer pouch and the inner blister packaging containing the individual implants are designed to be peeled open. Aseptically peel open the outer pouch, then remove and aseptically peel open the three inner blister packages containing XaraColl. To avoid cutting the implants prior to placement, do not open the blister packaging using scissors or a scalpel. Carefully remove XaraColl from the inner blister packages and inspect each implant prior to use. Using aseptic technique, cut each XaraColl implant in half prior to placement into the surgical site. Place three halves below the site of mesh placement and three halves just below the skin closure. XaraColl may become difficult to move once placed in the surgical site and moistened. Use care when moving XaraColl after placement.

[0036] In one aspect, the disclosure provides a method of making a mature lyophilized milled collagen (LMC), the method comprising the steps of: (a) providing isolated collagen, optionally an isolated collagen dispersion; (b) freezing the isolated collagen; (c) dehydrating the frozen collagen; and (d) maturing the dehydrated collagen. In an embodiment, the dehydrated collagen is placed in a permeable pouch before step (d) and step (d) comprises heating the dehydrated collagen in an environment with controlled temperature and controlled humidity. In an embodiment, the dehydrated collagen is heated to about 40 °C in an environment of about 65% relative humidity. In an embodiment, the dehydrated collagen is maintained in the environment with controlled temperature and controlled humidity until the dehydrated collagen reaches a LOD (loss on drying) of about 18%. In an embodiment, an aqueous dispersion comprising 0.9 wt% of the dehydrated collagen matured to an LOD of about 18% has a viscosity of between about 110 cP and about 250 cP. In an embodiment, the method further comprises the step of (e) dehumidifying the mature LMC to form dehumidified mature LMC. In an embodiment, the mature LMC is dehumidified in a permeable pouch in an environment with controlled temperature and controlled humidity. In an embodiment, the mature LMC is dehumidified at a temperature of about 25 °C in an environment of about 15% relative humidity. In an embodiment, the matured collagen is dehumidified until a loss on drying of about 10% is reached.

[0037] In another aspect, the present disclosure provides a method of making a drug delivery device, the method comprising the steps of: (a) forming a dispersion of dehumidified mature lyophilized milled collagen (LMC); (b) adding a solution of bupivacaine, or a salt thereof, to the dispersion to form a bupivacaine-collagen mixture; (c) filling a container with the bupivacaine-collagen mixture; and (d) freeze drying the contents of the container to form a drug delivery device comprising a collagen matrix comprising bupivacaine, or a salt thereof. In an embodiment, the dehumidified mature LMC comprises dehydrated LMC that has a loss on drying (LOD) of about 18% which has been dehumidified to an LOD of about 10%. In an embodiment, the method further comprises the steps of: (e) placing the containers into a secondary packaging; (f) sterilizing the drug delivery device in the secondary packaging; and (g) aerating the drug delivery device in secondary packaging. In an embodiment, step (f) comprises sterilizing the drug delivery device with a mixture of about 6% ethylene oxide and about 94% CO2. In an embodiment, step (g) comprises aerating the drug delivery device until it comprises less than about 175 ppm ethylene chlorohydrin. In an embodiment, step (g) comprises aerating the drug delivery device until it comprises less than about 0.9 ppm ethylene oxide, less than about 1 ,000 ppm ethylene glycol, or a combination thereof. In an embodiment, the drug delivery device comprises about 4 mg/cm³ to about 8 mg/cm³ collagen and about 6 mg/cm³ to about 10 mg/cm³ bupivacaine, or a salt thereof. In an embodiment, the drug delivery device comprises about 6 mg/cm³ collagen and about 8 mg/cm³ bupivacaine, or a salt thereof.

[0038] In yet another aspect, the present disclosure provides a drug delivery device made by the above method. In an embodiment, the device comprises a collagen matrix having dimensions of about 5 cm x 5 cm x 0.5 cm. In an embodiment, the collagen matrix comprises about 4 mg/cm³ to about 8 mg/cm³ collagen and about 6 mg/cm³ to about 10 mg/cm³ bupivacaine, or a salt thereof. In an embodiment, the collagen matrix comprises about 6 mg/cm³ collagen and about 8 mg/cm³ bupivacaine, or a salt thereof. In an embodiment, the device comprises at least one of (i)-(iii): (i) less than about 175 ppm ethylene chlorohydrin; (ii) less than about 0.9 ppm ethylene oxide; or (iii) less than about 1,000 ppm ethylene glycol. In an embodiment, bupivacaine, or a salt thereof, is released from the device with an in vitro release profile of 50% ± 10% in the first 30 minutes, 75% ± 10% within 2 hours, and greater than 80% within 6 hours. In an embodiment, the device has a dry tensile strength of about 1.6 N to about 2.4 N. In an embodiment, the device has a wet tensile strength of about 0.6 N to about 1.2 N.

[0039] In yet another aspect, the present disclosure provides a method of performing a soft tissue surgery procedure in a subject in need thereof, the method comprising placing a drug delivery device at a surgical site, wherein the device comprises a collagen matrix and bupivacaine, or a salt thereof. In an embodiment, the device comprises a collagen matrix having dimensions of about 5 cm x 5 cm x 0.5 cm. In an embodiment, the collagen matrix comprises about 4 mg/cm³ to about 8 mg/cm³ collagen and about 6 mg/cm³ to about 10 mg/cm³ bupivacaine, or a salt thereof. In an embodiment, the collagen matrix comprises about 6 mg/cm³ collagen and about 8 mg/cm³ bupivacaine, or a salt thereof. In an embodiment, the device comprises at least one of (i)-(iii): (i) less than about 175 ppm ethylene chlorohydrin; (ii) less than about 0.9 ppm ethylene oxide; or (iii) less than about 1,000 ppm ethylene glycol. In an embodiment, bupivacaine, or a salt thereof, is released from the device with an in vitro release profile of 50% ± 10% in the first 30 minutes, 75% ± 10% within 2 hours, and greater than 80% within 6 hours. In an embodiment, the device has a dry tensile strength of about 1.6 N to about 2.4 N. In an embodiment, the device has a wet tensile strength of about 0.6 N to about 1.2 N. In an embodiment, the surgery procedure is selected from: an abdominoplasty, an open ventral hernia repair, an open abdominal hysterectomy, a laparoscopic-assisted colectomy, a reduction mammoplasty, and combinations thereof. In an embodiment, bupivacaine, or a salt thereof, is present in the drug delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia, or nerve blockade which lasts for at least about one day after administration. In an embodiment, more than one drug delivery device is placed at the surgical site. In an embodiment, three drug delivery devices are placed at multiple layers in the soft tissue at the surgical site.

[0040] In one aspect, the present disclosure relates to a drug delivery device comprising a fibrillar collagen matrix and at least one anesthetic drug substance. In an embodiment, the at least one drug substance is substantially homogeneously dispersed in the collagen matrix. In an embodiment, the at least one drug substance is in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day after administration. In an embodiment, the incorporation of the at least one drug substance in the fibrillar collagen matrix delays the release of the at least one drug substance from the fibrillar collagen matrix and, thereby, prolongs the duration of local analgesia, local anesthesia or nerve blockade to at least about one day after administration of the disclosed compositions. In an embodiment, the fibrillar collagen matrix prolongs the duration of local analgesia, local anesthesia or nerve blockade to at least about 72 hours after administration of the disclosed compositions.

[0041] Examples of drug delivery device including a collagen matrix and a drug substance include a bupivacaine-collagen implant which is described in US Patent No. 8,034,368, which is incorporated herein by reference in its entirety for all purposes. Formulations for and methods of obtaining collagen that can be used in a drug-release collagen implant are described in US Patent No. 10,487,134, which is incorporated herein by reference in its entirety for all purposes. Other examples of drug delivery implants for controlled, sustained drug delivery are described in International Patent Application Publication Nos. WO 2019/071243, WO 2019/071245, WO 2019071246, WO 2019/136490, WO 2019/221853, WO 2020/047013, and WO 2020/046973; US Patent Application Publication Nos. US 2020/0246255, US 2021/0069101, and US 2020/0368398; and Chinese Patent Application Publication Nos. CN 111432807, CN 111655303, and CN 112367980, each of which is incorporated herein by reference in its entirety for all purposes.

[0042] Suitable drug substances comprise amino amide anesthetics and amino ester anesthetics and their salts, hydrates and prodrugs. Such drug substances include, but are not limited to, amino amides such as Bupivacaine, Levobupivacaine, Lidocaine, Mepivacaine, Prilocaine, Ropivacaine, Articaine, Trimecaine and their salts and prodrugs; and amino esters such as Benzocaine, Chloroprocaine, Cocaine, Procaine, Tetracaine and their salts and prodrugs. Bupivacaine, and its salts and prodrugs is an optional drug substance. Mixtures of amino amides are contemplated, as are mixtures of amino esters. Mixtures of amino amides and amino esters are also contemplated.

[0043] The drug delivery device uses a collagen matrix to achieve extended delivery of the drug substance when placed in the surgical wound during soft tissue surgery. In an embodiment, the drug delivery device, while implanted in a patient, releases the drug substance at the treatment site over a period of time such as, for example, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or any amount of time between any two of these periods. In an embodiment, the drug delivery device releases the drug substance over about 24 hours. In another embodiment, the drug delivery device releases the drug substance over about 72 hours. In another embodiment, the drug delivery device releases the drug substance over about 24 hours wherein the drug substance provides an anesthetic effect to the patient for more than 24 hours. In an embodiment, the drug delivery device releases the drug substance over about 24 hours wherein the drug substance provides an anesthetic effect to the patient for about 72 hours.

[0044] The release profde of the drug delivery device may be tailored depending on the drug and particular application of the drug. Thus, in some embodiments, the drug delivery device is configured to release the drug substance at a first rate for a first period of time and at a second rate for a second period of time. The first rate may be greater than the second rate. In an embodiment, 50% ± 10% of the drug substance is released in the first 30 minutes, 75% ± 10% of the drug substance is released within 2 hours, and greater than 80% of the drug substance is released within 6 hours.

[0045] In an embodiment, the extended delivery of the drug substance results in a reduction in pain intensity up to 72 hours and an analgesic temporal profile that matches that of maximal soft tissue postsurgical pain.

[0046] The collagen matrix in the drug delivery device is manufactured using proprietary technology, which results in a highly purified, porous, biocompatible, biodegradable, and bioresorbable collagen matrix that releases the locally acting drug substance over time into the surgical wound. In an embodiment, the drug substance comprises bupivacaine, or a salt thereof. In an embodiment, the drug substance comprises bupivacaine HC1.

[0047] In an embodiment, the collagen matrix comprises Type I collagen. Type I collagen is ubiquitous in humans and animals. Human and animal (e.g., bovine) Type I collagen have almost identical amino acid sequencing, including positioning of antigenic determinates outside of the triple helix. Bovine Type I collagen is used in numerous clinical applications. The lack of an adverse immune response to the use of xenogeneic collagen in implantable materials is attributed to the common nature between species of amino acid sequences and surface epitopes. When in its native ultrastructure, implanted xenogeneic material is generally recognized as “self’ tissue, regardless of the species of origin, and is subjected to the fundamental biological process of degradation and integration into adjacent host tissues. Some collagen products, e.g., those used in the dermatologic field intended to remain intact in the body for an extended period of time, undergo structural modifications during manufacturing (e.g., cross-linking) designed to alter the rate of enzymatic degradation and remodeling. Collagen products without modifications degrade rapidly in vivo, generally over 1 to 3 months. In an embodiment, the collagen in the drug delivery device comprises collagen that has not undergone structural modifications and thus degrades over 1 to 3 months in vivo.

[0048] In an embodiment, the Type I collagen used in drug delivery device is purified from bovine Achilles tendons. In an embodiment, the Type I collagen is obtained exclusively from New Zealand closed herds that have been certified as transmissible spongiform encephalopathy-free and negligible for the risk of bovine spongiform encephalopathy. The tendon undergoes a collagen extraction and purification process that does not result in cross-linking (structural modification), which differs from collagen products designed to remain intact in the body for an extended period of time. Therefore, the finished collagen matrix of drug delivery device contains a significant content of tropocollagen microfibrils, which are more susceptible to enzymatic degradation and promote resorption in the body, in contrast to cross-linked collagen products.

[0049] The collagen matrix in drug delivery device is designed to act as a vehicle for delivery of bupivacaine into the wound and has no positive or detrimental effect on wound healing. After placement of the drug delivery device into the surgical site, it absorbs liquid from the site, resulting in dissolution and diffusion of bupivacaine from the porous lyophilized collagen matrix. In an embodiment, nearly 100% of bupivacaine is released from the matrix within 24 hours. The collagen matrix subsequently degrades via slow chemical and enzymatic hydrolysis to soluble peptides and amino acids, which are absorbed into the tissue. The quantity of matrix material decreases over time in the wound. In an embodiment, the collagen matrix based is no longer present by 56 days after placement in an animal.

[0050] In an embodiment, the drug delivery device has a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm. In some embodiments, the drug delivery device may have any shape, in particular, cylindrical, semi-cylindrical, corrugated, cuboid, hexahedral, or any other shape. [0051] In an embodiment, the drug delivery device comprises a collagen matrix having dimensions of about 5 cm x 5 cm x 0.5 cm. In an embodiment, the matrix comprises about 10 mg to about 500 mg, about 10 mg to about 450 mg, about 10 mg to about 400 mg, about 10 mg to about 350 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about 100 mg, about 65 mg to about 85 mg, or about 75 mg collagen. In an embodiment, the matrix comprises about 10 mg to about 500 mg, about 10 mg to about 450 mg, about 10 mg to about 400 mg, about 10 mg to about 350 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 75 mg to about 125 mg, about 90 mg to about 110 mg, or about 100 mg bupivacaine, or a salt thereof. In an embodiment, the matrix comprises about 0.5 mg/cm³ to about 20 mg/cm³ , about 0.5 mg/cm³ to about 18 mg/cm³ , about 0.5 mg/cm³ to about 16 mg/cm³, about0.5 mg/cm³to about 14 mg/cm³ , about 0.5 mg/cm³to about 12 mg/cm³, about 0.5 mg/cm³ to about 10 mg/cm³, about 2 mg/cm³to about 10 mg/cm³, about 4 mg/cm³to about 10 mg/cm³, about 4 mg/cm³ to about 8 mg/cm³, or about 6 mg/cm³ collagen. In an embodiment, the matrix comprises about 0.5 mg/cm³ to about 20 mg/cm³, about 0.5 mg/cm³to about 18 mg/cm³, about 0.5 mg/cm³to about 16 mg/cm³, about 0.5 mg/cm³to about 14 mg/cm³, about 0.5 mg/cm³ to about 12 mg/cm³, about 2 mg/cm³to about 12 mg/cm³, about 4 mg/cm³ to about 12 mg/cm³, about 4 mg/cm³ to about 10 mg/cm³, about 6 mg/cm³ to about 10 mg/cm³, or about 8 mg/cm³ bupivacaine.

[0052] In an embodiment, drug delivery device has a dry tensile strength of about 0.5 N to about 10 N, about 0.5 N to about 9 N, about 0.5 N to about 8 N, about 0.5 N to about 7 N, about 0.5 N to about 6 N, about 0.5 N to about 5 N, about 0.5 N to about 4 N, about 1 N to about 3.5 N, about 1.5 N to about 3 N, about 1.6 N to about 2.4, or about 1.8 N to about 2.2

N.

[0053] In an embodiment, the drug delivery device has a wet tensile strength of about 0.1 N to about 10 N, about 0.1 N to about 9 N, about 0.1 N to about 8 N, about 0.1 N to about 7 N, about 0.1 N to about 6 N, about 0.1 N to about 5 N, about 0.1 N to about 4 N, about

O.1 N to about 3 N, about 0.5 N to about 2.5 N, about 0.5 N to about 2 N, about 0.5 N to about 1.5 N, or about 0.6 N to about 1.2 N. [0054] In an embodiment, the drug delivery device comprises 100 mg bupivacaine HC1 (equivalent to 88.8 mg of bupivacaine) homogeneously dispersed in 75 mg of collagen in a matrix measuring approximately 5 cm x 5 cm x 0.5 cm. In an embodiment, the proposed dose of bupivacaine HC1 is 300 mg (equivalent to a total of 266.4 mg of bupivacaine), achieved by implanting 3 x 100 mg collagen matrices during surgery. In an embodiment, the drug delivery device is implanted during a soft tissue surgery. In an embodiment, the drug delivery device is implanted at multiple layers in the soft tissue (e.g., between the fascia/muscle closure and in the layers below the skin closure).

[0055] In an embodiment, the drug delivery device is made using a method described elsewhere herein. In an embodiment, the drug delivery device is made using a method described herein from dehumidified mature LMC described elsewhere herein. In an embodiment, the dehumidified mature LMC is made using a method described elsewhere herein.

[0056] In an embodiment, using the dehumidified mature LMC prepared as described elsewhere herein to make a drug delivery device results in a drug delivery device with one or more different properties than a drug delivery device that is made from LMC that is not matured or is matured using a different process. In an embodiment, while an aqueous dispersion of 0.9 wt% dehydrated collagen matured to an LOD as described elsewhere herein has a viscosity within a desired range, a dispersion of unmatured dehydrated collagen or a dispersion of dehydrated collagen matured using different parameters and/or a different process has a viscosity below or above the desired range. In an embodiment, the desired viscosity range is between about 50 cP and about 500 cP, about 75 cP and about 500 cP, about 100 cP and about 500 cP, about 100 cP and about 450 cP, about 100 cP and about 400 cP, about 100 cP and about 350 cP, about 100 cP and about 300 cP, about 100 cP and about 250 cP, about 110 cP and about 250 cP, about 150 cP and about 250 cP, or about 160 cP and about 250 cP. In an embodiment, lower viscosities have a more adverse effect on the resulting drug delivery device. Therefore, in an embodiment, the dispersion of dehydrated collagen matured to an LOD as described elsewhere herein should have a viscosity of at least about 110 cP, at least about 120 cP, at least about 130 cP, at least about 140 cP, at least about 150 cP, at least about 160 cP, or at least about 170 cP, but may have a viscosity of greater than 250 cP. [0057] In an embodiment, using unmatured LMC or matured LMC obtained from dehydrated collagen with a viscosity outside of the range about 110 cP - 250 cP to make a drug delivery device results in a device with one or more different properties than a device made from the dehumidified mature LMC described elsewhere herein.

[0058] In one aspect, the present disclosure relates to a method of making a mature LMC, the method comprising the steps of: (a) providing isolated collagen, optionally an isolated collagen dispersion; (b) freezing the isolated collagen; (c) dehydrating the frozen collagen; and (d) maturing the dehydrated collagen.

[0059] The collagen of step (a) can be isolated from equine or bovine tendons. In an embodiment, the collagen is isolated from bovine tendons. In an embodiment, the isolated collagen is obtained by milling the tendons to degrade the collagen source and treating the milled collagen to extract and purify Type I collagen. In an embodiment, the tendons are lyophilized. In an embodiment, the cutting gap of the mill is set to 0.1 mm-0.2 mm with a discharge sieve setting of 7 mm as detailed in Figure 1. In an embodiment, the milled collagen is treated with 1 N sodium hydroxide (NaOH) to remove microbiological contamination such as prions, bacteria, and viruses. In one embodiment, the milled collagen is treated with IN NaOH by soaking the milled collagen for 60 min-90 min in 1M NaOH at a pH > 13.5. In an embodiment, the NaOH treated milled collagen is neutralized to a pH of about 7.0 ± 0.5. In one embodiment, the NaOH treated milled collagen is transferred to a vessel containing a defined amount of purified water USP (PW) and neutralized with 1 M HC1 to a pH of about 7.0 ± 0.5 while mixing. Although not wishing to be limited by theory, it is believed that neutralization of the NaOH treated milled collagen results in the formation of NaCl, which aids in the removal of low molecular weight soluble intrinsic impurities of the collagen. After neutralization, the solid portion of the milled collagen is subsequently separated from the liquid portion through centrifugation. The solid portion is re-suspended in 0.9 % NaCl, and mixed under slow agitation, which enhances the solubility of intrinsic impurities. Following centrifugation, the milled collagen is washed two additional times with PW to further remove low molecular weight soluble components from the collagen. In some embodiments, the milled collagen is treated a second time with NaOH. In one embodiment, the second NaOH treatment comprises treating the milled collagen with 0.1 M NaOH at a pH of about 13.0 ± 0.5 for a period of 14 h-16 h incubation. Although not wishing to be limited by theory, it is believed that the second NaOH treatment contributes to the depletion of fat content and soluble impurities (Figure 3). After the second NaOH treatment, the milled collagen is neutralized to a pH of about 7.0 ± 0.5. In an embodiment, the second neutralization comprises treating the milled collagen with 1 M HC1 to a pH of about 7.0 ± 0.5 and washing the milled collagen twice with PW.

[0060] The milled collagen is treated with H2O2. In an embodiment, the milled collagen is treated for with about 1.7% H2O2 for about 10-15 mins. Although not wishing to be limited by theory, it is believed that the H202 bleaches the milled collagen and aids in further removal of fat content. The bleached milled collagen is centrifuged and washed with PW to remove residual peroxides. Although not wishing to be limited by theory, it is believed that the bleached milled collagen should be washed to remove residual peroxides that can cause inactivation of the pepsin used in a later process step.

[0061] The bleached milled collagen is dispersed in acidified PW (pH of about 2.3- 2.7) to affect swelling of the fibrous material (Figure 4). The swollen milled collagen is then shredded. In an embodiment, the swollen milled collagen is shredded utilizing a tank bottom mounted rotor stator cutter. The shredded collagen is then combined with a prepared pepsin solution. In an embodiment, the pepsin solution is prepared by dissolving the pepsin in acidified water at pH of between about 1.8-2.1 and a temperature of between about 34.1 °C- 35.1 °C for 30 min-60 min. Although not wishing to be limited by theory, it is believed that the pepsin reduces the potential for non-collagen protein contamination (e.g., bovine serum protein), reduces the potential species related immunogenicity of the collagen through cleavage of telopeptides (i.e., the short non -helical domains at the end of the collagen chains), and/or removes viral contaminates.

[0062] The pepsin treated milled collagen is then centrifuged, the solubilized collagen is retained, and the solid centrifugate is discarded. In an embodiment, the solubilized collagen is fdtered. In one embodiment, the solubilized collagen is passed through a 250 pm filter. In an embodiment, the fdtered collagen is precipitated through pH adjustment. In one embodiment, the pH adjustment comprises treating the filtered collagen with 1 M NaOH to a pH of about 7.5 ± 0.5. The precipitated collagen is centrifuged, washed twice with PW, and pH adjusted to a pH of about 7.5 ± 0.5 with acid and/or base as necessary to provide the isolated collagen (Figure 5). In an embodiment, the acid is acetic acid and/or the base is NaOH. At this point in the manufacturing process, the isolated collagen may be placed into LDPE bags and stored before step (b). In an embodiment, the isolated collagen is stored for no more than 2 days at 2 °C-8 °C awaiting step (b) or immediately distributed in trays and lyophibzed (Figure 6)·

[0063] In some embodiments, the providing step (step (a)) comprises the step of removing the fluid prior to the providing step. In some embodiments, the providing step comprises the step of removing at least some of the fluid prior to the providing step. In some embodiments, the providing step comprises the step of removing at least some of the fluid prior to the providing step; to provide an isolated collagen dispersion. In some embodiments, the fluid is a liquid. In some embodiments, the liquid is an aqueous medium. In some embodiments, the providing step comprises the step of removing the fluid prior to the providing step to provide a dispersion having a concentration of about 3-30%, optionally 3-4%, (w/w) collagen particles. In some embodiments, the fluid is a liquid. In some embodiments, the liquid is an aqueous medium.

[0064] In an embodiment, the freezing step (step (b)) comprises freezing to a temperature of about -33 °C to about -42 °C. In one embodiment, the freezing step comprises freezing to a temperature of about -38 °C. In some embodiments, the freezing step comprises freezing at a rate of about 0.3 °C to about 1.5 °C per minute, optionally a rate of about 0.5 °C per minute.

[0065] In an embodiment, the dehydrating step (step (c)) comprises removing the aqueous phase. In one embodiment, the dehydrating step comprises removing the aqueous phase by reducing the pressure. In one embodiment, the dehydrating step comprises removing the aqueous phase by reducing the pressure to about 0.05 to about 0.5 mbar. In one embodiment, the dehydrating step comprises removing the aqueous phase by applying a vacuum. In an embodiment, the dehydrating step comprises evacuating a chamber comprising the frozen collagen to a pressure of about 0.05 to about 0.5 mbar. In one embodiment, the dehydrating step comprises evacuating a chamber comprising the frozen collagen to a pressure of about 0.2 mbar.

[0066] Optionally or additionally, the dehydrating step comprises increasing the temperature of the frozen collagen. Further optionally or additionally, the dehydrating step comprises increasing the temperature of the frozen collagen under vacuum. Still further optionally or additionally, the dehydrating step comprises increasing the temperature of the collagen to about +30 °C. Still further optionally or additionally, the dehydrating step comprises increasing the temperature of the collagen to about +30 °C under vacuum. In one embodiment, the dehydrating step comprises increasing the temperature of the collagen to about +30 °C under vacuum and holding the collagen at this temperature for about 15 to 36 hours. In one embodiment, the collagen is held at about +30 °C at a pressure of about 0.2 mbar for about 24-26 hours.

[0067] Optionally or additionally, the dehydrating step comprises increasing the temperature of the collagen to about +30 °C at a rate of about 0.3 °C to about 1.5 °C per minute, further optionally at a rate of about 0.5 °C per minute. Further optionally or additionally, the dehydrating step comprises increasing the temperature of the collagen to about +30 °C at a rate of about 0.3 °C to about 1.5 °C per minute, further optionally at a rate of about 0.5 °C per minute, under vacuum.

[0068] In an embodiment, the dehydrating step comprises decreasing the temperature to about +20 °C and holding the collagen at this temperature under vacuum. In an embodiment, the collagen is held at +20 °C at a pressure of about 0.05 to 0.5 mbar. In one embodiment, the collagen is held at +20 °C at a pressure of about 0.2 mbar. In one embodiment, the collagen is held at collagen is held at +20 °C under vacuum for about 1 hour.

[0069] In an embodiment, steps (b) and (c) together comprise a step of lyophilizing the isolated collagen. In an embodiment, the lyophilization parameters are found in Figure ?.

[0070] In an embodiment, the dehydrated collagen is placed in a permeable pouch before step (d). The permeable pouch can be any pouch, bag, container, box, etc. that is fully permeable, semi permeable, or partially permeable to the surrounding environment. In an embodiment, the permeable pouch is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% permeable to the surrounding environment. In one embodiment, the permeable pouch is a paper, Medipeel, or Stericlean pouch.

[0071] In an embodiment, step (d) comprises heating the dehydrated collagen in an environment with controlled humidity. In an embodiment, dehydrated collagen in a permeable pouch is heated in an environment with controlled humidity. In one embodiment, dehydrated collagen in a permeable pouch is heated to about 30 °C to about 50 °C in an environment of about 50% to about 75% relative humidity (RH). In one embodiment, dehydrated collagen in a permeable pouch is heated to about 40 °C in an environment of about 65% relative humidity (RH). In an embodiment, the dehydrated collagen is maintained in the heated environment with controlled humidity until the dehydrated collagen reaches an LOD (loss on drying) of between about 16% and about 20%. In an embodiment, the dehydrated collagen is maintained in the heated environment with controlled humidity until the dehydrated collagen reaches an LOD (loss on drying) of about 18%. In one embodiment, dehydrated collagen in a permeable pouch maintained at a temperature of about 40 °C and about 65% RH reaches an LOD of about 18% in about six to eight weeks.

[0072] In an embodiment, the dehydrated collagen is placed in a permeable pouch and heated to about 40 °C at about 60% RH for about four to seven days before the dehydrated collagen is heated to about 40 °C at about 65% RH.

[0073] In an embodiment, the dehydrated collagen is matured until an LOD of about 18% is reached. In an embodiment, an aqueous dispersion of 0.9 wt% dehydrated collagen matured to an LOD of about 18% has a viscosity of between about 100 cP and about 250 cP (measurement taken of the dispersion having a pH of about 4.5 and held at a temperature of about 40 °C). In an embodiment, an aqueous dispersion of 0.9 wt% dehydrated collagen matured to an LOD of about 18% has a viscosity of between about 150 cP and about 250 cP.

[0074] In an embodiment, the matured collagen is dehumidified to form dehumidified mature LMC. In one embodiment, the matured collagen is dehumidified in the permeable pouch. In an embodiment, the matured collagen is dehumidified in an environment with a controlled temperature and controlled RH. In an embodiment, the temperature is maintained at about 15 °C to about 35 °C, about 18 °C to about 32 °C, about 20 °C to about 30 °C, or about 25 °C. In an embodiment, the RH is maintained at about 5% to about 25%, about 8% to about 22%, about 10% to about 20%, about 12% to about 18%, or about 15%. In one embodiment, the matured collagen is dehumidified in a permeable pouch at a temperature of about 25 °C and a RH of about 15%. In an embodiment, the matured collagen is dehumidified until an LOD of about 8% to about 12% is reached. In one embodiment, the matured collagen is dehumidified until an LOD of about 10% is reached. In one embodiment, matured collagen in a permeable pouch is dehumidified for about one week at a temperature of about 25 °C and a RH of about 15% to reach an LOD of about 10%. [0075] In an embodiment, the dehumidified mature LMC can be used directly in a dispersion which is mixed with one or more drug substances. In another embodiment, the dehumidified mature LMC is stored before further use. In one embodiment, the dehumidified mature LMC is sealed in an impermeable pouch before storage. In one embodiment, the dehumidified mature LMC is refrigerated for storage. In one embodiment, the dehumidified mature LMC is sealed in an impermeable pouch and stored in a refrigerator. In one embodiment, the impermeable pouch is an aluminum pouch.

[0076] It is understood that, in conducting the maturing step, the parameters of temperature, time, pressure, and relative humidity are not necessarily mutually exclusive, and the skilled person would recognize that as one parameter is varied, one or both of the other parameters may also be varied accordingly.

[0077] In some embodiments, the isolated collagen is fibrillar collagen. Fibrillar collagen from different sources may be used including commercially available fibrillar collagen, for example, biomedical collagen from Devro Biomedical Collagen, Australia. Currently there are five known types of fibrillar collagen; Type I, II, PI, V and XI. Alternatively, collagen can be extracted from tendons or hides of different mammals, including human, horse, cattle, sheep and pigs. Collagen can also be extracted from a non-mammal such as fish. Details on the various types of collagen are described by Gelse et al, (Advanced Drug Delivery Reviews 55 (2003), 1531 -1546), the whole contents of which are incorporated herein by reference. The present inventors have used a bovine-derived collagen Type I for the manufacture of bupivacaine-collagen sponges. Equine-derived collagen Type I is also suitable for use in the present invention, as are fibrillar collagen such as type I collagen from pigs and sheep. Type I collagen is a connective tissue extracted from animal tendons and other sources; in this case, the collagen is derived from bovine tendons. The Type I collagen consists of three approximately 1,050 amino-acid-long polypeptide chains, two alpha-1 chains, and one alpha- 2 chain. These are coiled to form a right-hand helix (known as a triple helix) around a common axis. The rod-shaped molecule has a length of 2900 Angstrom, a diameter of 14 Angstrom and a molecular weight of approx. 300,000 Daltons. Type I collagen can be typified by its reaction with the protein core of another connective tissue component known as a proteoglycan. Type I collagen contains signaling regions that facilitate cell migration. [0078] Optionally, the isolated collagen is selected from Type I collagen, Type II collagen, Type IP collagen, and a mixture thereof. Still further optionally, the isolated collagen is Type I collagen.

[0079] In another aspect, the present disclosure relates to a method of making a drug delivery device, the method comprising the steps of: (a) forming a dispersion of dehumidified mature LMC; (b) adding a solution of bupivacaine, or a salt thereof, to the dispersion to form a bupivacaine-collagen mixture; (c) filling a container with the bupivacaine- collagen mixture; and (d) freeze drying the contents of the container to form a drug delivery device comprising a collagen matrix and bupivacaine, or a salt thereof.

[0080] In one embodiment, the collagen dispersion comprises an aqueous solution of dehumidified mature LMC. In an embodiment, the collagen dispersion comprises between about 0.1 wt% and about 10 wt%, about 0.1 wt% and about 8 wt%, about 0.1 wt% and about 6 wt%, about 0.1 wt% and about 4 wt%, about 0.1 wt % and about 2 wt%, about 0.1 wt% and about 1 wt%, about 0.4 wt% and about 0.8 wt%, or about 0.6 wt% dehumidified mature LMC. In one embodiment, the aqueous solution is acidic with a pH of about 3.0 to about 5.0, about 3.3 to about 4.7, about 3.6 to about 4.4, about 3.9 to about 4.2, or about 4.1. Although not wishing to be limited by theory, it is believed that the acidic conditions are required to ensure optimum swelling of the collagen during the homogenization step. In one embodiment, the collagen dispersion is maintained at a temperature of about 20 °C to about 50 °C, about 24 °C to about 47 °C, about 27 °C to about 44 °C, about 30 °C to about 41 °C, about 35 °C to about 41 °C, or about 38 °C. In one embodiment, acetic acid is used to acidify the aqueous solution. Although not wishing to be limited by theory, it is believed that using acetic acid rather than HC1 leads to a reduction in the concentration of chloride in the drug delivery product and thus minimizes the formation of ECH during EO sterilization.

[0081] In an embodiment, the collagen dispersion is homogenized to ensure complete and uniform dispersion of the collagen. In one embodiment, the collagen dispersion is maintained at a temperature of below about 50 °C, about 48 °C, about 46 °C, about 44 °C, or about 42 °C during homogenization. The collagen dispersion should be maintained below the collagen denaturation temperature. In an embodiment, the collagen denaturation temperature is about 50 °C. In an embodiment, the collagen dispersion is homogenized at about 3,000 rpm ± 100 rpm for about 5 min ± 1 min. In an embodiment, the homogenizer comprises a rotor head that can provide high shear forces to separate the fibrous mass of collagen that is present at the beginning of the dispersion preparation and thus to promote adequate swelling of the collagen.

[0082] A solution of bupivacaine is added to the collagen dispersion to form a bupivacaine-collagen mixture. In an embodiment, the solution of bupivacaine is an aqueous solution. In an embodiment, the solution of bupivacaine is added to the collagen dispersion such that the resulting bupivacaine-collagen mixture comprises about 0.1 wt% to about 10 wt%, about 0.1 wt% and about 8 wt%, about 0.1 wt% and about 6 wt%, about 0.1 wt% and about 4 wt%, about 0.1 wt % and about 2 wt%, about 0.1 wt% and about 1 wt%, about 0.4 wt% and about 1 wt%, about 0.6 wt% and about 1 wt%, or about 0.8 wt% bupivacaine. In an embodiment the bupivacaine is bupivacaine HC1. In an embodiment, the aqueous solution has an acidic pH. In one embodiment, the aqueous solution has a pH of about 3.0 to about 5.0, about 3.3 to about 4.7, about 3.6 to about 4.4, about 3.9 to about 4.2, or about 4.1. In one embodiment, the aqueous solution is acidified with acetic acid. In an embodiment, the solution of bupivacaine is maintained at a temperature of about 20 °C to about 50 °C, about 24 °C to about 47 °C, about 27 °C to about 44 °C, about 30 °C to about 41 °C, about 35 °C to about 41 °C, or about 38 °C before it is added to the collagen dispersion. In one embodiment, the bupivacaine-collagen mixture is stirred. In one embodiment, the bupivacaine-collagen mixture is mixed using a homogenizer. In one embodiment, the bupivacaine-collagen mixture is mixed at about 3,000 rpm for about one minute. In an embodiment, the bupivacaine-collagen mixture is maintained at a temperature of about 20 °C to about 50 °C, about 24 °C to about 47 °C, about 27 °C to about 44 °C, about 34 °C to about 44 °C, about 38 °C to about 42 °C, or about 40 °C. In an embodiment, the bupivacaine-collagen mixture is maintained under low shear mixing to ensure temperature homogeneity.

[0083] In an embodiment, bupivacaine-collagen mixture is filtered. In one embodiment, bupivacaine-collagen mixture is filtered through a 250 pm filter. In an embodiment, after filtering, the bupivacaine-collagen mixture is maintained at a temperature of about 20 °C to about 50 °C, about 24 °C to about 47 °C, about 27 °C to about 44 °C, about 34 °C to about 44 °C, about 38 °C to about 42 °C, or about 40 °C. In an embodiment, the filtered bupivacaine-collagen mixture is maintained under low shear mixing to ensure temperature homogeneity. [0084] A container is filled with the bupivacaine-collagen mixture or the filtered bupivacaine-collagen mixture. The container can be any type of container known to a person of skill in the art that does not react with the components of the mixture. In an embodiment, the container is a polyethylene terephthalate (PET). In one embodiment, the PET is chemically modified. In one embodiment, the chemically modified PET is glycol modified PET (PETG). In an embodiment, the container is a blister pack. In one embodiment, the container is a PETG blister pack. In an embodiment, the container has dimensions of about 5 cm x 5 cm x 1.5 cm. In an embodiment, the container is filled with about 10 g to about 15 g of the bupivacaine- collagen mixture or the filtered bupivacaine-collagen mixture.

[0085] In an embodiment, the filled container is covered with a lid. In another embodiment, the filled container is left uncovered. The lid can be any kind of gas-permeable lid known to a person of skill in the art. In one embodiment, the lid is a Tyvek lid. In one embodiment, the lid seals to the top of the container.

[0086] The filled container is freeze dried and the contents of the container form a collagen matrix comprising bupivacaine. In one embodiment, the filled container is freeze dried using a lyophilizer.

Clinical trial experience

[0087] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

[0088] The safety of XaraColl was evaluated in 11 clinical studies, including two Phase 3 double-blind, placebo implant-controlled studies in patients undergoing open, unilateral inguinal hernia repair. Overall, 612 patients were treated with a single dose of XaraColl, total dose ranged from 100 mg to 300 mg bupivacaine HC1. Patients treated with XaraColl ranged in age from 18 of 85 years (median age 51 years), with 88% male, 88% White, 9% African-American, and 3% all other races.

[0089] Across the XaraColl drug development program, which included evaluations in various surgery models, there was one patient death reported in the placebo implant treatment group, and 16 patients who experienced one or more serious adverse events; 11 patients in the XaraColl treatment group and 5 patients in the placebo implant or comparator treatment groups. Serious adverse reactions reported in the XaraColl treatment group included wound infection and seroma. There was a single patient who experienced signs and symptoms consistent with local anesthetic systemic toxicity (LAST) approximately four hours after administration of an early formulation of the bupivacaine collagen implant, 150 mg, during bladder sling surgery. LAST treatment included administration of lipid emulsion and surgical removal of the XaraColl implants.

[0090] The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo implant) following XaraColl administration were dysgeusia, headache, scrotal swelling, tremor, pyrexia, vision blurred, and seroma. Common incision site adverse reactions (incidence greater than or equal to 2% and higher in either the XaraColl or placebo implant groups compared to non-implant comparator treatment groups) were swelling, pain, other complication, post-procedural discharge, erythema, dehiscence, and inflammation. Adverse Reactions Reported in Phase 3 Placebo-controlled Trials

[0091] There were 619 patients who underwent open inguinal hernia repair in the two Phase 3 studies. Patients received general anesthesia intra-operatively, and a standard acetaminophen regimen, in addition to intravenous and oral morphine as needed, post- operatively. The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo implants) following XaraColl administration were incision site swelling, dysgeusia, headache, tremor, vision blurred, seroma, scrotal swelling, pyrexia, hypoesthesia oral, and post-procedural discharge, shown in Table 1.

Table 1. Adverse Reactions (ARs) with Incidence Greater Than or Equal to 2% and Greater Than Placebo Reported in the Phase 3 Placebo-controlled Studies

a Placebo consisted of three collagen implants. b Includes sensation of warmth, hardness and popping sensation at the incision site. No adverse reactions were related to wound healing (wound dehiscence, wound infection).

Clinical pharmacology

Mechanism of Action:

[0092] Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Clinically, the order of loss of nerve function is (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Pharmacodynamics :

[0093] Systemic absorption of bupivacaine produces effects on the cardiovascular system and CNS. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of liquid formulations of bupivacaine.

[0094] Following systemic absorption, bupivacaine can produce CNS stimulation, CNS depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, bupivacaine has a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state.

Pharmacokinetics :

[0095] Local placement of XaraColl within the surgical site during open inguinal hernia repair resulted in detectable plasma levels of bupivacaine at the first measured time point (0.5 hours) and throughout the 96-hour observation period. Systemic plasma levels of bupivacaine following application of XaraColl do not correlate with local efficacy.

Absorption:

[0096] The rate of systemic absorption of bupivacaine is dependent on the total dose administered, the route of administration, and the vascularity of the administration site.

[0097] Pharmacokinetic parameters for XaraColl following placement in the surgical site during hernioplasty are presented in Table 2.

Table 2: Pharmacokinetic Parameters for Bupivacaine After Placement of XaraColl in the Surgical Site During Open Inguinal Hernia Repair

¹ Arithmetic mean (SD)

² Median

[0098] The highest individual bupivacaine plasma concentration observed in the

XaraColl clinical program was 1230 ng/mL, which occurred 2 hours after placement of the three XaraColl 100 mg implants (total bupivacaine HC1 dose 300 mg) in the surgical site of one patient.

Distribution:

[0099] After bupivacaine is released from XaraColl it is absorbed systemically. Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with higher concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

[0100] Local anesthetics including bupivacaine appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs such as bupivacaine readily enter the fetal blood from the maternal circulation.

Elimination:

[0101] Metabolism - Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecoloxylidine is the major metabolite of bupivacaine. The elimination of drug from tissue distribution depends largely upon the availability of binding sites in the circulation to carry it to the liver where it is metabolized.

[0102] Excretion - After bupivacaine has been released from XaraColl and is absorbed systemically, bupivacaine excretion is expected to be the same as for other bupivacaine formulations. The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of bupivacaine is excreted unchanged in the urine.

Specific Populations:

[0103] Age - Various pharmacokinetic parameters of the local anesthetics such as bupivacaine can be significantly altered by the age of the patient.

[0104] Hepatic Impairment - Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics.

[0105] Renal Impairment - Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow.

Clinical studies

[0106] The efficacy and safety of XaraColl were evaluated in two randomized, multi-center, double-blind, placebo -controlled Phase 3 trials in patients undergoing open inguinal repair under general anesthesia.

[0107] In Study 1, 298 patients were enrolled. The mean age was 53.2 years (range 19 to 86) and patients were predominantly male (96%). In Study 2, 312 patients were enrolled. The mean age was 49.7 years (range 18 to 85) and patients were predominantly male (98%). In each study, three XaraColl implants, containing 100 mg bupivacaine HC1 each, were cut in half. Three halves were placed into the hernia repair site below the site of mesh placement. The muscle/fascial layer was closed and the remaining three halves were placed between the fascia/muscle closure and the skin closure. The placebo consisted of three implants without bupivacaine HC1, similarly prepared and placed. Use of low-dose lidocaine, administered topically or subcutaneously for intravenous catheter placement, or administered intravenously during the induction of general anesthesia prior to surgery and placement of XaraColl, was reported.

[0108] Pain intensity was rated by the patients using a 0 to 10 numerical rating scale at multiple time points up to 72 hours. Immediately postoperatively, patients were allowed parenteral morphine rescue medication as needed. Once tolerating oral intake, patients received a standard acetaminophen regimen (650 mg orally three times daily) and immediate- release oral morphine (15 mg) was available as needed.

[0109] The primary outcome measure was the time-weighted sum of pain intensity from Time 0 through 24 hours (SPI24). The secondary endpoints were total use of opioid analgesia from Time 0 through 24 hours (TOpA24), time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48), total use of opioid analgesia from Time 0 through 48 hours (TOpA48), time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72), and total use of opioid analgesia from Time 0 through 72 hours (TOpA72). [0110] In both Study 1 and Study 2, there was a statistically significant treatment effect for XaraColl compared to placebo in SPI24 and TOpA24. There was no statistically significant treatment effect for XaraColl compared to placebo in SPI72 and TOpA72. Table 3 shows the mean sum of pain intensity over the first 24 hours after surgery.

Table 3: Mean Sum of Pain Intensity Over the First 24 Hours After Surgery (Primary Endpoint)

¹ Placebo consisted of three collagen implants.

² Primary endpoint

³ Treatment compared with placebo

SD=standard deviation; CI=confidence interval

SPI (sum of pain intensity)

[0111] The proportion of patients who did not receive opioid rescue analgesia through 72 hours in the XaraColl and placebo treatment groups was 36% and 22%, respectively, in Study 1, and 28% and 12%, respectively, in Study 2. The median time to first opioid rescue analgesia in the XaraColl and placebo treatment groups was 11 hours and 1 hour, respectively, in Study 1 , and 6 hours and 1 hour, respectively in Study 2.

[0112] In some embodiments, the bupivacaine-collagen implant may be in the form of a depot for the treatment of postoperative pain via sustained, controlled release of bupivacaine. The depot may include a therapeutic region comprising bupivacaine. A control region of the depot comprises a bioresorbable polymer and a releasing agent mixed with the polymer. The releasing agent is configured to dissolve when the depot is placed in vivo to form diffusion openings in the control region. The depot is configured to be implanted at a treatment site in vivo and, while implanted, release bupivacaine at the treatment site for no less than 7 days, no less than 6 days, no less than 5 days, no less than 4 days, no less than 3 days, no less than 2 days, or no less than 1 day. In some embodiments, bupivacaine in the therapeutic region comprises at least 50% of the total weight of the depot.

[0113] In some embodiments, the depot is configured to release the analgesic at the treatment site for no less than 14 days. In some embodiments, about 20% to about 50% of bupivacaine is released in the first about 3 to about 5 days of the 14 days, and at least 80% of the remaining bupivacaine is released in the last 11 days of the 14 days. In some embodiments, about 20% to about 40% of bupivacaine is released in the first 3 days of the 14 days, and at least 80% of the remaining bupivacaine is released in the last 11 days of the 14 days.

[0114] In some embodiments, at least 90% of the remaining bupivacaine is released in the last 11 days of the 14 days. In some embodiments, no more than 15% of the amount of bupivacaine is released in the first 2 days of the 14 days.

[0115] In some embodiments, the depot is configured to release bupivacaine at a first rate for a first period of time and at a second rate for a second period of time. The first rate may be greater than the second rate. The depot may be configured to release at least 90% of the analgesic in the therapeutic region within 14 days.

[0116] In some embodiments, the depot is configured to release about 100 mg to about 500 mg of bupivacaine to the treatment site per day.

[0117] In some embodiments, depot for the treatment of postoperative pain via sustained, controlled release of bupivacaine includes a therapeutic region comprising bupivacaine. A control region of the depot comprises a bioresorbable polymer and a releasing agent mixed with the polymer. The releasing agent is configured to dissolve when the depot is placed in vivo to form diffusion openings in the control region. The depot is configured to be implanted at a treatment site in vivo and, while implanted, release bupivacaine at the treatment site for no less than 14 days. About 20% to about 40% of bupivacaine is released in the first 3 days of the 14 days, and wherein at least 80% of the remaining bupivacaine is released in the last 11 days of the 14 days.

[0118] In some embodiments, a depot for the treatment of postoperative pain via sustained, controlled release of bupivacaine includes a therapeutic region comprising bupivacaine. A control region of the depot comprises a bioresorbable polymer and a releasing agent mixed with the polymer. The releasing agent is configured to dissolve when the depot is placed in vivo to form diffusion openings in the control region. The depot is configured to be implanted at a treatment site in vivo and, while implanted, release bupivacaine at the treatment site for no less than 3 days. The control region does not include bupivacaine at least prior to implantation of the depot at the treatment site.

[0119] In some embodiments, the implant may further include an antibiotic, an antifungal, and/or an antimicrobial. The antibiotic, the antifungal, and/or the antimicrobial is selected from at least one of amoxicillin, amoxicillin/clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole/trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin, gentamycin, cephalosporin(s), carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropin- mellitin, magainin, dermaseptin, cathelicidin, a-defensins, and a-protegrins, ketoconazole, clortrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafme, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

[0120] In some embodiments, the implant may further includes an antiinflammatory agent selected from at least one of steroids, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone and methylprednisolone, non-steroidal antiinflammatory drugs (NSAIDs), aspirin, Ibuprofen, naproxen sodium, diclofenac, diclofenac- misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and COX-2 inhibitors.

[0121] In some embodiments, the implant further includes at least one of: epinephrine, clonidine, transexamic acid.

[0122] In some embodiments, the releasing agent is a non-ionic surfactant. In some embodiments, the releasing agent has hydrophilic properties. In some embodiments, the releasing agent is a polysorbate. In some embodiments, the releasing agent is Tween 20. In some embodiments, the releasing agent is Tween 80. In some embodiments, the releasing agent is non-polymeric. In some embodiments, the releasing agent is not a plasticizer. [0123] In some embodiments, the polymer is configured to degrade only after substantially all of bupivacaine has been released from the depot.

[0124] In some embodiments, the polymer is a copolymer. In some embodiments, the polymer is a terpolymer.

[0125] In some embodiments, the polymer includes at least one of pol-yglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acids), poly(lactide-co-glycolide)(PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester), poly(amino acid), pol-ydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co- caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co- D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(gycolide- trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy- carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly 1,3- bis-(p-carboxyphenoxy) hex-ane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone co-butylacrylate, a copolymer of polyhydroxybutyrate, a copolymer of maleic anhydride, a copoly-mer of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan and starch), pro-teins (such as gelatin and collagen) or PEG derivatives, polyaspirins, polyphosphagenes, colla-gen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L- lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO- PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG- PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate)hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or salts thereof, Carbo-pol®, poly(hydroxyethylmethacrylate), poly (methoxyethylmethacry late), poly(methoxyethoxy-ethylmethacrylate), polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin, polyvi-nyl alcohols, propylene glycol, and poly(DL- lactide-co-glycolide-co-caprolactone).

[0126] In some embodiments, the polymer is one of poly(DL-lactide-co-glycolide- co-caprolactone) and poly(DL-lactide-co-glycolide)(PLGA).

[0127] In some embodiments, the polymer is poly(DL-lactide-co-glycolide-co- caprolactone) in a molar ratio of 60:30:10. In some embodiments, the polymer is poly(DL- lactide-co-glycolide)(PLGA) in a molar ratio of 50:50.

[0128] In some embodiments, the polymer is ester-terminated. In some embodiments, the polymer is a terpolymer that includes three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), poly-dioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

[0129] In some embodiments, the polymer is a first polymer, and the therapeutic region includes a second polymer mixed with bupivacaine. In some embodiments, the first polymer and the second polymer are the same. In some embodiments, the first polymer and the second polymer are different.

[0130] In some embodiments, the first polymer and/or the second polymer include at least one of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic ac-id) (PLA), poly(alpha-hydroxy acids), poly(lactide-co-glycolide)(PLGA or DLG), poly(DL-lactide-co- caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate es-ter), poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, poly(lactide-co- caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate), poly(ethyl glutamate- co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly l,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphos-phazene, polycaprolactone co-butylacrylate, a copolymer of polyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic ac-id, chitosan and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirins, polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alpha to-copheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyr- ate)hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, car-boxymethylcellulose or salts thereof, Carbopolpoly(hydroxyethylmethacrylate), poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate), polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone).

[0131] In some embodiments, the first polymer and/or the second polymer selected from the following: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co- glycolide)(PLGA). In some embodiments, the first polymer and/or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of 60:30:10. In some embodiments, the first polymer and/or the second polymer is poly(DL-lactide-co-glycolide) and has a molar ratio of 50:50.

[0132] In some embodiments, the first polymer and/or the second polymer is ester- terminated. In some embodiments, the first polymer and/or the second polymer is a terpolymer that includes three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

[0133] In some embodiments, the ratio of the releasing agent to the polymer in the control region is at least 1:1.

[0134] In some embodiments, the releasing agent is configured to dissolve when the depot is placed in contact with phosphate buffered saline to form diffusion openings. [0135] In some embodiments, the releasing agent dissolves at a first rate and the polymer degrades at a second rate, wherein the first rate is greater than the second rate.

[0136] In some embodiments, the releasing agent dissolves in response to contact between the control region and the physiologic fluids at the treatment site. In some embodiments, diffusion openings in the control region are created via the dissolution of the releasing agent in response to physiologic fluids at the treatment site.

[0137] In some embodiments, the releasing agent is a first releasing agent and the therapeutic region includes a second releasing agent. Microchannels are created in the therapeutic region and the control region via dissolution of the first and/or second releasing agents. In some embodiments, at least some of the microchannels penetrate both the therapeutic region and the control region.

[0138] In some embodiments, the therapeutic region comprises a plurality of microlayers, and wherein at least some of the microchannels extend through consecutive microlayers.

[0139] In some embodiments, the control region comprises a first plurality of microlayers and the therapeutic region comprises a second plurality of microlayers, and wherein at least some of the microchannels extend through the first and second plurality of microlayers.

[0140] In some embodiments, a porosity of the depot is increased via dissolution of the releasing agent.

[0141] In some embodiments, bupivacaine is released one or more times in substantially discrete doses after implantation.

[0142] In some embodiments, the implant may have a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm. In some embodiments, the implant may have any shape, in particular, cylindrical, semi-cylindrical, corrugated, cuboid, hexahedral, or any other suitable shape. The method may further include cutting the implant into segments having a shape or a size suitable for placing at the implantation site. For example, a sheet-like implant may be cut into one or more segments having a shape selected from a square, a rectangle, a right triangle, and an elongate triangle. The segments may be 1/2, 1/3 or 1/4 in size relative to the implant.

[0143] The following clauses describe certain embodiments. [0144] Clause 1. A method of performing a soft tissue surgery procedure in a subject in need thereof, comprising placing a drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising a type I fibrillar collagen matrix and about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day.

[0145] Clause 2. The method of clause 1, wherein the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

[0146] Clause 3. The method of clause 1, wherein the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure.

[0147] Clause 4. The method of clause 1 , wherein the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement.

[0148] Clause 5. The method of clause 1, wherein the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

[0149] Clause 6. The method of clause 1 , wherein the surgery procedure is open ventral hernia repair comprising onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath. [0150] Clause 7. The method of clause 1, wherein the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

[0151] Clause 8. The method of clause 1, wherein the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

[0152] Clause 9. The method of clause 1, wherein the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets.

[0153] Clause 10. The method of any one of clauses 1 to 9, wherein the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

[0154] Clause 11. The method of any one of clauses 1 to 10, wherein the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

[0155] Clause 12. The method of any one of clauses 1 to 11, further comprising partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently.

[0156] Clause 13. The method of any one of clauses 1 to 12, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

[0157] Clause 14. The method of clause 12 or 13, wherein the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

[0158] Clause 15. The method of clause 12 or 13, wherein the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profde of the unpartitioned drug delivery device. [0159] Clause 16. Use of a type I fibrillar collagen matrix and bupivacaine hydrochloride for the manufacture of drug delivery device for a soft tissue surgery procedure in a subject in need thereof, the procedure comprising placing the drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day.

[0160] Clause 17. The use of clause 16, wherein the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

[0161] Clause 18. The use of clause 16, wherein the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure.

[0162] Clause 19. The use of clause 16, wherein the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement.

[0163] Clause 20. The use of clause 16, wherein the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

[0164] Clause 21. The use of clause 16, wherein the surgery procedure is open ventral hernia repair comprising onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath. [0165] Clause 22. The use of clause 16, wherein the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

[0166] Clause 23. The use of clause 16, wherein the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

[0167] Clause 24. The use of clause 16, wherein the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets.

[0168] Clause 25. The use of any one of clauses 16 to 24, wherein the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

[0169] Clause 26. The use of any one of clauses 16 to 25, wherein the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

[0170] Clause 27. The use of any one of clauses 16 to 26, further comprising partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently.

[0171] Clause 28. The use of any one of clauses 16 to 27, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

[0172] Clause 29. The use of clause 27 or 28, wherein the release dissolution profde of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

[0173] Clause 30. The use of clause 27 or 28, wherein the release dissolution profde of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device. [0174] Clause 31. A kit for performing a soft tissue surgery procedure in a subject in need thereof, the kit comprising a drug delivery device and instructions for placement of the drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising a type I fibrillar collagen matrix and about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day.

[0175] Clause 32. The kit of clause 31, wherein the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

[0176] Clause 33. The kit of clause 31 , wherein the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure.

[0177] Clause 34. The kit of clause 31, wherein the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement.

[0178] Clause 35. The kit of clause 31, wherein the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

[0179] Clause 36. The kit of clause 31, wherein the surgery procedure is open ventral hernia repair comprising mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath. [0180] Clause 37. The kit of clause 31, wherein the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

[0181] Clause 38. The kit of clause 31, wherein the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

[0182] Clause 39. The kit of clause 31 , wherein the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets.

[0183] Clause 40. The kit of any one of clauses 31 to 39, wherein the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

[0184] Clause 41. The kit of any one of clauses 31 to 40, wherein the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

[0185] Clause 42. The kit of any one of clauses 31 to 41, further comprising instructions for partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently.

[0186] Clause 43. The kit of any one of clauses 31 to 42, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

[0187] Clause 44. The kit of clause 42 or 43, wherein the release dissolution profde of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

[0188] Clause 45. The kit of clause 42 or 43, wherein the release dissolution profde of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device. [0189] Clause 1001. A method of performing a soft tissue surgery procedure in a subject in need thereof, comprising placing a drug delivery device comprising an analgesic or anesthetic drug substance at a surgical site, for controlled and/or sustained release of the drug substance.

[0190] Clause 1002. The method of clause 1001, wherein the surgery procedure is an abdominoplasty.

[0191] Clause 1003. The method of clause 1002, wherein the abdominoplasty surgery procedure comprises rectus sheath plication.

[0192] Clause 1004. The method of clause 1002 or 1003, wherein the abdominoplasty surgery procedure is conducted under general anesthesia.

[0193] Clause 1005. The method of any one of clauses 1002 to 1004, wherein the abdominoplasty surgery procedure comprises making an incision that does not extend above the umbilicus.

[0194] Clause 1006. The method of any one of clauses 1002 to 1005, wherein the abdominoplasty surgery procedure comprises an anterior approach.

[0195] Clause 1007. The method of any one of clauses 1002 to 1006, wherein the abdominoplasty surgery procedure comprises making an incision from one anterior superior iliac spine (ASIS) to the other.

[0196] Clause 1008. The method of any one of clauses 1002 to 1007, wherein the abdominoplasty surgery procedure comprises placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication.

[0197] Clause 1009. The method of any one of clauses 1002 to 1008, wherein the abdominoplasty surgery procedure comprises placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

[0198] Clause 1010. The method of clause 1001, wherein the surgery procedure is open ventral hernia repair.

[0199] Clause 1011. The method of clause 1010, wherein the open ventral hernia repair surgery procedure comprises mesh placement at different subcutaneous layers, including intraperitoneal placement.

[0200] Clause 1012. The method of clause 1010, wherein the open ventral hernia repair surgery procedure comprises underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

[0201] Clause 1013. The method of clause 1010, wherein the open ventral hernia repair surgery procedure comprises onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath.

[0202] Clause 1014. The method of clause 1001, wherein the surgery procedure is open abdominal hysterectomy.

[0203] Clause 1015. The method of clause 1014, wherein the open abdominal hysterectomy surgery procedure comprises placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

[0204] Clause 1016. The method of clause 1001, wherein the surgery procedure is laparoscopic-assisted colectomy.

[0205] Clause 1017. The method of clause 1016, wherein the laparoscopic-assisted colectomy surgery procedure comprises placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

[0206] Clause 1018. The method of clause 1001, wherein the surgery procedure is reduction mammoplasty.

[0207] Clause 1019. The method of clause 1018, wherein the reduction mammoplasty surgery procedure comprises placing the drug delivery device in part in one or both breast pockets.

[0208] Clause 1020. The method of any one of clauses 1001 to 1019, wherein the subject is between 18-75 years of age, or between 18-65 years of age.

[0209] Clause 1021. The method of any one of clauses 1001 to 1020, wherein the subject has a body mass index of 18-35 kg/m². [0210] Clause 1022. The method of any one of clauses 1001 to 1020, wherein the subject is free of hypersensitivity to amide-type local anesthetics, fentanyl, morphine, oxycodone, acetaminophen, NSAIDs, or bovine products.

[0211] Clause 1023. The method of any one of clauses 1001 to 1020, wherein the subject is free of a chronic painful condition.

[0212] Clause 1024. The method of any one of clauses 1001 to 1020, wherein the subject has liver function test (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) values lower than 3 times the upper limit of normal.

[0213] Clause 1025. The method of any one of clauses 1001 to 1020, wherein the subject is free of cirrhosis and/or has no history of cirrhosis.

[0214] Clause 1026. The method of any one of clauses 1001 to 1020, wherein the subject is free of an active inflammatory bowel disease flare.

[0215] Clause 1027. The method of any one of clauses 1001 to 1020, wherein the subject is free of malignancy and/or a cancer diagnosis within 5 years before the surgery procedure.

[0216] Clause 1028. The method of any one of clauses 1001 to 1027, wherein the drug delivery device comprises a fibrillar collagen matrix, and the drug substance is selected from amino amide anesthetics, amino ester anesthetics, and mixtures thereof.

[0217] Clause 1029. The method of clause 28, wherein the drug substance is substantially homogeneously dispersed in the collagen matrix.

[0218] Clause 1030. The method of any one of clauses 1001 to 1029, wherein the drug substance is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day after administration.

[0219] Clause 1031. The method of any one of clauses 1001 to 1030, wherein the drug substance is selected from bupivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, articaine, trimecaine, and their salts and prodrugs.

[0220] Clause 1032. The method of any one of clauses 1028 to 1031, wherein the fibrillar collagen matrix is a type I collagen matrix. [0221] Clause 1033. The method of clause 1032, wherein the fibrillar collagen matrix is a type I collagen matrix and the drug substance is an amino amide anesthetic selected from bupivacaine and salts and prodrugs thereof.

[0222] Clause 1034. The method of clause 1032, wherein the fibrillar collagen matrix is a type I collagen matrix and the drug substance is bupivacaine hydrochloride.

[0223] Clause 1035. The method of any one of clauses 1001 to 1034, wherein the drug delivery device comprises one or more collagen sponges.

[0224] Clause 1036. The method of clause 1035, wherein a collagen sponge comprises about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride.

[0225] Clause 1037. The method of clause 1035, wherein a collagen sponge comprises about 2.0 to about 12.0 mg/cm³ bupivacaine hydrochloride.

[0226] Clause 1038. The method of clause 1035, wherein a collagen sponge comprises about 4.0 to about 10.0 mg/cm³ bupivacaine hydrochloride.

[0227] Clause 1039. The method of clause 1035, wherein a collagen sponge comprises about 6.0 to about 10.0 mg/cm³ bupivacaine hydrochloride.

[0228] Clause 1040. The method of clause 1035, wherein a collagen sponge comprises about 6.0 mg/cm³ bupivacaine hydrochloride, about 7.0 mg/cm³ bupivacaine hydrochloride, about 8.0 mg/cm³ bupivacaine hydrochloride, or about 9.0 mg/cm³ bupivacaine hydrochloride.

[0229] Clause 1041. The method of clause 1035, wherein a collagen sponge comprises about 8.0 mg/cm³ bupivacaine hydrochloride.

[0230] Clause 1042. The method of clause 1035, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

[0231] Clause 1043. The method of clause 1035, wherein a collagen sponge comprises about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg bupivacaine hydrochloride.

[0232] Clause 1044. The method of clause 1035, wherein a collagen sponge comprises about 100 mg bupivacaine hydrochloride.

[0233] Clause 1045. The method of any one of clauses 1035 to 1044, wherein a collagen sponge comprises about 1.0 to about 20.0 mg/cm³ type I collagen. [0234] Clause 1046. The method of any one of clauses 1001 to 1045, further comprising partitioning the drug delivery device into segments with a predetermined size.

[0235] Clause 1047. The method of clause 1046, wherein partitioning the drug delivery device comprises cutting the drug delivery device.

[0236] Clause 1048. The method of clause 1046 or 1047, wherein the drug delivery device is partitioned into two or more segments, wherein each segment is placed at the surgical site independently.

[0237] Clause 1049. The method of any one of clauses 1001 to 1048, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm.

[0238] Clause 1050. The method of any one of clauses 1001 to 1048, wherein the drug delivery device has a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

[0239] Clause 1051. The method of any one of clauses 1046 to 1050, wherein the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profde of the unpartitioned drug delivery device.

[0240] Clause 1052. The method of any one of clauses 1046 to 1050, wherein the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

[0241] Clause 1053. Use of a fibrillar collagen matrix and at least one drug substance selected from amino amide anesthetics, amino ester anesthetics and mixtures thereof, for the manufacture of a drug delivery device for providing local analgesia, local anesthesia or nerve blockade at a surgical site of a soft tissue surgery procedure in a subject in need thereof.

[0242] Clause 1054. The use of clause 1053, wherein the surgery procedure is an abdominoplasty.

[0243] Clause 1055. The use of clause 1054, wherein the abdominoplasty surgery procedure comprises rectus sheath plication.

[0244] Clause 1056. The use of clause 1054 or 1055, wherein the abdominoplasty surgery procedure is conducted under general anesthesia. [0245] Clause 1057. The use of any one of clauses 1054 to 1056, wherein the abdominoplasty surgery procedure comprises making an incision that does not extend above the umbilicus.

[0246] Clause 1058. The use of any one of clauses 1054 to 1057, wherein the abdominoplasty surgery procedure comprises an anterior approach.

[0247] Clause 1059. The use of any one of clauses 1054 to 1058, wherein the abdominoplasty surgery procedure comprises making an incision from one anterior superior iliac spine (ASIS) to the other.

[0248] Clause 1060. The use of any one of clauses 1054 to 1059, wherein the abdominoplasty surgery procedure comprises placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication.

[0249] Clause 1061. The use of any one of clauses 1054 to 1060, wherein the abdominoplasty surgery procedure comprises placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

[0250] Clause 1062. The use of clause 1053, wherein the surgery procedure is open ventral hernia repair.

[0251] Clause 1063. The use of clause 1062, wherein the open ventral hernia repair surgery procedure comprises mesh placement at different subcutaneous layers, including intraperitoneal placement.

[0252] Clause 1064. The use of clause 1062, wherein the open ventral hernia repair surgery procedure comprises underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

[0253] Clause 1065. The use of clause 1062, wherein the open ventral hernia repair surgery procedure comprises onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath.

[0254] Clause 1066. The use of clause 1053, wherein the surgery procedure is open abdominal hysterectomy. [0255] Clause 1067. The use of clause 1066, wherein the open abdominal hysterectomy surgery procedure comprises placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

[0256] Clause 1068. The use of clause 1053, wherein the surgery procedure is laparoscopic-assisted colectomy.

[0257] Clause 1069. The use of clause 1068, wherein the laparoscopic-assisted colectomy surgery procedure comprises placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

[0258] Clause 1070. The use of clause 1052, wherein the surgery procedure is reduction mammoplasty.

[0259] Clause 1071. The use of clause 1070, wherein the reduction mammoplasty surgery procedure comprises placing the drug delivery device in part in one or both breast pockets.

[0260] Clause 1072. The use of any one of clauses 1053 to 1071, wherein the subject is between 18-75 years of age, or between 18-65 years of age.

[0261] Clause 1073. The use of any one of clauses 1053 to 1072, wherein the subject has a body mass index of 18-35 kg/m².

[0262] Clause 1074. The use of any one of clauses 1053 to 1073, wherein the subject is free of hypersensitivity to amide-type local anesthetics, fentanyl, morphine, oxycodone, acetaminophen, NSAIDs, or bovine products.

[0263] Clause 1075. The use of any one of clauses 1053 to 1074, wherein the subject is free of a chronic painful condition.

[0264] Clause 1076. The use of any one of clauses 1053 to 1075, wherein the subject has liver function test (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) values lower than 3 times the upper limit of normal.

[0265] Clause 1077. The use of any one of clauses 1053 to 1076, wherein the subject is free of cirrhosis and/or has no history of cirrhosis. [0266] Clause 1078. The use of any one of clauses 1053 to 1077, wherein the subject is free of an active inflammatory bowel disease flare.

[0267] Clause 1079. The use of any one of clauses 1053 to 1078, wherein the subject is free of malignancy and/or a cancer diagnosis within 5 years before the surgery procedure.

[0268] Clause 1080. The use of any one of clauses 1053 to 1079, wherein the drug delivery device comprises a fibrillar collagen matrix, and the drug substance is selected from amino amide anesthetics, amino ester anesthetics, and mixtures thereof.

[0269] Clause 1081. The use of clause 1080, wherein the drug substance is substantially homogeneously dispersed in the collagen matrix.

[0270] Clause 1082. The use of any one of clauses 1053 to 1081, wherein the drug substance is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day after administration.

[0271] Clause 1083. The use of any one of clauses 1053 to 1082, wherein the drug substance is selected from bupivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, articaine, trimecaine, and their salts and prodrugs.

[0272] Clause 1084. The use of any one of clauses 1080 to 1083, wherein the fibrillar collagen matrix is a type I collagen matrix.

[0273] Clause 1085. The use of clause 1084, wherein the fibrillar collagen matrix is a type I collagen matrix and the drug substance is an amino amide anesthetic selected from bupivacaine and salts and prodrugs thereof.

[0274] Clause 1086. The use of clause 1084, wherein the fibrillar collagen matrix is a type I collagen matrix and the drug substance is bupivacaine hydrochloride.

[0275] Clause 1087. The use of any one of clauses 1053 to 1086, wherein the drug delivery device comprises one or more collagen sponges.

[0276] Clause 1088. The use of clause 1087, wherein a collagen sponge comprises about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride.

[0277] Clause 1089. The use of clause 1087, wherein a collagen sponge comprises about 2.0 to about 12.0 mg/cm³ bupivacaine hydrochloride. [0278] Clause 1090. The use of clause 1087, wherein a collagen sponge comprises about 4.0 to about 10.0 mg/cm³ bupivacaine hydrochloride.

[0279] Clause 1091. The use of clause 1087, wherein a collagen sponge comprises about 6.0 to about 10.0 mg/cm³ bupivacaine hydrochloride.

[0280] Clause 1092. The use of clause 1087, wherein a collagen sponge comprises about 6.0 mg/cm³ bupivacaine hydrochloride, about 7.0 mg/cm³ bupivacaine hydrochloride, about 8.0 mg/cm³ bupivacaine hydrochloride, or about 9.0 mg/cm³ bupivacaine hydrochloride.

[0281] Clause 1093. The use of clause 1087, wherein a collagen sponge comprises about 8.0 mg/cm³ bupivacaine hydrochloride.

[0282] Clause 1094. The use of clause 1087, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

[0283] Clause 1095. The use of clause 1087, wherein a collagen sponge comprises about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg bupivacaine hydrochloride.

[0284] Clause 1096. The use of clause 1087, wherein a collagen sponge comprises about 100 mg bupivacaine hydrochloride.

[0285] Clause 1097. The use of any one of clauses 1087 to 1096, wherein a collagen sponge comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

[0286] Clause 1098. The use of any one of clauses 1053 to 1097, further comprising partitioning the drug delivery device into segments with a predetermined size.

[0287] Clause 1099. The use of clause 1098, wherein partitioning the drug delivery device comprises cutting the drug delivery device.

[0288] Clause 1100. The use of clause 1098 or 1099, wherein the drug delivery device is partitioned into two or more segments, wherein each segment is placed at the surgical site independently.

[0289] Clause 1101. The use of any one of clauses 1053 to 1100, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm. [0290] Clause 1102. The use of any one of clauses 1053 to 1100, wherein the drug delivery device has a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

[0291] Clause 1103. The use of any one of clauses 1098 to 1102, wherein the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profde of the unpartitioned drug delivery device.

[0292] Clause 1104. The use of any one of clauses 1098 to 1102, wherein the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

[0293] Clause 1105. A kit for placing at a surgical site a drug delivery device or a segment thereof during a soft tissue surgery procedure, comprising: a drug delivery device for providing local analgesia, local anesthesia or nerve blockade at a site in a human or animal in need thereof, the device comprising a fibrillar collagen matrix; and at least one drug substance selected from the group consisting of amino amide anesthetics, amino ester anesthetics and mixtures thereof, the at least one drug substance being substantially homogeneously dispersed in the collagen matrix, and the at least one drug substance being present in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day after administration; and instructions for a clinician for placing the drug delivery device at a surgical site during a soft tissue surgery procedure.

[0294] Clause 1106. The kit of clause 1105, wherein the drug delivery device comprises a depot for providing local analgesia, local anesthesia or nerve blockade at a site in a human or animal in need thereof, the device comprising a fibrillar collagen matrix; and at least one drug substance selected from the group consisting of amino amide anesthetics, amino ester anesthetics and mixtures thereof, the at least one drug substance being substantially homogeneously dispersed in the collagen matrix, and the at least one drug substance being present in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day after administration.

[0295] Clause 1107. The kit of clause 1105, wherein the drug substance is selected from bupivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, articaine, trimecaine and their salts and prodrugs. [0296] Clause 1108. The kit of clause 1105, comprising a drug delivery device disclosed herein.

[0297] Clause 1109. The kit of clause 1105, wherein the surgery procedure is an abdominoplasty.

[0298] Clause 1110. The kit of clause 1109, wherein the abdominoplasty surgery procedure comprises rectus sheath plication.

[0299] Clause 1111. The kit of clause 1109 or 1110, wherein the abdominoplasty surgery procedure is conducted under general anesthesia.

[0300] Clause 1112. The kit of any one of clauses 1109 to 1111, wherein the abdominoplasty surgery procedure comprises making an incision that does not extend above the umbilicus.

[0301] Clause 1113. The kit of any one of clauses 1109 to 1112, wherein the abdominoplasty surgery procedure comprises an anterior approach.

[0302] Clause 1114. The kit of any one of clauses 1109 to 1113, wherein the abdominoplasty surgery procedure comprises making an incision from one anterior superior iliac spine (ASIS) to the other.

[0303] Clause 1115. The kit of any one of clauses 1109 to 1114, wherein the abdominoplasty surgery procedure comprises placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication.

[0304] Clause 1116. The kit of any one of clauses 1109 to 1115, wherein the abdominoplasty surgery procedure comprises placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

[0305] Clause 1117. The kit of clause 1105, wherein the surgery procedure is open ventral hernia repair.

[0306] Clause 1118. The kit of clause 1117, wherein the open ventral hernia repair surgery procedure comprises mesh placement at different subcutaneous layers, including intraperitoneal placement.

[0307] Clause 1119. The kit of clause 1117, wherein the open ventral hernia repair surgery procedure comprises underlay or inlay mesh repair, wherein the instructions comprise placing the drug delivery device in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

[0308] Clause 1120. The kit of clause 1117, wherein the open ventral hernia repair surgery procedure comprises onlay mesh repair, wherein the instructions comprise placing the drug delivery device in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath.

[0309] Clause 1121. The kit of clause 1105, wherein the surgery procedure is open abdominal hysterectomy.

[0310] Clause 1122. The kit of clause 1121, wherein the instructions comprise placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

[0311] Clause 1123. The kit of clause 1105, wherein the surgery procedure is laparoscopic-assisted colectomy.

[0312] Clause 1124. The kit of clause 1123, wherein the instructions comprise placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

[0313] Clause 1125. The kit of clause 1105, wherein the surgery procedure is reduction mammoplasty.

[0314] Clause 1126. The kit of clause 1125, wherein the instructions comprise placing the drug delivery device in part in one or both breast pockets.

EXAMPLES

Example 1 : Non-clinical studies

[0315] Bupivacaine has been widely used as a local anesthetic and has demonstrated efficacy in animal models in multiple species (Li, et al., 2013, Hersh, et al., 1992). The pharmacology of bupivacaine is well understood.

[0316] The distribution, metabolism, and excretion of bupivacaine across species is characterized in the literature including data showing that, following absorption, bupivacaine is rapidly and readily distributed to tissues, with the highest concentrations in highly perfused tissues. In general, the metabolic profile of bupivacaine is similar across species although quantitatively different, with no novel metabolite identified in humans (Goehl, et al., 1973, Carson 2000). The excretion of bupivacaine in monkeys and humans is predominantly in the urine; in rats, excretion in urine and feces is generally similar; and in dogs, only small amounts of excretion of bupivacaine in the urine have been reported. The dog excretion data in the literature for bupivacaine is consistent with excretion data obtained in the dog following implantation of INL-001, which showed approximately 0.16 % of the bupivacaine dose was collected in the urine over a 72-hour period. The genotoxicity of bupivacaine HC1 was evaluated in 4 in vitro studies and 2 in vivo studies, with no safety concerns identified.

[0317] Clinically significant pharmacokinetic drug interactions with bupivacaine have been reported with verapamil, diazepam, and cimetidine in humans, animals, and/or in vitro test systems. These interactions occurred with bupivacaine administered epidurally or intravenously (iv).

[0318] The uniformity of bupivacaine in the INL-001 implant and the release of bupivacaine from the implant was evaluated in in vitro and/or in vivo assessments. The in vitro uniformity study demonstrated that bupivacaine content is homogeneously dispersed throughout INL 001. An in vitro dissolution study of a whole matrix found that bupivacaine was released as early as 5 minutes and complete release of bupivacaine occurred by 24 hours. An in vivo study showed the in vitro drug release profile was similar to that seen in vivo in dogs with INL-001 implanted into the abdomen and subcutaneous tissues through a surgical incision.

[0319] Two studies were conducted in which INL-001 was surgically implanted in rats followed by a 56 day postsurgical period to assess potential local and systemic effects, determine potential effects on wound healing, and characterize the resolution of any implant related findings. The initial study was conducted with early development drug product and the second study with the clinical Phase 3/commercial formulation using generally the same study design. INL-001 was well tolerated following implantation. By day 28 following INL-001 implantation, attrition of the implant was approximately 95% and the implant was not observed microscopically by day 56 after dosing. INL-OOl-associated findings were limited to observations at the injection site, including transient edema through day 10 and microscopic findings associated with the repair process. [0320] Biocompatibility studies were conducted with extracts from INL-001 and the drug-free implant; these studies did not identify any safety concerns. There was no evidence of acute systemic toxicity or effects on body temperature (i.e., pyrogenicity) associated with administration of drug free implant extract or evidence of skin irritation, sensitization, or genotoxicity following exposure to bupivacaine implant extract.

Example 2: Clinical Studies

[0321] The clinical pharmacology, efficacy, and safety of INL-001 (at single doses of 100, 150, 200, and 300 mg) have been evaluated in 11 completed clinical studies (Phases 1- 3) in adults, including 2 well controlled pivotal Phase 3 studies of INL-001 in open inguinal hernia repair, at its recommended approved dose (three 100-mg bupivacaine HC1 implants).

[0322] In a pharmacokinetic/relative bioavailability study in patients following inguinal hernioplasty (Study INN-CB-022), the commercial formulation of INL 001 at a dose of 300 mg was compared with Marcaine 0.25% injection at a dose of 175 mg (the maximum recommended single dose). Quantifiable bupivacaine concentrations were evident at the first posttreatment time point measured (30 minutes) for all patients treated with INL-001 or Marcaine. Bupivacaine concentrations were detectable through the 96-hour posttreatment time point (last time point) in both treatment groups but at higher concentrations with INL-001 than with Marcaine. Pharmacokinetic analysis led to the following additional conclusions:

[0323] Lor the INL-001 treatment group, the mean maximum observed plasma concentration (Cmax) (minimum, maximum) was 663.412 ng/mL (274.00 ng/mL, 1230.00 ng/mL) compared with a mean Cmax (minimum, maximum) for the Marcaine treatment group of 641.000 ng/mL (275.00 ng/mL, 1140.00 ng/mL).

[0324] Lor the INL-001 treatment group, the median time to maximum observed plasma concentration (T_max) was 3.03 hours with a mean terminal elimination half-life (ti_/2) of 18.95 hours compared with a T_max of 1.01 hours and a mean ti/2 of 9.08 hours for the Marcaine treatment group.

[0325] Lor INL-001, the geometric means for area under the concentration-time curve (AUC) from Time 0 to the last quantifiable concentration (AUCo-_Iast) was 18186.9 h*ng/niL and the AUC from Time 0 extrapolated through infinity (AUCo-_¥) was 19012.5 Irng/mL. For Marcaine, the geometric means for AUCo-iast and AUCo-¥ were 8836.9 Irng/mL and 8920.1 Irng/mL, respectively.

[0326] In clinical studies of an earlier bupivacaine collagen implant formulation, following implantation of INL-001 at 100, 150, and 200 mg in various abdominopelvic surgeries, quantifiable bupivacaine plasma concentrations were observed from 30 minutes after placement (at the first posttreatment time point). Bupivacaine concentrations increased in a slightly higher than dose-proportional manner with increasing doses of INL-001.

[0327] The efficacy of INL-001 was evaluated in 2 multicenter, double-blind, placebo controlled Phase 3 studies in adults that independently demonstrated the effectiveness of locally placed INL 001 (300 mg implanted in layers at the surgical site) in reducing both pain intensity and the need for opioid rescue analgesia after surgery; together, these studies demonstrate the reproducibility of the INL-001 treatment effects (Studies INN-CB-014 and INN-CB-016). In each study, INL-001 achieved the primary endpoint, with patients treated with INL-001 experiencing statistically significantly less pain (p<0.0004) as evaluated by the (time weighted) sum of pain intensity (SPI) through 24 hours (SPI24). These reductions in pain intensity were coupled with less total use of opioid rescue analgesic medication (TOpA) in the INL-001 treatment group compared with the placebo implant group. In data pooled from the 2 pivotal studies, patients used statistically significantly (p<0.0004) less opioid rescue analgesia and had statistically significantly (p=0.0007) fewer opioid-related treatment emergent adverse events (i.e., nausea, vomiting, and constipation) over the post-implantation period compared with subjects in the combined placebo implant group.

[0328] The existing INL-001 safety database is derived from a clinical development program of 11 studies conducted in soft tissue surgeries in adults, including the 2 positive Phase 3 studies in inguinal hernia repair. A total of 892 adult patients have received collagen matrix implants in this program (612 INL-001 and 280 placebo implants). Of the 892 patients, 816 patients underwent inguinal hernia repair, 69 patients underwent hysterectomy, and 7 patients underwent other types of soft-tissue surgeries (i.e., nonlaparoscopic benign gynecological procedure other than hysterectomy or elective surgery requiring a vertical or transverse abdominal incision).

[0329] Across these 11 studies: adverse events occurring at an incidence of 2% or more patients following administration of INL-001 at 300 mg and at a higher incidence than placebo implants, respectively, were somnolence (19.2% vs 13.9%), dizziness (16.4% vs 13.9%), incision site swelling (13% vs 10.7%), incision site pain (11.7% vs 11.4%), restlessness (7.7% vs 6.8%), dysgeusia (7.5% vs 4.6%), vision blurred (4.9% vs 2.1%), headache (4.7% vs 2.1%), tremor (4.5% vs 2.1%), postprocedural discharge (4.3% vs 3.6%), scrotal swelling (2.8% vs 1.8%), seroma (2.6% vs 1.8%), oral hypoesthesia (2.6% vs 1.4%), pyrexia (2.3% vs 1.8%), and wound dehiscence (2.1% vs 1.8%).

[0330] In these studies, adverse events considered by the investigator to be treatment related following INL-001 placement in the surgical site occurred at a rate of 1.5% or less. The only treatment-related adverse event that occurred in 1% or more of all patients who received INL-001 at 300 mg was dysgeusia (1.3%), which also occurred in 0.7% of patients in the placebo group.

[0331] Across the INL-001 clinical development program, 16 patients experienced 1 or more serious adverse events: 11 patients in the INL-001 (including earlier formulation) treatment group and 5 patients in the placebo implant or other comparator group. Serious adverse events reported in the INL-001 treatment group included wound infection and seroma. One patient had the INL-001 implant removed after placement of an earlier formulation of bupivacaine collagen matrix implant during bladder sling surgery (see event described below).

[0332] There were no verbatim reports of systemic bupivacaine toxicity or LAST during any inguinal hernia repair study done as part of the development program for INL-001. The safety assessments conducted during the development program included monitoring adverse events, measurement of vital signs, and assessments with multiday cardiac Holter monitors. These assessments revealed no constellation of neurologic or cardiovascular (CV) signs or symptoms to suggest systemic bupivacaine toxicity in patients undergoing open inguinal hernia repair receiving INL 001.

[0333] One patient experienced signs and symptoms thought to be consistent with LAST approximately 4 hours after administration of an earlier formulation of the INL-001 (at 150 mg) following bladder sling surgery. Treatment included administration of lipid emulsion and surgical removal of the INL-001 implants.

[0334] Across the INL-001 clinical development program, incision-site adverse events occurring with an incidence of 2% or more in either the INL-001 (including earlier formulation) or placebo group compared with a non-implant comparator treatment group (n=52) included swelling, pain, other complication, postprocedural discharge, erythema, dehiscence, and inflammation.

Example 3 : Study for postoperative pain management following soft-tissue surgery

[0335] The primary objective of the study is to evaluate the safety and tolerability of the INL-001 implant in patients following open ventral hernia repair, abdominoplasty, open abdominal hysterectomy, laparoscopic-assisted colectomy, and reduction mammoplasty.

[0336] The secondary objective of the study is to characterize the pharmacokinetic profile of bupivacaine from the INL 001 implant through 96 hours after implantation in patients following study surgery.

[0337] Exploratory objectives are: (i) to assess the impact of the INL-001 implant on pain intensity in patients over time through 72 hours after implantation following study surgery; (ii) to assess the impact of the INL-001 implant on postsurgical opioid use in patients following study surgery; (iii) to assess the impact of opioid medication use, with the Opioid Related Symptom Distress Scale (OR-SDS), after implantation of INL 001 in patients following study surgery; and (iv) to explore health-related quality of life in patients after implantation of INL 001 following study surgery.

General Study Design

[0338] The study is designed to be a multicenter, Phase 3, open-label, safety, tolerability, and characterization of pharmacokinetics study of the INL-001 (bupivacaine HC1) implant, at 300 mg, in patients following various soft-tissue surgeries: open ventral hernia repair, abdominoplasty, open abdominal hysterectomy, laparoscopic-assisted colectomy, and reduction mammoplasty. After a screening period, on the day of surgery (study day 1), eligible patients undergo study surgery under general anesthesia and have INL-001 implanted intraoperatively. Efficacy is also an exploratory measure in this study.

[0339] The duration of study participation for each patient is a maximum of 75 (±4) days, consisting of a screening period (up to 45 days before surgery), an inpatient period (preoperative, intraoperative, postoperative) of approximately 5 days, and an outpatient follow-up period (up to 30 days [±3 days] after treatment) including an end-of-study visit. Posttreatment (time measured from Time 0 [placement of first INL-001 implant]) safety assessments are made throughout the study after the informed consent form (I CP) is signed, and as specifically scheduled through 96 hours posttreatment, on day 7 (±1 day) (telephone), on day 15 (±3 days) (clinic visit), and on day 30 (±3 days) (clinic visit). Unless the investigator determines further hospitalization is necessary, patients are discharged approximately 96 hours posttreatment (inpatient day 5). Efficacy assessments are made through 72 hours after treatment.

[0340] During the screening period, all patients provide informed consent and undergo eligibility and other screening and safety assessments (medical history including review of prior medications, physical examination, urine drug screen, serum pregnancy test for women of childbearing potential, clinical laboratory tests [hematology, chemistry, urinalysis], vital signs measurement, and 12-lead electrocardiography [ECG]). Vital signs include body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry. The reason(s) a patient does not meet screening criteria are recorded. In addition, the investigator administers the Pain Catastrophizing Scale (PCS) (screening only) as an exploratory measure and the 15 item Quality of Recovery (QoR-15) questionnaire (baseline). Recording of adverse events and concomitant medication use commences once a patient signs an ICF.

[0341] On the day of surgery (day 1), patient eligibility is reconfirmed before the start of surgery (including medical history, urine drug screen, urine pregnancy test for women of childbearing potential, vital signs), and adverse events and prior/concomitant medications are reviewed.

[0342] Patients undergo study surgery using standard surgical procedures conducted under general anesthesia with no other local anesthetic used at the surgical site. All packs/gauze should be removed and adequate hemostasis must be achieved prior to skin closure. Surgical drains should be placed at the discretion of the surgeon and their use recorded. Ancillary procedures (e.g., liposuction) are prohibited.

[0343] Placement of study drug is detailed elsewhere herein. The time of the first placement of study drug (placement of first implant) is considered Time 0 and is recorded. Use of analgesic and all medications during surgery is recorded. At the surgeon’s discretion, if a significant surgical/medical complication is encountered during surgery, study drug is not implanted and the patient is considered enrolled but not treated. [0344] After surgery, patients are transferred to a postanesthesia care unit (PACU) or other postoperative recovery area for monitored observation. The times patients enter and are discharged from the PACU are recorded to calculate time to discharge from the PACU. Patients are monitored with pulse oximetry starting in the PACU through 24 hours posttreatment. After leaving the PACU (time in PACU to be at the discretion of the investigator), patients are placed in the postoperative unit or clinical research unit for domiciled observation. Vital signs, including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry, are assessed at multiple time points through discharge, and in the clinic on days 15 and 30; 12-lead ECG will be done on day 30.

[0345] Adverse event and concomitant medication information, including use of rescue medication, are collected throughout the study (inpatient and outpatient). Surgical wound healing assessments will be made at 24, 48, 72, and 96 hours after Time 0, and on days 7, 15, and 30 using the specified list and assessed for and recorded as adverse events as appropriate. The Southampton Wound Grading System will be completed 72 hours (±3 hours) posttreatment and on days 15 and 30. Assessment for signs and symptoms potentially indicative of systemic bupivacaine toxicity are made after Time 0 at the following time points: 0.5, 1, 2, 3, and 4 hours (each ±15 minutes), and 5, 7, 9, 12, 15, 18, 24, 48, 72, and 96 hours (each ±1 hour), and days 7 (±1 day) and 15 (±3 days) using the specified list and assessment made and recorded as adverse events as appropriate.

[0346] At any time that a patient is determined to be exhibiting signs and/or symptoms suggestive of systemic bupivacaine toxicity, at the discretion of the investigator, a bupivacaine blood sample will be collected and 12 lead ECG are performed. The patient may be treated at the discretion of the investigator, including obtaining repeat bupivacaine blood concentrations, 12 lead ECG, or removal of the implants.

[0347] Blood samples for pharmacokinetic assessments are collected from patients at the following posttreatment time points: 0.5, 1, 1.5, 2, 3, 4, 5 (all ±15 minutes); 6, 8, 10, 12, 18 (all ±1 hour); 24, 36, 48, 72, 96 (all ±3 hours) hours. Concentrations of bupivacaine in plasma are assayed using a validated bioanalytical method.

[0348] After surgery, patient reports of pain intensity using an 11 point numeric pain rating scale (NPRS) are recorded at multiple time points through 96 hours (discharge). Scheduled pain intensity scores are recorded after Time 0 at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 20, 24, 28, 32, 36, 48, 72, and 96 hours. Each assessment prior to hour 10 has a ±15-minute window; each assessment after and including hour 10 has a ±30-minute window. The 0.5 hour and 1 hour NPRS assessments may be omitted if, on the basis of clinical judgement, the patient is not yet awake and alert enough to appropriately answer the NPRS after surgery. Pain intensity assessments scheduled between 2400 (midnight) and 0600 (6 am) may be limited to collection every 4 hours if the patient is sleeping. However, consecutive pain assessments may not be missed, and the hour 12, 24, 48, and 72 posttreatment pain assessments is to be completed even if they fall between 2400 (midnight) and 0600 (6 am). A pain intensity score is also be collected before any rescue pain medication use.

[0349] The QoR-15 questionnaire (see Section 8.2.4) will be administered 24, 48, 72, and 96 hours posttreatment and on day 7. The Patient Global Assessment (PGA) is administered 24, 48, 72, and 96 hours posttreatment and on day 7 by study staff. Patients are asked to rate how well their pain has been controlled during the study on the basis of the following criteria: 0 poor, 1 fair, 2 good, 3 very good, or 4 excellent. The OR SDS is administered at 24, 48, 72, and 96 hours posttreatment.

[0350] Patients are permitted rescue medication to manage breakthrough pain when it occurs. Oral acetaminophen at 1000 mg every 4-6 hours as needed for pain (maximum daily dosage 3000 mg) and/or oxycodone 5-mg tablet(s) may be given (not to exceed 10 mg in a 4-hour period during the inpatient stay). Immediately prior to receiving any rescue medication, a pain intensity score is recorded. If the NPRS score is 4 or less, patients are discouraged from taking opioid rescue medication; however, rescue medication may be requested and provided at any time. If patients require opioid rescue medication, but are unable to take oral medications, they are permitted to receive intravenous (iv) morphine (2-3 mg) every 3 hours until they are able to take oral rescue medication. As assessed by the investigator, if a patient’s pain is not relieved by oxycodone and/or acetaminophen, the patient is not yet eligible for further treatment with oxycodone and/or acetaminophen, and more than 3 hours have passed since the previous iv morphine dose, a patient may receive a dose of iv morphine (23 mg) for pain relief. If the pain remains unrelieved or increases in intensity before additional rescue medication is allowed, additional treatment options will be discussed with the medical monitor. [0351] Following discharge, to report an adverse event, a patient contacts study staff by telephone and report adverse event information, including incidence, duration, and any associated treatment. Patients with pain intensity scores of 4 or more at discharge is given a written prescription for immediate release oxycodone at a dosage of 5-10 mg every 4-6 hours as needed as rescue medication for breakthrough pain. Patients prescribed opioid rescue medication will also be permitted to take oral acetaminophen at 1000 mg every 4-6 hours (maximum daily dosage 3000 mg) and/or ibuprofen at 400 mg every 4- 6 hours as needed for pain, on an outpatient basis. Patients with pain intensity scores of less than 4 at discharge are instructed to take oral acetaminophen at 1000 mg every 4-6 hours as needed for pain (maximum daily dosage 3000 mg) and/or ibuprofen at 400 mg every 4- 6 hours as needed for pain, on an outpatient basis. Patients who do not receive a written prescription for oxycodone upon discharge are permitted to request immediate-release oxycodone 5-10 mg if their pain is unrelieved by acetaminophen. Use of opioids, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or any other medications after discharge from the hospital will be recorded, with data reviewed by study staff at subsequent contacts.

[0352] A detailed table of procedures and assessments is provided in Table 4.

[0353] Planned Number of Patients and Countries

[0354] Approximately 140 patients will be screened to achieve a planned number of approximately 100 enrolled patients (20 per each of the 5 surgery types). Once 20 evaluable patients for a study surgery type are completed, enrollment in that surgery type will be halted. Enrollment for open abdominal hysterectomy may not achieve 20 patients but all efforts will be made to achieve this goal.

[0355] The number of evaluable patients is planned to be approximately 100. Details about the definition of evaluable patients and sample size are given herein.

[0356] The study is planned to be conducted in the US at a number of investigational centers to be determined. The study is expected to start at a time to be determined. Screening to the end of the study for each patient will be approximately 75 (±4) days.

[0357] Justification for Study Design and Selection of Population

[0358] This is an open-label study designed primarily to assess the safety and characterize the pharmacokinetics of IND-001 in adult patients scheduled to undergo soft tissue surgery, including open ventral hernia repair, abdominoplasty, open abdominal hysterectomy, laparoscopic-assisted colectomy, and reduction mammoplasty. The open-label nature of the study allows for bupivacaine plasma samples to be obtained.

[0359] The surgical procedures selected for evaluation in the study are representative of the diversity of soft-tissue surgical procedures currently conducted. Justifications for selection of each surgery type are:

[0360] Open ventral hernia repair is representative of nonvisceral abdominopelvic procedures that may utilize a variety of surgical incisions and involve abdominal wall penetration and superficial peritoneal involvement (e.g., laparotomy, surgical abscess removal). Repair of the hernia can involve mesh placement at different subcutaneous layers, including intraperitoneal placement, and incorporates dissection and manipulation of abdominal wall muscular sheaths.

[0361] Abdominoplasty is representative of procedures with large incision lengths, incisions that involve intrusion of the superficial dermal layers and vascular surgical sites.

[0362] Laparoscopic-assisted colectomy is conducted through the use of a 3- to 6- cm abdominal incision for placement of an extraction site for removal of viscera in addition to several (e.g., 3) trocar ports (Heili et al 1999, Vanderpool and Westmoreland 2000). The extraction site incision and subsequent linea alba (if dissected), musculature, and deep fascial layer dissection provides a sufficient surface area for placement of INL-001 at multiple soft- tissue layers. Laparoscopic-assisted colectomy represents an area of superficial vasculature; however, the extensive dissection through the abdominal wall provides an opportunity to evaluate the absorption profile of INL-001 following placement at deep abdominal levels which supply blood to highly vascular muscle.

[0363] Open abdominal hysterectomy is representative of surgical procedures in which the peritoneal cavity is entered to either extract or modify visceral organs (e.g., cholecystectomy, nephrectomy, and colectomy).

[0364] Reduction mammoplasty is unique from the other soft-tissue surgical models utilized in this study in that it involves thoracic placement of INL-001 and thus different vasculature as well. In addition, the dose of INL-001 is administered across 2 separate breast pockets. Reduction mammoplasty surgery allows for the evaluation of INL-001 with substantially different vasculature than the other surgeries under investigation. [0365] Stopping Rules for the Study

[0366] Innocoll reserves the right to discontinue the study for safety or administrative reasons at any time.

[0367] The study will be stopped, until further benefit-risk evaluation is made, if 2 patients require removal of the INL-001 implants due to suspected systemic bupivacaine toxicity as outlined below in Section 4.3.2.

[0368] During the conduct of the study, serious adverse events will be reviewed (see Section 6.1.5), as they are reported from the investigational centers, to identify safety concerns.

[0369] The study may also be terminated by the sponsor for any reason at any time. For example, the sponsor could terminate the study in the event of: (i) new toxicologic or pharmacologic findings or safety issues from any source (e.g., other clinical studies, postmarketing experience) that invalidate the earlier positive benefit-risk assessment; or discontinuation of the development of the investigational medical product.

[0370] If the entire study is stopped or if elements of the study are stopped, the patients whose participation is terminated early will be monitored according to withdrawal criteria and procedures.

[0371] If the study is terminated prematurely, investigator(s) will inform their patients and arrange their appropriate follow-up.

[0372] Schedule of Study Procedures and Assessments

[0373] Study procedures and assessments by visit with their respective time points are presented in Table 4. Detailed descriptions of each method of procedures and assessments are provided herein (safety assessments), (pharmacokinetics assessments), and (exploratory efficacy assessments). The end of the study is defined as the last visit of the last patient.

^a Procedures and assessments have timing windows that may go beyond those specified. b The times patients enter and are discharged from the postanesthesia care unit (PACU) will be recorded. c Patients will be discharged after all procedures/assessments have been completed. Whether a patient is prescribed opioid pain medication at hospital discharge will be recorded. d=day(s); EOS=end of study; h=hour(s); m=minute(s).

Time points for record of vital signs measurements after Time 0: 0.5 hour (±5 m); 1, 2, 4 hours (±15 m); 8, 12 hours (±2 h); 24, 48, 72 hours, (each ±3 h); 96 hours (±4 h) (prior to discharge); days 15 (±3 d) and 30 (± 3 d). (Vital signs include body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry.) NOTE: Measurements from 0.5 through 12 hours will/may occur on day 1.

Time points for assessment of signs and symptoms potentially indicative of systemic bupivacaine toxicity after Time 0: 0.5, 1, 2, 3, and 4 hours (each ±15 m), and 5, 7, 9, 12, 15, 18, 24, 48, 72, and 96 hours (each±l h), and days 7 (±1 day) and 15 (±3 days). NOTE: Assessments from 0.5 through 18 hours will/may occur on day 1.

Time points for NPRS for pain intensity after Time 0: 0.5, 1, 2, 3, 4, 5, 6, 8 hours (each ±15 m); 10, 12, 18, 20, 24, 28, 32, 36, 48, 72, 96 hours (each ±30 m). (The 0.5-hour and 1-hour NPRS assessment may be omitted if, on the basis of clinical judgment, the patient is not yet awake and alert enough to appropriately answer the NPRS after surgery. In the case of use of a rescue pain medication, scores will also be obtained within 15 minutes before any rescue medication use.) NOTE: Assessments done 0.5 through 20 hours will/may occur on day 1. No NPRS scores will be recorded after discharge.

Time points (hours for blood collection for pharmacokinetic assessments relative to Time 0):

(NOTE: Blood collection from 0.5 h through 18 h will/may occur on day 1.)

• immediately preoperative

• 0.5, 1, 1.5, 2, 3, 4, 5 (all ±15 m)

• 6, 8, 10, 12, 18 (all ±1 h)

• 24, 36, 48, 72, 96 (all ±3 h)

DB1/ 129475967.2

TREATMENT

Investigational Medicinal Product Used in the Study and Other Treatment Information

[0374] The study drug used in this study is: INL-001 [XARACOLL (bupivacaine hydrochloride) implant],

[0375] INL-001 is a drug-device combination product containing 100 mg of bupivacaine HC1 per implant, equivalent to 88.8 mg of bupivacaine, for placement in the surgical site. The dose to be evaluated is three 100-mg implants (300 mg bupivacaine HC1), equivalent to 266.4 mg of bupivacaine. Each implant is 5 cm x 5 cm x 0.5 cm in size and is white to off-white in color. Implants are terminally sterilized.

[0376] Additional details may be found in the IB for INL-001.

Anesthetic Protocol

[0377] The anesthetic regimen used follows standard anesthetic procedures for each respective surgical model. Other than the study drug (which contains bupivacaine), no administration of local anesthetic to the patient is allowed (via intrathecal administration, nerve block, infiltration, or any other means). Lidocaine HC1 1% injection at a dose of no more than 20 mg may be administered once through iv access to decrease venous irritation (e.g., as caused by propofol) at the time of surgical anesthesia.

Placement of Study Drug

[0378] Surgery is performed using standard surgical procedures. INL-001 is administered as three 100-mg implants, for a total dose of 300 mg bupivacaine HC1. Implants may be divided to accommodate placement, but an individual implant may not be cut into more than 2 parts. An implant may be divided disproportionately (e.g., divided into 2 pieces with the implant divided by ¼, leaving ¾ remaining, and both divisions placed), if needed to accommodate placement, but no individual division should be less than approximately ¼ of an intact implant. Placement of 3 INL-001 implants for the 5 surgery types is:

Lor open ventral hernia with primary suture repair and mesh underlay, inlay, or onlay:

[0379] Underlay or inlay mesh repair: hollowing mesh placement and peritoneal closure, 1 ½ matrix implants should be placed in the preperitoneal space between the closed peritoneum and posterior rectus sheath. The remaining 1 ½ matrix implants should be placed subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices. Repair of multiple hernias through a single incision is permitted provided only 1 mesh is used.

[0380] Onlay mesh repair: Prior to mesh placement, 1 ½ matrix implants should be placed in the preperitoneal space between the closed peritoneum and posterior rectus sheath, then the remaining 1 ½ matrix implants should be laid in direct contact with the closed anterior rectus sheath. The mesh should then be placed over the matrices. The mesh should then be fixed and the subcutaneous tissue closed according to standard protocol. Repair of multiple hernias through a single incision is permitted provided only 1 mesh is used.

For abdominoplasty:

[0381] Following tissue removal and repair of the abdominal musculature (if conducted), 3 matrix implants should be placed in the subcutaneous space between the scarpa fascia and deep dermis. The implants should, to the greatest extent possible, be placed so they span the fascia that is exposed prior to surgical closure.

For open abdominal hysterectomy (with or without adnexectomy)

[0382] One implant should be placed at the vaginal vault. One matrix implant should be divided and placed at the site of the peritoneal incision between the visceral peritoneum and muscle. One matrix implant should be placed on the fascia immediately below the subcutaneous fat under the site of the incision.

For laparoscopic-assisted colectomy

[0383] One and half implants should be placed at the site of fascial repair and one and a half implants should be placed superficially above the abdominal wall musculature and beneath extraction site incision

For reduction mammoplasty

[0384] One and a half implants should be placed in each breast pocket.

Clinical Laboratory Tests

[0385] Hematology, Serum Chemistry, and Urinalysis

[0386] Blood and urine samples for clinical laboratory tests will be collected at the screening visit and at the day 30 follow-up visit (see Table 4).

[0387] The following clinical laboratory tests are performed:

Table 5: Clinical Laboratory Tests

[0388] The following additional laboratory tests are also performed:

[0389] For women of childbearing potential, a serum sample for pregnancy test is collected at screening, and a urine sample on the day of surgery (with results available before study drug kit assignment) and on day 30.

[0390] All clinical laboratory test results outside the reference range are assessed by the investigator as belonging to one of the following categories: abnormal and not clinically significant; and abnormal and clinically significant.

[0391] A laboratory test result that is judged by the investigator as clinically significant is recorded both on the source documentation and the CRF as an adverse event and will be monitored as described herein. An event may include a laboratory or diagnostic test abnormality that results in the withdrawal of the patient from the study, the temporary or permanent withdrawal of medical treatment, or further diagnostic work up. (NOTE: Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient from entering the study or receiving study drug are not considered adverse events.)

[0392] Clinical laboratory tests (serum chemistry, hematology, and urinalysis) are performed at the time points detailed in Table 4. Blood samples (approximately 16 mL total per patient) will be collected. Clinical laboratory tests are performed using the central laboratory.

[0393] Urine Drug Screen

[0394] A urine drug screen is performed at the screening visit and immediately before surgery (see Table 4). Urine screening is done for drugs of abuse/misuse, with testing during the screening period and on the day of surgery (with results available before study drug kit number assignment).

[0395] A positive result for any excluded drugs of misuse/abuse or their metabolites without medical explanation will preclude the patient from enrollment or continued participation in the study.

[0396] Vital Signs

[0397] Vital signs, including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation, are measured/recorded at screening, preoperatively, and at the following posttreatment time points: 0.5 hours (±5 minutes); 1, 2, 4 hours (±15 minutes); 8, 12 hours (±2 hours); 24, 48, 72 hours (±3 hours); 96 (±4 hours); day 15 (±3 days); and day 30 (±3 days) (see Table 4).

[0398] Oxygen saturation will be monitored by pulse oximetry during the inpatient study period. Oxygen saturation is recorded at the individual time points listed above. Pulse oximeter alarms should be set according to clinic standards, with oxygen desaturation that occurs in concordance with the delay period and the specified limits recorded as an adverse event. Patients should be evaluated to ensure proper pulse oximeter placement and to ensure desaturation is not due to patient movement or device-related issues.

[0399] All vital sign results outside the reference ranges are judged by the investigator as belonging to one of the following categories: abnormal and not clinically significant; and abnormal and clinically significant.

[0400] Physical Examinations

[0401] A complete physical examination are performed at screening and on day 30 (±3 days) after treatment (including screening body weight and height and posttreatment weight only) (see Table 4). A complete physical examination includes at a minimum skin, lungs, CV, respiratory, gastrointestinal, musculoskeletal, and neurological assessments. Any physical examination finding that is judged by the investigator as clinically significant (except at the screening visit) are considered an adverse event, recorded in the CRF, and monitored. Investigators should pay special attention to clinical signs related to previous serious diseases.

[0402] Electrocardiography

[0403] A standard 12 lead ECG is performed locally and recorded (after the patient has been supine for at least 5 minutes) at screening and on day 30 (±3 days) (see Table 4). All ECG recordings is identified with the patient number, date, and time of the recording.

[0404] All ECG results outside of the reference ranges should be evaluated and are judged as belonging to one of the following categories: abnormal and not clinically significant; and abnormal and clinically significant.

[0405] Any ECG finding that is judged as clinically significant (except at the screening visit) are considered an adverse event, recorded on the source documentation and on the CRF, and monitored.

Assessment of Pharmacokinetics

[0406] Instructions for the collection and handling of pharmacokinetic samples are provided by the sponsor. The dates and times of INL-001 placement and the date and time (24- hour clock time) of each pharmacokinetic sample collected are recorded both on the source documentation and in the CRF.

[0407] Details on sample handling, storage, shipment, and analysis are given in the laboratory manual or in respective instruction given in a separate document.

[0408] Blood samples (approximately 75 mL total per patient) are collected via indwelling catheter at the time points shown below for measurement of plasma concentration of bupivacaine.

[0409] Patients will undergo blood collection for pharmacokinetic assessments immediately preoperative, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 72, and 96 hours after Time 0 (see Table 4).

[0410] NOTE: Time points for blood collection for pharmacokinetic assessment (pretreatment and posttreatment relative to Time 0): immediately preoperative

0.5, 1, 1.5, 2, 3, 4, 5 hours (all ±15 minutes)

6, 8, 10, 12, 18 hours (all ±1 hour)

24, 36, 48, 72 hours (all ±3 hours) 96 hours (±4 hours)

[0411] Samples are analyzed for concentration of bupivacaine in plasma using an appropriate validated method.

[0412] The pharmacokinetic parameters to be calculated for each patient include: maximum observed plasma concentration (C_max) time to maximum observed plasma concentration (Tmax) time of first measurable plasma concentration after Time 0 (Ti_ag) terminal elimination half-life (t_½) terminal phase rate constant (l_z) area under the plasma concentration-time curve (AUC) through last observed concentration (AUCo-_Iast)

AUC extrapolated through infinity (AUCo-/ )

[0413] A pharmacokinetics analysis plan (PAP) will be developed and approved before the final pharmacokinetic analysis, and will include the methods to calculate the pharmacokinetic parameters and detail on the summary of pharmacokinetic parameters.

Example 4: Non-clinical Study for Postoperative analgesic efficacy and safety of INL-001 versus placebo collagen implant in patients undergoing abdominoplasty.

[0414] Bupivacaine has been widely used as a local anesthetic and has demonstrated efficacy in animal models in multiple species (Li et al 2013, Hersh et al 1992). The pharmacology of bupivacaine is well understood.

[0415] The distribution, metabolism, and excretion of bupivacaine across species is characterized in the literature including data showing that, following absorption, bupivacaine is rapidly and readily distributed to tissues, with the highest concentrations in highly perfused tissues. In general, the metabolic profile of bupivacaine is similar across species although quantitatively different, with no novel metabolite identified in humans (Goehl et al 1973, Carson 2000). The excretion of bupivacaine in monkeys and humans is predominantly in the urine; in rats, excretion in urine and feces is generally similar; and in dogs, only small amounts of excretion of bupivacaine in the urine have been reported. The dog excretion data in the literature for bupivacaine is consistent with excretion data obtained in the dog following implantation of INL-001, which showed approximately 0.16% of the bupivacaine dose was collected in the urine over a 72-hour period. The genotoxicity of bupivacaine HC1 was evaluated in 4 in vitro studies and 2 in vivo studies, with no safety concerns identified.

[0416] Clinically significant pharmacokinetic drug interactions with bupivacaine have been reported with verapamil, diazepam, and cimetidine in humans, animals, and/or in vitro test systems. These interactions occurred with bupivacaine administered epidurally or intravenously (iv).

[0417] The uniformity of bupivacaine in the INL-001 implant and the release of bupivacaine from the implant was evaluated in in vitro and/or in vivo assessments. The in vitro uniformity study demonstrated that bupivacaine content is homogeneously dispersed throughout INL 001. An in vitro dissolution study of a whole matrix found that bupivacaine was released as early as 5 minutes and complete release of bupivacaine occurred by 24 hours. An in vivo study showed the in vitro drug release profile was similar to that seen in vivo in dogs with INL-001 implanted into the abdomen and subcutaneous tissues through a surgical incision.

[0418] Two studies were conducted in which INL-001 was surgically implanted in rats followed by a 56 day postsurgical period to assess potential local and systemic effects, determine potential effects on wound healing, and characterize the resolution of any implant related findings. The initial study was conducted with early development drug product and the second study with the clinical Phase 3/commercial formulation using generally the same study design. INL-001 was well tolerated following implantation. By day 28 following INL-001 implantation, attrition of the implant was approximately 95% and the implant was not observed microscopically by day 56 after dosing. INL-OOl-associated findings were limited to observations at the injection site, including transient edema through day 10 and microscopic findings associated with the repair process.

[0419] Biocompatibility studies were conducted with extracts from INL-001 and the drug-free implant; these studies did not identify any safety concerns. There was no evidence of acute systemic toxicity or effects on body temperature (i.e., pyrogenicity) associated with administration of drug free implant extract or evidence of skin irritation, sensitization, or genotoxicity following exposure to bupivacaine implant extract.

Example 5: Clinical Study for Postoperative analgesic efficacy and safety of INL-001 versus placebo collagen implant in patients undergoing abdominoplasty. [0420] The clinical pharmacology, efficacy, and safety of INL-001 (at single doses of 100, 150, 200, and 300 mg) have been evaluated in 11 completed clinical studies (Phases 1- 3) in adults, including 2 well controlled pivotal Phase 3 studies of INL-001 in open inguinal hernia repair, at its recommended approved dose (three 100-mg bupivacaine HC1 implants).

[0421] In a pharmacokinetic/relative bioavailability study in patients following inguinal hernioplasty (Study INN-CB-022), the commercial formulation of INL 001 at a dose of 300 mg was compared with Marcaine 0.25% injection at a dose of 175 mg (the maximum recommended single dose). Quantifiable bupivacaine concentrations were evident at the first posttreatment time point measured (30 minutes) for all patients treated with INL-001 or Marcaine. Bupivacaine concentrations were detectable through the 96-hour posttreatment time point (last time point) in both treatment groups but at higher concentrations with INL-001 than with Marcaine. Pharmacokinetic analysis led to the following additional conclusions:

[0422] For the INL-001 treatment group, the mean maximum observed plasma concentration (Cmax) (minimum, maximum) was 663.412 ng/mL (274.00 ng/mL, 1230.00 ng/mL) compared with a mean C_max (minimum, maximum) for the Marcaine treatment group of 641.000 ng/mL (275.00 ng/mL, 1140.00 ng/mL).

[0423] For the INL-001 treatment group, the median time to maximum observed plasma concentration (T_max) was 3.03 hours with a mean terminal elimination half-life (ti_/2) of 18.95 hours compared with a T_max of 1.01 hours and a mean ti/2 of 9.08 hours for the Marcaine treatment group.

[0424] For INL-001, the geometric means for area under the concentration-time curve (AUC) through last observed concentration (AUCo-_Iast) was 18186.9 irng/niL and the AUC extrapolated through infinity (AUCo-_Iast) was 19012.5 h· ng/mL. For Marcaine, the geometric means for AUCo-_Iast and AUCo-_Iast were 8836.9 h*ng/mL and 8920.1 h· ng/mL, respectively.

[0425] In clinical studies of an earlier bupivacaine collagen implant formulation, following implantation of INL-001 at 100, 150, and 200 mg in various abdominopelvic surgeries, quantifiable bupivacaine plasma concentrations were observed from 30 minutes after placement (at the first posttreatment time point). Bupivacaine concentrations increased in a slightly higher than dose-proportional manner with increasing doses of INL-001. [0426] The efficacy of INL-001 was evaluated in 2 multicenter, double-blind, placebo controlled Phase 3 studies in adults that independently demonstrated the effectiveness of locally placed INL 001 (300 mg implanted in layers at the surgical site) in reducing both pain intensity and the need for opioid rescue analgesia after surgery; together, these studies demonstrate the reproducibility of the INL-001 treatment effects (Studies INN-CB-014 and INN-CB-016). In each study, INL-001 achieved the primary endpoint, with patients treated with INL-001 experiencing statistically significantly less pain (p<0.0004) as evaluated by the (time weighted) sum of pain intensity through 24 hours (SPI24). These reductions in pain intensity were coupled with less total opioid rescue analgesic medication use in the INL-001 treatment group compared with the placebo implant group. In data pooled from the 2 pivotal studies, patients used statistically significantly (p<0.0004) less opioid rescue analgesia and had statistically significantly (p=0.0007) fewer opioid-related treatment emergent adverse events (i.e., nausea, vomiting, and constipation) over the post-implantation period compared with subjects in the combined placebo implant group.

[0427] The existing INL-001 safety database is derived from a clinical development program of 11 studies conducted in soft tissue surgeries in adults, including the 2 positive Phase 3 studies in inguinal hernia repair. A total of 892 adult patients have received collagen matrix implants in this program (612 INL-001 and 280 placebo implants). Of the 892 patients, 816 patients underwent inguinal hernia repair, 69 patients underwent hysterectomy, and 7 patients underwent other types of soft-tissue surgeries (i.e., nonlaparoscopic benign gynecological procedure other than hysterectomy or elective surgery requiring a vertical or transverse abdominal incision).

[0428] Across these 11 studies:

[0429] Adverse events occurring at an incidence of 2% or more patients following administration of INL-001 at 300 mg and at a higher incidence than placebo implants, respectively, were somnolence (19.2% vs 13.9%), dizziness (16.4% vs 13.9%), incision site swelling (13% vs 10.7%), incision site pain (11.7% vs 11.4%), restlessness (7.7% vs 6.8%), dysgeusia (7.5% vs 4.6%), vision blurred (4.9% vs 2.1%), headache (4.7% vs 2.1%), tremor (4.5% vs 2.1%), postprocedural discharge (4.3% vs 3.6%), scrotal swelling (2.8% vs 1.8%), seroma (2.6% vs 1.8%), oral hypoesthesia (2.6% vs 1.4%), pyrexia (2.3% vs 1.8%), and wound dehiscence (2.1% vs 1.8%). [0430] In these studies, adverse events considered by the investigator to be treatment related following INL-001 placement in the surgical site occurred at a rate of 1.5% or less. The only treatment-related adverse event that occurred in 1% or more of all patients who received INL-001 at 300 mg was dysgeusia (1.3%), which also occurred in 0.7% of patients in the placebo group.

[0431] Across the INL-001 clinical development program, 16 patients experienced 1 or more serious adverse events: 11 patients in the INL-001 (including earlier formulation) treatment group and 5 patients in the placebo implant or other comparator group. Serious adverse events reported in the INL-001 treatment group included wound infection and seroma. One patient had the INL-001 implant removed after placement of an earlier formulation of bupivacaine collagen matrix implant during bladder sling surgery (see event described below).

[0432] There were no verbatim reports of systemic bupivacaine toxicity or LAST during any inguinal hernia repair study done as part of the development program for INL-001. The safety assessments conducted during the development program included monitoring adverse events, measurement of vital signs, and assessments with multiday cardiac Holter monitors. These assessments revealed no constellation of neurologic or cardiovascular (CV) signs or symptoms to suggest systemic bupivacaine toxicity in patients undergoing open inguinal hernia repair receiving INL 001.

[0433] One patient experienced signs and symptoms thought to be consistent with LAST approximately 4 hours after administration of an earlier formulation of the INL-001 (at 150 mg) following bladder sling surgery. Treatment included administration of lipid emulsion and surgical removal of the INL-001 implants.

[0434] Across the INL-001 clinical development program, incision-site adverse events occurring with an incidence of 2% or more in either the INL-001 (including earlier formulation) or placebo group compared with a non-implant comparator treatment group (n=52) included swelling, pain, other complication, postprocedural discharge, erythema, dehiscence, and inflammation.

Example 6: Study for Postoperative analgesic efficacy and safety of INL-001 versus placebo collagen implant in patients undergoing abdominoplasty.

[0435] This is a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of the INL 001 (bupivacaine HC1) implant, at 300 mg, in patients following abdominoplasty. On the day of surgery (study day 1), eligible patients are randomly assigned to treatment in a 1 :1 ratio to receive either INL-001 (three 100-mg implants containing a total dose of 300 mg of bupivacaine HC1) or 3 placebo collagen implants. Patients then undergo abdominoplasty under general anesthesia and have INL-001 or placebo implanted intraoperatively.

[0436] The duration of study participation for each patient is a maximum of 75 (±4) days, consisting of a screening period (up to 45 days before surgery), an inpatient period (preoperative, intraoperative, immediately postoperative) of approximately 4 days, and an outpatient follow-up period (up to 30 days [±3 days] after treatment) including an end-of-study visit. Efficacy assessments are made through 72 hours after treatment (after implant placement). Posttreatment (time measured from Time 0 [placement of first implant]) safety assessments are made throughout the study after the informed consent form (ICF) is signed, and as specifically scheduled through 72 hours posttreatment, on day 7 (±1 day) (telephone) , on day 15 (±3 days) (clinic visit), and on day 30 (±3 days) (clinic visit). Unless the investigator determines further hospitalization is necessary, the patient is discharged on the day occurring 72 hours (day 4) after surgery.

[0437] During the screening period, all patients provide informed consent and undergo eligibility and other screening and safety assessments (medical history including review of prior medications, physical examination, urine drug screen, serum pregnancy test for women of childbearing potential, clinical laboratory tests [hematology, chemistry, urinalysis], vital signs measurement, and 12-lead electrocardiography [ECG]). Vital signs include body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry. The reason(s) a patient does not meet screening criteria is recorded, if applicable. Recording of adverse events and concomitant medication use commences once a patient signs the ICF.

[0438] On the day of surgery (day 1), patient eligibility is reconfirmed before the start of surgery (including medical history, urine drug screen, urine pregnancy test for women of childbearing potential, vital signs), patients are randomly assigned to treatment with study drug (INL-001 or placebo collagen implant), and adverse events and prior/concomitant medications are reviewed. [0439] Patients undergo an abdominoplasty with rectus sheath plication using standard surgical procedures conducted under general anesthesia (see anesthesia protocol below in Section 5.1.1), with no other local anesthetic used at the surgical site. All patients should undergo an abdominoplasty procedure with an incision that does not extend above the umbilicus. The approach should be anterior. The incision should in general be from one anterior superior iliac spine (ASIS) to the other. The exact incision length may vary depending on the patient’s anatomy and the desired cosmetic outcome. All packs/gauze should be removed and adequate hemostasis must be achieved prior to skin closure. Surgical drains should be placed at the discretion of the surgeon and their use recorded. Ancillary procedures (e.g., liposuction, breast augmentation/reduction) are prohibited.

[0440] Placement of study drug is detailed elsewhere herein. The time of the first placement of study drug (placement of first implant) is considered Time 0 and is recorded. Use of analgesic and all medications during surgery is recorded. At the surgeon’s discretion, if a significant surgical/medical complication is encountered during surgery, study drug will not be implanted and the patient is considered enrolled but not treated.

[0441] After surgery, patients are transferred to a postanesthesia care unit (PACU) or other postoperative recovery area for monitored observation. The times patients enter and are discharged from the PACU are recorded to calculate time to discharge from the PACU. Patients are monitored with pulse oximetry starting in the PACU through 24 hours posttreatment. After leaving the PACU (time in PACU to be at the discretion of the investigator), patients are placed in the postoperative unit or clinical research unit for domiciled observation. Vital signs, including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry, are assessed at multiple time points through discharge, and in the clinic on days 15 and 30; 12-lead ECG will be done on day 30.

[0442] Adverse event and concomitant medication information, including use of rescue medication, are collected throughout the study (inpatient and outpatient). Surgical wound healing assessments are made at 24, 48, and 72 hours after Time 0 and on days 7, 15, and 30 using the specified list and assessed for and recorded as adverse events as appropriate. The Southampton Wound Grading System is also completed 72 hours posttreatment/prior to discharge (±4 hours) and on days 15 and 30. Assessment for signs and symptoms potentially indicative of systemic bupivacaine toxicity is made after Time 0 at the following time points: 0.5, 1, 2, 3, and4 hours (each ±15 minutes), and 5, 7, 9, 12, 15, 18, 24, 48, and 72 hours (each ±1 hour), and days 7 (±1 day) and 15 (±3 days) using the specified list and assessment made and recorded as adverse events as appropriate.

[0443] At any time that a patient is determined to be exhibiting signs and/or symptoms suggestive of systemic bupivacaine toxicity, at the discretion of the investigator, a bupivacaine blood sample will be collected and 12 lead ECG will be performed. The patient may be treated at the discretion of the investigator, including obtaining repeat bupivacaine blood levels, 12-lead ECG, or removal of the implants.

[0444] After surgery, patient reports of pain intensity using an 11 point numeric pain rating scale (NPRS) are recorded at multiple time points through 72 hours posttreatment. Scheduled pain intensity scores are recorded after Time 0 at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 20, 24, 28, 32, 36, 48, and 72 hours. Each assessment prior to hour 10 has a ±15-minute window; each assessment after and including hour 10 has a ±30-minute window. The 0.5 hour and 1 hour NPRS assessments may be omitted if, on the basis of clinical judgement, the patient is not yet awake and alert enough to appropriately answer the NPRS after surgery. Pain intensity assessments scheduled between 2400 (midnight) and 0600 (6 am) may be limited to collection every 4 hours if the patient is sleeping. However, consecutive pain assessments may not be missed, and the hour 12, 24, 48, and 72 posttreatment pain assessments must be completed even if they fall between 2400 (midnight) and 0600 (6 am). A pain intensity score is also collected before any rescue pain medication use.

[0445] Patients are permitted rescue medication to manage breakthrough pain when it occurs. Oral acetaminophen at 1000 mg every 4-6 hours as needed for pain (maximum daily dosage 3000 mg) and/or oxycodone 5-mg tablet(s) may be given (not to exceed 10 mg in a 4-hour period during the inpatient stay). Immediately prior to receiving any rescue medication, a pain intensity score must be recorded. If the NPRS score is 4 or less, patients are discouraged from taking opioid rescue medication; however, rescue medication may be requested and provided at any time. If patients require opioid rescue medication, but are unable to take oral medications, they are permitted to receive intravenous (iv) morphine (2-3 mg) every 3 hours until they are able to take oral rescue medication. As assessed by the investigator, if a patient’s pain is not relieved by oxycodone and/or acetaminophen, the patient is not yet eligible for further treatment with oxycodone and/or acetaminophen, and more than 3 hours have passed since the previous iv morphine dose, a patient may receive a dose of iv morphine (2-3 mg) for pain relief. If the pain remains unrelieved or increases in intensity before additional rescue medication is allowed, additional treatment options will be discussed with the medical monitor.

[0446] Following discharge, to report an adverse event, a patient contacts study staff by telephone and report adverse event information, including incidence, duration, and any associated treatment. Patients with pain intensity scores of 4 or more at discharge are given a written prescription for immediate release oxycodone at a dosage of 5-10 mg every 4-6 hours as needed as rescue medication for breakthrough pain. Patients prescribed opioid rescue medication are also permitted to take oral acetaminophen at 1000 mg every 4-6 hours (maximum daily dosage 3000 mg) and/or ibuprofen at 400 mg every 4-6 hours as needed for pain, on an outpatient basis. Patients with pain intensity scores of less than 4 at discharge are instructed to take oral acetaminophen at 1000 mg every 4-6 hours as needed for pain (maximum daily dosage 3000 mg) and/or ibuprofen at 400 mg every 4-6 hours as needed for pain, on an outpatient basis. Patients who do not receive a written prescription for oxycodone upon discharge are permitted to request immediate-release oxycodone 5-10 mg if their pain is unrelieved by acetaminophen. Use of opioids, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or any other medications after discharge from the hospital is recorded, with data reviewed by study staff at subsequent contacts.

[0447] A detailed table of procedures and assessments is provided in Table 6.

Planned Number of Patients and Countries

[0448] Up to approximately 432 patients will be screened in order to randomize 372 patients to achieve a minimum of 360 patients randomized and treated [180 evaluable patients per treatment group]).

[0449] The study is expected to start at a time to be determined, with an estimated enrollment period of approximately 6 months, including an interim analysis. Screening to the end of the study for each patient will be approximately 75 (±4) days.

Justification for Study Design and Selection of Population

[0450] This is a randomized, double-blind, placebo-controlled study designed primarily to assess the efficacy and safety of IND-001 in adult patients scheduled for abdominoplasty. The study design employed in this study has previously been used successfully in 2 clinical Phase 3 studies conducted to demonstrate the efficacy and safety of INL 001 to manage acute postoperative pain in patients undergoing open inguinal hernia repair.

Stopping Rules for the Study

[0451] Innocoll reserves the right to discontinue the study for safety or administrative reasons at any time.

[0452] The study will be stopped, until further benefit-risk evaluation is made, if 2 patients require removal of the INL-001 implants due to suspected systemic bupivacaine toxicity.

[0453] During the conduct of the study, serious adverse events are reviewed, as they are reported from the investigational centers, to identify safety concerns.

[0454] The study may also be terminated by the sponsor for any reason at any time. For example, the sponsor could terminate the study in the event of: (i) new toxicologic or pharmacologic findings or safety issues from any source (e.g., other clinical studies, postmarketing experience) that invalidate the earlier positive benefit-risk assessment; or (ii) discontinuation of the development of the investigational medical product.

[0455] If the entire study is stopped or if elements of the study are stopped, the patients whose participation is terminated early will be monitored according to withdrawal criteria and procedures.

[0456] If the study is terminated prematurely, investigator(s) will inform their patients and arrange their appropriate follow-up.

Schedule of Study Procedures and Assessments

[0457] Study procedures and assessments by visit with their respective time points are presented in Table 6. The end of study is defined as the last visit of the last patient.

Table 6: Schedule of Procedures/Assessments

Continued on next page.

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Footnotes to table and detailed time points on next page.

Footnotes to table and detailed time points: a Procedures and assessments have timing windows that may go beyond those specified. b The times patients enter and are discharged from the postanesthesia care unit (PACU) will be recorded. c Patients will be discharged after all procedures/assessments have been completed. Whether a patient is prescribed opioid pain medication at hospital discharge will be recorded. d=day(s); EOS=end of study; h=hour(s); m=minute(s).

DB1/ 129475967.2 -90-

Time points for record of vital signs measurements after Time 0: 0.5 hour (±5 m); 1, 2, 4 hours (±15 m); 8, 12 hours (±2 h); 24, 48 hours (±3 h); 72 hours (±4 h) (prior to discharge); days 15 (±3 d) and 30 (±3 d). (Vital signs include body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry.) NOTE: Measurements from 0.5 through 12 hours will/may occur on day 1.

Time points for assessment of signs and symptoms potentially indicative of systemic bupivacaine toxicity after Time 0: 0.5, 1, 2, 3, and 4 hours

(each ±15 m); 5, 7, 9, 12, 15, 18, 24, 48, and 72 hours (each±l h); and days 7 (±1 day) and 15 (±3 days). NOTE: Assessments from 0.5 through 18 hours will/may occur on day 1.

Time points for NPRS for pain intensity after Time 0: 0.5, 1, 2, 3, 4, 5, 6, 8 hours (each ±15 m); 10, 12, 18, 20, 24, 28, 32, 36, 48, 72 hours (each ±30 m).

(The 0.5-hour and 1-hour NPRS assessment may be omitted if, on the basis of clinical judgment, the patient is not yet awake and alert enough to appropriately answer the NPRS after surgery. In the case of use of a rescue pain medication, scores will also be obtained within 15 minutes before any rescue medication use.) NOTE: Assessments done 0.5 through 20 hours will/may occur on day 1. No NPRS scores will be collected after discharge.

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TREATMENT

[0458] The study drugs used in this study are: INL-001 [XARACOLL (bupivacaine hydrochloride) implant] and placebo collagen implant.

[0459] INL-001 is a drug-device combination product containing 100 mg of bupivacaine HC1 per implant, equivalent to 88.8 mg of bupivacaine, for placement in the surgical site. The dose to be evaluated is three 100-mg implants (300 mg bupivacaine HC1), equivalent to 266.4 mg of bupivacaine. Each implant is 5 cm x 5 cm x 0.5 cm in size and is white to off-white in color. Placebo implants contain collagen but no bupivacaine. Implants are terminally sterilized.

[0460] Additional details may be found in the IB for INL-001.

Anesthetic Protocol

[0461] The standardized anesthetic regimen includes general anesthesia with fentanyl (maximum dose of 4 mcg/kg) and propofol (dose at discretion of the anesthesia provider), with or without volatile anesthetics or muscle relaxants. The standardized anesthetic regimen is a guide that should be followed to minimize interpatient variability to the greatest extent possible. However, it is understood that hemodynamic fluctuations and other intraoperative events may necessitate some deviation from this standard regimen. Neuraxial techniques, such as epidural and spinal anesthesia, are not allowed. No epinephrine is permitted during the procedure. No local anesthetic other than INL-001 (study drug) in the surgical field or regional anesthesia is permitted. Lidocaine HC1 1% injection at a dose of no more than 20 mg may be administered once through iv access to decrease venous irritation (e.g., as caused by propofol) at the time of surgical anesthesia. Intraoperatively, fentanyl (maximum dose of 4 mcg/kg) is permitted for analgesia. No other analgesic agents may be used during the procedure including, but not limited to, opioids (other than fentanyl), acetaminophen (oral or iv), NSAIDs (e.g., ketorolac or COX-2 inhibitors), ketamine, pregabalin, and others. A preoperative dose of an antiemetic, ondansetron iv 4 mg, for nausea prophylaxis is allowed; however, postoperative antiemetic medications should be given to treat only patients who report nausea and/or vomiting. Administration of fentanyl should be avoided 30 minutes prior to the anticipated conclusion of the procedure if medically acceptable in the judgement of the anesthesiologist.

Placement of Study Drug [0462] Following tissue removal and repair of the abdominal musculature, 2 implants should be placed on the rectus diastasis at the site of rectus sheath plication and 1 implant should be placed below the abdominal incision between Scarpa’s fascia and the subcutaneous fat. The implants should, to the greatest extent possible, be placed so they span the fascia that is exposed prior to surgical closure. Implants may be divided to accommodate placement, but an individual implant may not be cut into more than 2 halves.

[0463] Clinical Laboratory Tests

[0464] Hematology, Serum Chemistry, and Urinalysis

[0465] Blood and urine samples for clinical laboratory tests are collected at the screening visit and at the day 30 follow-up visit (see Table 6).

[0466] The following clinical laboratory tests are performed:

Table 7: Clinical Laboratory Tests

[0467] The following additional laboratory tests are also performed:

[0468] For women of childbearing potential, a serum sample for pregnancy test is collected at screening, and a urine sample on the day of surgery (with results available before study drug kit assignment) and on day 30. [0469] All clinical laboratory test results outside the reference range are assessed by the investigator as belonging to one of the following categories: abnormal and not clinically significant; and abnormal and clinically significant.

[0470] A laboratory test result that is judged by the investigator as clinically significant will be recorded both on the source documentation and the CRF as an adverse event and will be monitored. An event may include a laboratory or diagnostic test abnormality that results in the withdrawal of the patient from the study, the temporary or permanent withdrawal of medical treatment, or further diagnostic work up. (NOTE: Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient from entering the study or receiving study drug are not considered adverse events.)

[0471] Clinical laboratory tests (serum chemistry, hematology, and urinalysis) are performed at the time points detailed in Table 6. Blood samples (approximately 16 mL total per patient) are collected. Clinical laboratory tests will be performed using the central laboratory.

Urine Drug Screen

[0472] A urine drug screen is performed at the screening visit and immediately before surgery (see Table 6). Urine screening is done for drugs of abuse/misuse, with testing during the screening period and on the day of surgery (with results available before study drug kit number assignment).

[0473] A positive result for any excluded drugs of misuse/abuse or their metabolites without medical explanation will preclude the patient from enrollment or continued participation in the study.

Vital Signs

[0474] Vital signs, including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation, are measured/recorded at screening, preoperatively, and at the following posttreatment time points: 0.5 hours (±5 minutes); 1, 2, 4 hours (±15 minutes); 8, 12 hours (±2 hours); 24, 48, 72 hours (±4 hours) prior to discharge; day 15 (±3 days); and day 30 (±3 days) (see Table 6).

[0475] Oxygen saturation is monitored by pulse oximetry during the inpatient study period. Oxygen saturation will be recorded at the individual time points listed above. Pulse oximeter alarms should be set according to clinic standards, with oxygen desaturation that occurs in concordance with the delay period and the specified limits recorded as an adverse event. Patients should be evaluated to ensure proper pulse oximeter placement and to ensure desaturation is not due to patient movement or device-related issues.

[0476] All vital sign results outside the reference ranges are judged by the investigator as belonging to one of the following categories: abnormal and not clinically significant; and abnormal and clinically significant.

Physical Examinations

[0477] A complete physical examination is performed at screening and on day 30 (±3 days) after treatment (including screening body weight and height and posttreatment weight only) (see Table 6). A complete physical examination includes at a minimum skin, lungs, CV, respiratory, gastrointestinal, musculoskeletal, and neurological assessments. Any physical examination finding that is judged by the investigator as clinically significant (except at the screening visit) is considered an adverse event, recorded in the CRF, and monitored. Investigators should pay special attention to clinical signs related to previous serious diseases.

Electrocardiography

[0478] A standard 12 lead ECG is performed locally and recorded (after the patient has been supine for at least 5 minutes) at screening and on day 30 (±3 days) (see Table 6). All ECG recordings are identified with the patient number, date, and time of the recording.

[0479] All ECG results outside of the reference ranges should be evaluated and are judged as belonging to one of the following categories: abnormal and not clinically significant; and abnormal and clinically significant.

[0480] Any ECG finding that is judged as clinically significant (except at the screening visit) will be considered an adverse event, recorded on the source documentation and on the CRF, and monitored.

Example 7: A Randomized. Double-blind. Placebo -controlled Study to Evaluate the Efficacy and Safety of a 300-mg Dose of the INL-001 (Bupivacaine Hydrochloride] Implant in Patients Undergoing Abdominoplasty

[0481] The primary objective of the study is to evaluate the analgesic effect of treatment (i.e., efficacy) with INL-001 implants compared with placebo implants after placement into the surgical site during abdominoplasty. [0482] The secondary objective is to assess the safety and tolerability of INL-001 implants after placement in the surgical site during abdominoplasty.

General Study Design

[0483] The study is a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of the INL-001 (bupivacaine HC1) implant, at 300 mg, in patients following abdominoplasty. On the day of surgery (study day 1), eligible patients will be randomly assigned to treatment in a 1 : 1 ratio to receive either INL-001 (three 100-mg implants containing a total dose of 300 mg of bupivacaine HC1) or 3 placebo collagen implants. Patients will then undergo abdominoplasty under general anesthesia and have INL-001 or placebo implanted intraoperatively.

[0484] The duration of study participation for each patient will be a maximum of 75 (±4) days, consisting of a screening period (up to 45 days before surgery), an inpatient period (preoperative, intraoperative, immediately postoperative) of approximately 4 days, and an outpatient follow-up period (up to 30 days [±3 days] after treatment) including an end-of- study visit. Efficacy assessments will be made through 72 hours after treatment (after implant placement). Posttreatment (time measured from Time 0 [placement of first implant]) safety assessments will be made throughout the study after the informed consent form (ICF) is signed, and as specifically scheduled through 72 hours posttreatment, on day 7 (±1 day) (telephone), on day 15 (±3 days) (clinic visit), and on day 30 (±3 days) (clinic visit). Unless the investigator determines further hospitalization is necessary, the patient will be discharged on the day occurring 72 hours (day 4) after surgery.

[0485] During the screening period, all patients will provide informed consent and undergo eligibility and other screening and safety assessments (medical history including review of prior medications, physical examination, urine drug screen, serum pregnancy test for women of childbearing potential, clinical laboratory tests [hematology, chemistry, urinalysis], vital signs measurement, and 12-lead electrocardiography [ECG]). Vital signs include body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry. The reason(s) a patient does not meet screening criteria will be recorded, if applicable. Recording of adverse events and concomitant medication use will commence once a patient signs the ICF. [0486] On the day of surgery (day 1 ), patient eligibility will be reconfirmed before the start of surgery (including medical history, urine drug screen, urine pregnancy test for women of childbearing potential, vital signs), patients will be randomly assigned to treatment with study drug (INL-001 or placebo collagen implant), and adverse events and prior/concomitant medications will be reviewed.

[0487] Patients will undergo an abdominoplasty with rectus sheath plication using standard surgical procedures conducted under general anesthesia, with no other local anesthetic used at the surgical site. All patients should undergo an abdominoplasty procedure with an incision that does not extend above the umbilicus. The approach should be anterior. The incision should in general be from one anterior superior iliac spine (ASIS) to the other. The exact incision length may vary depending on the patient’s anatomy and the desired cosmetic outcome. All packs/gauze should be removed and adequate hemostasis must be achieved prior to skin closure. Surgical drains should be placed at the discretion of the surgeon and their use recorded. Ancillary procedures (e.g., liposuction, breast augmentation/reduction) are prohibited.

[0488] The time of the first placement of study drug (placement of first implant) is considered Time 0 and will be recorded. Use of analgesic and all medications during surgery will be recorded. At the surgeon’s discretion, if a significant surgical/medical complication is encountered during surgery, study drug will not be implanted and the patient will be considered enrolled but not treated.

[0489] After surgery, patients will be transferred to a postanesthesia care unit (PACU) or other postoperative recovery area for monitored observation. The times patients enter and are discharged from the PACU will be recorded to calculate time to discharge from the PACU. Patients will be monitored with pulse oximetry starting in the PACU through 24 hours posttreatment. After leaving the PACU (time in PACU to be at the discretion of the investigator), patients will be placed in the postoperative unit or clinical research unit for domiciled observation. Vital signs, including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry, will be assessed at multiple time points through discharge, and in the clinic on days 15 and 30; 12- lead ECG will be done on day 30. [0490] Adverse event and concomitant medication information, including use of rescue medication, will be collected throughout the study (inpatient and outpatient). Surgical wound healing assessments will be made at 24, 48, and 72 hours after Time 0 and on days 7, 15, and 30 using the specified list and assessed for and recorded as adverse events as appropriate. The Southampton Wound Grading System will also be completed 72 hours posttreatment/prior to discharge (±4 hours) and on days 15 and 30. Assessment for signs and symptoms potentially indicative of systemic bupivacaine toxicity will be made after Time 0 at the following time points: 0.5, 1, 2, 3, and 4 hours (each ±15 minutes), and 5, 7, 9, 12, 15, 18, 24, 48, and 72 hours (each ±1 hour), and days 7 (±1 day) and 15 (±3 days) using the specified list and assessment made and recorded as adverse events as appropriate.

[0491] At any time that a patient is determined to be exhibiting signs and/or symptoms suggestive of systemic bupivacaine toxicity, at the discretion of the investigator, a bupivacaine blood sample will be collected and 12-lead ECG will be performed. The patient may be treated at the discretion of the investigator, including obtaining repeat bupivacaine blood levels, 12-lead ECG, or removal of the implants.

[0492] After surgery, patient reports of pain intensity using an 11 -point numeric pain rating scale (NPRS) will be recorded at multiple time points through 72 hours posttreatment. Scheduled pain intensity scores will be recorded after Time 0 at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 20, 24, 28, 32, 36, 48, and 72 hours. Each assessment prior to hour 10 has a ±15-minute window; each assessment after and including hour 10 has a ±30-minute window. The 0.5-hour and 1-hour NPRS assessments may be omitted if, on the basis of clinical judgement, the patient is not yet awake and alert enough to appropriately answer the NPRS after surgery. Pain intensity assessments scheduled between 2400 (midnight) and 0600 (6 am) may be limited to collection every 4 hours if the patient is sleeping. However, consecutive pain assessments may not be missed, and the hour 12, 24, 48, and 72 posttreatment pain assessments must be completed even if they fall between 2400 (midnight) and 0600 (6 am). A pain intensity score will also be collected before any rescue pain medication use.

[0493] Patients will be permitted rescue medication to manage breakthrough pain when it occurs. Oral acetaminophen at 1000 mg every 4-6 hours as needed for pain (maximum daily dosage 3000 mg) and/or oxycodone 5-mg tablet(s) may be given (not to exceed 10 mg in a 4-hour period during the inpatient stay). Immediately prior to receiving any rescue medication, a pain intensity score must be recorded. If the NPRS score is 4 or less, patients will be discouraged from taking opioid rescue medication; however, rescue medication may be requested and provided at any time. If patients require opioid rescue medication, but are unable to take oral medications, they will be permitted to receive intravenous (iv) morphine (2-3 mg) every 3 hours until they are able to take oral rescue medication. As assessed by the investigator, if a patient’s pain is not relieved by oxycodone and/or acetaminophen, the patient is not yet eligible for further treatment with oxycodone and/or acetaminophen, and more than 3 hours have passed since the previous iv morphine dose, a patient may receive a dose of iv morphine (2-3 mg) for pain relief. If the pain remains unrelieved or increases in intensity before additional rescue medication is allowed, additional treatment options will be discussed with the medical monitor.

[0494] Following discharge, to report an adverse event, a patient will contact study staff by telephone and report adverse event information, including incidence, duration, and any associated treatment. Patients with pain intensity scores of 4 or more at discharge will be given a written prescription for immediate-release oxycodone at a dosage of 5-10 mg every 4-6 hours as needed as rescue medication for breakthrough pain. Patients prescribed opioid rescue medication will also be permitted to take oral acetaminophen at 1000 mg every 4-6 hours (maximum daily dosage 3000 mg) and/or ibuprofen at 400 mg every 4- 6 hours as needed for pain, on an outpatient basis. Patients with pain intensity scores of less than 4 at discharge will be instructed to take oral acetaminophen at 1000 mg every 4-6 hours as needed for pain (maximum daily dosage 3000 mg) and/or ibuprofen at 400 mg every 4- 6 hours as needed for pain, on an outpatient basis. Patients who do not receive a written prescription for oxycodone upon discharge will be permitted to request immediate-release oxycodone 5-10 mg if their pain is unrelieved by acetaminophen. Use of opioids, acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or any other medications after discharge from the hospital will be recorded, with data reviewed by study staff at subsequent contacts.

[0495] Method of Randomization and Blinding: Eligible patients will be randomly assigned to treatment in a 1:1 ratio to receive either INL-001 or placebo collagen implants. Patients will not be aware of their treatment allocation and all study staff involved in efficacy and safety assessments will be blinded to treatment assignments until after database lock and release of unblinding randomization codes. Emergency unblinding is allowable if deemed necessary by the investigator, and discussed and agreed with the study medical monitor, for the safety of the patient and will be fully documented and included in protocol deviations. Patients will be stratified by study center and body mass index (BMI) (<30 kg/m² and >30 kg/m²).

[0496] Duration of Patient Participation and Maximal Exposure to Study Drug: The duration of study participation for each patient will be a maximum of 75 (±4) days, consisting of a screening period (up to 45 days before surgery), an inpatient period (preoperative, intraoperative, postoperative) lasting 4 days, and an outpatient follow-up period (up to 30 days after treatment [±3 days]) including an end-of-study visit.

[0497] Planned Number of Patients and Countries

[0498] Up to approximately 432 patients will be screened in order to randomize 372 patients to achieve a minimum of 360 patients randomized and treated [180 evaluable patients per treatment group]). Details about the definition of evaluable patients and sample size are given herein.

[0499] The study is expected to start at a time to be determined, with an estimated enrollment period of approximately 6 months, including an interim analysis. Screening to the end of the study for each patient will be approximately 75 (±4) days.

[0500] Justification for Study Design and Selection of Population

[0501] This is a randomized, double-blind, placebo-controlled study designed primarily to assess the efficacy and safety of INL-001 in adult patients scheduled for abdominoplasty. The study design employed in this study has previously been used successfully in 2 clinical Phase 3 studies con-ducted to demonstrate the efficacy and safety of INL 001 to manage acute postoperative pain in patients undergoing open inguinal hernia repair. The rationale for studying patients undergoing abdominoplasty was previously provided herein.

[0502] Stopping Rules for the Study

[0503] Innocoll reserves the right to discontinue the study for safety or administrative reasons at any time.

[0504] The study will be stopped, until further benefit-risk evaluation is made, if 2 patients require removal of the INL-001 implants due to suspected systemic bupivacaine toxicity as outlined herein. [0505] During the conduct of the study, serious adverse events will be reviewed, as they are reported from the investigational centers, to identify safety concerns.

[0506] The study may also be terminated by the sponsor for any reason at any time. For example, the sponsor could terminate the study in the event of:

[0507] new toxicologic or pharmacologic findings or safety issues from any source (e.g., other clinical studies, postmarketing experience) that invalidate the earlier positive benefit-risk assessment

[0508] discontinuation of the development of the investigational medical product

[0509] If the entire study is stopped or if elements of the study are stopped, the patients whose participation is terminated early will be monitored according to withdrawal criteria and procedures.

[0510] If the study is terminated prematurely, investigator(s) will inform their patients and arrange their appropriate follow-up.

[0511] Schedule of Study Procedures and Assessments

[0512] Study procedures and assessments by visit with their respective time points are presented in Table 8. Detailed descriptions of each method of procedures and assessments are provided (efficacy assessments) and (safety assessments). The end of study is defined as the last visit of the last patient.

[0513] Table 9 provides a summary of demographic and other baseline characteristics of the patients.

Table 8: Schedule of Procedures/ Assessments

Continued on next page.

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Table 9: Demography of Patients

Demographic Statistic or category INL-001 Placebo Total

Characteristic (N=181) (N=365)

Sex, n (%) Male 0 3 (0.8)

Female 181 100

362 (99.2)

Age (years) n 181 184 365

Mean (SD) 43.3 (8.95) 43.1 (8.98) 43.2 (8.95)

Median 43.0 43.0 43.0

Minimum - Maximum 20 - 65 20 - 65 20 - 65

Race, n (%) American Indian or Alaska Native 0 0 0

Asian 4 22 4 (2.2) 8 22

Black or African American 44 (24.3) 49 (26.6) 93 (25.5)

Native Hawaiian or Other Pacific Islander 1 06 0 1 (0.3)

White 130 (71.8) 128 (69.6) 258 (70.7)

Other 2 11 3 (1.6) 5 (1.4)

Ethnicity group, n (%) Hispanic or Latino 77 (42.5) 79 (42.9) 156 (42.7)

Not Hispanic or Latino 101 (55.8) 102 (55.4) 203 (55.6)

Not Reported 2 11 0 2 (0.5)

Unknown 1 06 3 (1.6) 4 (1.1)

Demographic INL-001 Placebo Total

Characteristic Statistic or Category 181 (N=184) (N=365)

Height (cm) n 181 184 365

Mean (SD) 161.65 (6.687) 162.49 (7.249) 162.07 (6.979)

Median 161.30 161.30 161.30

Minimum - Maximum 144.6 - 185.4 142.0 - 185.4 142.0 - 185.4

Weight (kg) 181 184 365

Mean (SD) 71.89 (10.604) 72.90 (9.752) 72.40 (10.182)

Median 72.20 72.45 72.20

Minimum - Maximum 45.8 - 101.7 50.8 - 106.9 45.8 - 106.9

Body Mass Index (kg/m²) 181 184 365

Mean (SD) 27.442 (3.1436) 27.566 (2.8295) 27.504 (2.9859)

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Median 27.610 27.915 27.770

Minimum - Maximum 19.42 - 34.84 19.88 - 33.62 19.42 - 34.84

BMI Strata, n (%) <30 kg/m2 144 (79.6) 146 (79.3) 290 (79.5)

>=30 kg/m2 37 (20.4) 38 (20.7) 75 (20.5)

% = 100 x n/N. SD = Standard Deviation

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Statistical Considerations

[0514] Sample Size Rationale: The sample size was chosen primarily on the basis of previous clinical study data for INL 001 in inguinal hernia repair, but also with the consideration of the results of other bupivacaine containing products studied in abdominoplasty. Sample size is estimated at 360 patients, with 180 patients per treatment group. The effect size with INL-001 in the combined results of 2 clinical Phase 3 studies in postoperative analgesia after open inguinal hernia repair was 0.525 for sum of pain intensity (SPI) through 24 hours (SPI24). The effect size with INL-001 was 0.25. With the historical SPI through 48 hours (SPI48) effect size of 0.25, 360 evaluable patients will yield a power of at least 66%; however, it is believed that a greater separation between the INL-001 and placebo treatment groups will be observed for abdominoplasty given that postoperative pain is more severe and longer lasting than with inguinal hernia repair, yielding greater power. This is increased to 372 patients to allow for some attrition of patients randomized to those randomized and treated; all randomized and treated patients will be evaluable and included in the modified intent-to-treat (mITT) analyses.

[0515] Efficacy Analysis : The SPI (area under the concentration-time curve [AUC] of pain intensity) as measured by the NPRS through various time points up to 72 hours posttreatment will be calculated using the trapezoidal method with NPRS scores and the actual assessment times in hours. The primary efficacy variable will be SPI24, but the same general rules and calculations will apply for all SPIO-time. For SPI24 calculation, both scheduled and unscheduled values (if available) from Time 0 through 24 hours posttreatment will be used in the calculation. For patients who receive rescue medication, just prior to it being administered, a pain score will be obtained; this will be included in the calculation of the SPI. Pain score(s) for the duration of the rescue efficacy following treatment with an opioid rescue medication will be excluded from the calculation if they are lower than the pain score just prior to rescue medication administration; those that are equal to or higher will be included. This period will be 2 hours following iv morphine and 3 hours following oxycodone.

[0516] All efficacy comparisons will be based on the comparison of INF-001 vs placebo. The primary efficacy variable, SPI24, will be analyzed using an analysis of covariance (ANCOVA) model with treatment as the main effect and a covariate for BMI. Summary statistics (sample size, mean, standard deviation [SD], median, minimum, maximum, and 25th and 75th percentiles) will be presented along with the p values from the ANCOVA model. To account for the interim analysis and potential sample size increase, the method of Cui et al 1999 will be employed. For the final analysis and resulting p-value, the data will be split for those patients included in the interim analysis and those not included in the interim analysis; data from these groups will be analyzed completely independently, then combined using the inverse normal method to test the null hypotheses that there is no difference between the treatment groups. For maximum statistical efficiency, the weights are defined prospectively according to the square root of the planned proportion of participants in the 2 stages, relative to the preplanned total enrollment of 360 patients, as wi=Vo.5. The calculation of these weights is fixed and will not be changed due to unblinded data; likewise, in the case of deviations from the planned proportions due to enrollment overrun, the weights will remain fixed. An approach identical to the primary efficacy analysis will be used for each of the continuous key secondary variables and the same statistics will be presented.

[0517] For key secondary outcomes of proportions, each proportion, the difference, and 95% confidence intervals (CIs) will be reported; difference will be tested with the 2- proportion Z test (and with the Cui Hung-Wang [CHW] method applied to account for the interim analysis). In the case of low counts (any expected cell count <5), a Fisher’s Exact test will be used. All continuous secondary efficacy variables will be summarized with appropriate descriptive statistics (sample size, mean, SD, coefficient of variation [CV], median, minimum, maximum, and 25th and 75th percentiles) and analyzed using ANCOVA models with treatment as the main effect and a covariate for BMI. Summary graphs of efficacy data including total use of opioid analgesia (TOpA) and NPRS scores by treatment group (arithmetic means and standard error [SE]) vs nominal time will be plotted). All categorical efficacy variables will be summarized with counts and proportions and compared by Cochran- Mantel-Haenszel tests (for ordered variables), Pearson chi-squared, or Fisher’s exact tests as needed. The time to first use of opioid rescue medication, time to discharge from the PACU, and time to no longer using rescue medication during the study will be summarized using Kaplan-Meier methods. Log rank tests will be used to compare treatment groups. The median time to discharge will be estimated together with the associated 95% Cl. Models containing additional blocking factors or covariates may be fit as secondary analyses. [0518] Safety Analyses: Safety variables include assessment of adverse events (including assessment for signs and symptoms of systemic bupivacaine toxicity and assessment of wound healing), clinical laboratory test results, vital signs measurements (including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation measured by pulse oximetry), ECG findings, surgical wound grading, and concomitant medications. These analyses will be conducted for the safety population. No formal statistical tests will be performed on safety evaluations.

[0519] Multiple Comparisons and Multiplicity: The key secondary efficacy variables will be tested sequentially each at the 0.05 level to control the overall Type-I error rate. Specifically, each key secondary variable will be tested in order. The next key secondary variable will be tested if the prior secondary variable comparison is statistically significant.

[0520] Planned Interim Analysis: An interim analysis will be performed when approximately 50% of the initially planned population is evaluable with respect to efficacy. This interim analysis will be performed by unblinded personnel separate from those responsible for the conduct and analysis of the study; all decisions will be made on the basis of SPI24, SPI48, and SPI72. An independent committee will review the data and recommend to the sponsor one of the following: increase the sample size by up to 180 patients or keep the current sample size and continue.

[0521] Investigational Medicinal Product Used in the Study and Other Treatment Information

[0522] The study drugs used in this study are: INL-001 [XARACOLL (bupivacaine hydrochloride) im-plant] and placebo collagen implant.

[0523] INL-001 is a drug-device combination product containing 100 mg of bupivacaine HC1 per im-plant, equivalent to 88.8 mg of bupivacaine, for placement in the surgical site. The dose to be evaluated is three 100-mg implants (300 mg bupivacaine HC1), equivalent to 266.4 mg of bupivacaine. Each implant is 5 cm x 5 cm x 0.5 cm in size and is white to off-white in color. Placebo implants contain collagen but no bupivacaine. Implants are terminally sterilized.

[0524] Additional details may be found in the IB for INL-001.

[0525] Anesthetic Protocol [0526] The standardized anesthetic regimen will include general anesthesia with fentanyl (maximum dose of 4 mcg/kg) and propofol (dose at discretion of the anesthesia provider), with or without volatile anesthetics or muscle relaxants. The standardized anesthetic regimen is a guide that should be followed to minimize interpatient variability to the greatest extent possible. However, it is understood that hemodynamic fluctuations and other intraoperative events may necessitate some deviation from this standard regimen. Neuraxial techniques, such as epidural and spinal an-esthesia, are not allowed. No epinephrine is permitted during the procedure. No local anesthetic other than INL-001 (study drug) in the surgical field or regional anesthesia is permitted. Lidocaine HC1 1% injection at a dose of no more than 20 mg may be administered once through iv access to decrease venous irritation (eg, as caused by propofol) at the time of surgical anesthesia. Intraoperatively, fentanyl (maximum dose of 4 mcg/kg) is permitted for analgesia. No other analgesic agents may be used during the procedure including, but not limited to, opioids (other than fentanyl), acetaminophen (oral or iv), NSAIDs (eg, ketorolac or COX-2 inhibitors), ketamine, pregabalin, and others. A preoperative dose of an antiemetic, ondansetron iv 4 mg, for nausea prophylaxis is allowed; however, postoperative antiemetic medications should be given to treat only patients who report nausea and/or vomiting. Administration of fentanyl should be avoided 30 minutes prior to the anticipated conclusion of the procedure if medically acceptable in the judgement of the anesthesiologist.

[0527] Placement of Study Drug

[0528] Following tissue removal and repair of the abdominal musculature, 2 implants should be placed on the rectus diastasis at the site of rectus sheath plication and 1 implant should be placed below the abdominal incision between Scarpa’s fascia and the subcutaneous fat. The implants should, to the greatest extent possible, be placed so they span the fascia that is exposed prior to surgical closure. Implants may be divided to accommodate placement, but an individual implant may not be cut into more than 2 halves.

[0529] Efficacy Assessments

[0530] Pain Intensity

[0531] Pain intensity will be assessed using NPRS at specified time points during the study (see Table 1). The NPRS is an 11 -point scale on which 0 indicates “no pain” and 10 indicates the “worst possible pain.” All postsurgical medication use will be recorded. In the case of a rescue medication being used, an NPRS score will be obtained within 15 minutes before the patient is administered rescue medication.

[0532] The primary efficacy variable is the sum of time-weighted pain intensity (SPI) from Time 0 through 24 hours (SPI24) as assessed by the pain intensity score using an NPRS. SPI will also be calculated for other time points.

[0533] Key secondary pain intensity efficacy variables are as follows:

SPI from Time 0 through 48 hours (SPI48)

SPI from Time 0 through 72 hours (SPI72)

NOTE: For order of statistical analysis for key secondary efficacy variables.

Other secondary pain intensity efficacy variables are as follows:

SPI through the following posttreatment time points: 2, 3, 4, 5, 6, 8, 10, 12, 18, 20, 28,

32, 36 hours pain intensity at each scheduled time point

[0534] Table 10 shows the SPI 24 data which shows that the primary endpoint is statistically significant compared to placebo implant.

[0535] Table 11 shows analysis of SPI through other time points, specifically SPI2 (sum of pain intensity through 2 hours), SPI3, SPI4, SPI5, SPI6, SPI8, SPI10, SPI12, SPI18, SPI20, SPI28, SPI32, and SPI36, indicating that the sum of pain intensity is statistically significantly different than placebo implant through 36 hours.

[0536] Opioid Use

[0537] Opioid use will be captured throughout the study (see Table 8). Various parameters will be calculated relating to opioid use, posttreatment through discharge and after discharge.

[0538] Key secondary opioid-use efficacy variables are as follows: proportion of patients who are opioid free through 24 hours proportion of patients who are opioid free through 48 hours proportion of patients that are opioid free through 72 hours NOTE: For order of statistical analysis for key secondary efficacy variables.

[0539] Other secondary opioid-use efficacy variables are as follows: proportion of patients who are opioid free from 24 through 48 hours, from 48 through 72 hours, and through day 7 proportion of patients who do not receive opioid rescue medication at discharge proportion of patients who do not use opioids following discharge total use of opioid analgesia (TOpA) through the following posttreatment time points: 2, 4, 6, 8, 10, 12, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 42, 44, 46, 48, and 72 hours, and prior to discharge total use of parenteral opioid analgesia (POpA) from Time 0 through 24 hours time to first use of opioid rescue medication time to no longer using opioid rescue medication during the study proportion of patients who used any oral opioid rescue medication through the following posttreatment time points: 2, 4, 6, 8, 10, 12, 18, 20, 22, 24, 26, 28, 30, 32,

34, 36, 42, 44, 46, 48, and 72 hours total rescue medication use through the following posttreatment time points: 2, 4, 6, 8, 10, 12, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 42, 44, 46, 48, and 72 hours proportion of patients who receive any rescue medication through 24, 48, and 72 hours [0540] Table 12 shows the analysis of patients who are opioid free through 24, 48 and 72 hours, all showing numeric difference between XARACOLL and placebo implant.

[0541] Table 13 shows analysis of total use of opioid analgesia (mg) in MEQ, indicating that all time points show a statistically significant difference between XARACOLL and placebo implant through 72 hours. Other Assessments: Time to Discharge From the Postanesthesia Care Unit (PACU)

[0542] The times a patient enters and is discharged from the PACU will be recorded to measure time to discharge from the PACU, another secondary efficacy variable.

Clinical Laboratory Tests

[0543] Hematology, Serum Chemistry, and Urinalysis

[0544] Blood and urine samples for clinical laboratory tests will be collected at the screening visit and at the day 30 follow-up visit (see Table 8).

[0545] The clinical laboratory tests performed are shown in Table 14:

Table 14:

[0546] The following additional laboratory tests will also be performed:

[0547] For women of childbearing potential, a serum sample for pregnancy test will be collected at screening, and a urine sample on the day of surgery (with results available before study drug kit assignment) and on day 30.

[0548] All clinical laboratory test results outside the reference range will be assessed by the investigator as belonging to one of the following categories: abnormal and not clinically significant abnormal and clinically significant

o

[0549] A laboratory test result that is judged by the investigator as clinically significant will be recorded both on the source documentation and the CRF as an adverse event and will be monitored as described herein. An event may include a laboratory or diagnostic test abnormality that results in the withdrawal of the patient from the study, the temporary or permanent withdrawal of medical treatment, or further diagnostic work up. (NOTE: Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient from entering the study or receiving study drug are not considered adverse events.)

[0550] Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be performed at the time points detailed in Table 8. Blood samples (approximately 16 mL total per patient) will be collected. Clinical laboratory tests will be performed using the central laboratory.

[0551] Urine Drug Screen

[0552] A urine drug screen will be performed at the screening visit and immediately before surgery (see Table 8). Urine screening will be done for drugs of abuse/misuse, with testing during the screening period and on the day of surgery (with results available before study drug kit number assignment).

[0553] A positive result for any excluded drugs of misuse/abuse or their metabolites without medical explanation will preclude the patient from enrollment or continued participation in the study.

[0554] Vital Signs

[0555] Vital signs, including body temperature, pulse, systolic and diastolic blood pressure, respiration rate, and oxygen saturation, will be measured/recorded at screening, preoperatively, and at the following posttreatment time points: 0.5 hours (±5 minutes); 1, 2, 4 hours (±15 minutes); 8, 12 hours (±2 hours); 24, 48, 72 hours (±4 hours) prior to discharge; day 15 (±3 days); and day 30 (±3 days) (see Table 8).

[0556] Oxygen saturation will be monitored by pulse oximetry during the inpatient study period. Oxy-gen saturation will be recorded at the individual time points listed above. Pulse oximeter alarms should be set according to clinic standards, with oxygen desaturation that occurs in concordance with the delay period and the specified limits recorded as an adverse event. Patients should be evaluated to ensure proper pulse oximeter placement and to ensure desaturation is not due to patient movement or device-related issues. [0557] All vital sign results outside the reference ranges will be judged by the investigator as belonging to one 1 of the following categories: abnormal and not clinically significant abnormal and clinically significant [0558] Physical Examinations

[0559] A complete physical examination will be performed at screening and on day 30 (±3 days) after treatment (including screening body weight and height and posttreatment weight only) (see Table 1). A complete physical examination will include at a minimum skin, lungs, CV, respiratory, gastrointestinal, musculoskeletal, and neurological assessments. Any physical examination finding that is judged by the investigator as clinically significant (except at the screening visit) will be considered an adverse event, recorded in the CRF, and monitored as described herein. Investigators should pay special attention to clinical signs related to previous serious diseases.

[0560] Electrocardiography

[0561] A standard 12 lead ECG will be performed locally and recorded (after the patient has been supine for at least 5 minutes) at screening and on day 30 (±3 days) (see Table 8). All ECG recordings will be identified with the patient number, date, and time of the recording.

[0562] All ECG results outside of the reference ranges should be evaluated and will be judged as belonging to one of the following categories: abnormal and not clinically significant abnormal and clinically significant

[0563] Any ECG finding that is judged as clinically significant (except at the screening visit) will be considered an adverse event, recorded on the source documentation and on the CRF, and monitored as described herein.

Example 8: An Open-label Study to Evaluate the Safety and Pharmacokinetics of the INL-001 (Bupivacaine Hydrochloride! Implant in Adults Following Various Open Soft-Tissue Surgeries: Open Ventral Hernia Repair. Abdominoplasty, Open Abdominal Hysterectomy, Laparoscopic-assisted Colectomy, and Reduction Mammoplastv [0564] Figs. 1A and IB illustrate the Mean Plasma Bupivacaine Concentration- Time Profiles; Mean (±SD) Plasma Bupivacaine Concentrations by Surgery Type on Linear (Fig. 1A) and Semi-Logarithmic Scale (Fig. IB) -PK Analysis Set.

[0565] Figs. 2A and 2B illustrate the Mean Plasma Bupivacaine Concentration- Time Profiles; Mean (±SD) Plasma Bupivacaine Concentrations by Surgery Type on Linear (Fig. 2A) and Semi-Logarithmic Scale (Fig. 2B) (0-6 Hours) - PK Analysis Set.

[0566] Figs. 3A and 3B illustrate the Mean Plasma Bupivacaine Concentration- Time Profiles; Mean (±SE) Plasma Bupivacaine Concentrations by Surgery Type on Linear (Fig. 3A) and Semi-Logarithmic Scale (Fig. 3B) - PK Analysis Set.

[0567] Figs. 4A and 4B illustrate Box Plots of Plasma Bupivacaine Pharmacokinetic Parameters; Fig. 4A: Box Plots of Plasma Bupivacaine C_max by Surgery Type on Linear Scale- PK Analysis Set; the dashed line is the median; the solid line is the arithmetic mean. The ends of the “box” are the 25th and 75th percentiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile, where IQR is the interquartile range. Data values that do not fall between the whiskers are plotted as outliers; Fig. 4B: Box Plot of Plasma Bupivacaine AUCo-_¥ by Surgery Type on Linear Scale- PK Analysis Set; The dashed line is the median; the solid line is the arithmetic mean. The ends of the “box” are the 25th and 75th percentiles. The whiskers show the lowest data value still within 1.5 IQR of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile, where IQR is the interquartile range. Data values that do not fall between the whiskers are plotted as outliers.

Table 15 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Open Ventral Hernia Repair (PK Analysis Set)

DBl/ 129475967.2 137

BLQ = Below the limit of quantification (< 1.00 ng/mL), treated as 0 for the calculation of PK parameters and descriptive statistics; NC = Not calculated;

. = Value missing or not reportable

Table 16 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Abdominoplasty (PK Analysis Set)

DBl/ 129475967.2 138

DBl/ 129475967.2 139

BLQ = Below the limit of quantification (< 1.00 ng/mL), treated as 0 for the calculation of PK parameters and descriptive statistics

Table 17 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Abdominoplasty (PK Analysis Set) - Continued

DBl/ 129475967.2 140

BLQ = Below the limit of quantification (< 1.00 ng/mL), treated as 0 for the calculation of PK parameters and descriptive statistics; NC = Not calculated

Table 18 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants I 300 mg) in Patients Following Open Abdominal Hysterectomy (PK Analysis Set)

103 -002 BLQ 356 467 575 545 558 547 550 503 575 545 547 551 570 239 195 73.6 21.8 103-005 BLQ 689 1410 1440 1400 1350 1280 1260 1100 1070 1090 1100 889 827 523 290 63.6 13.6 103-010 BLQ 236 481 511 532 631 550 567 551 587 625 663 731 724 638 473 167 29.2 103-012 BLQ 513 727 751 742 672 692 661 606 506 478 448 319 212 88.9 42.3 4.92 1.20 103-017 BLQ 553 621 547 356 612 702 636 839 593 586 531 453 323 212 186 94.7 29.1 103-018 BLQ 254 340 360 370 578 702 724 809 922 868 867 761 785 402 294 41.1 6.08 103-027 BLQ 552 502 746 703 668 680 595 605 592 545 501 530 473 363 234 69.7 13.7 103-028 BLQ 512 600 566 619 563 581 479 458 526 615 585 638 602 510 356 104 27.4

DBl/ 129475967.2 141

DBl/ 129475967.2 142

Table 19 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Laparoscopic-Assisted Colectomy (PK Analysis Set)

DBl/ 129475967.2 143

Table 20 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Reduction Mammoplasty (PK Analysis Set)

DBl/ 129475967.2 144

BLQ = Below the limit of quantification (< 1.00 ng/mL), treated as 0 for the calculation of PK parameters and descriptive statistics . = Value missing or not reportable

Table 21 Individual and Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Reduction Mammoplasty (PK Analysis Set) - Continued

NC = Not calculated

DBl/ 129475967.2 145

Table 22 Individual Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Unspecified Surgery (Subject 103-043) (PK Analysis Set)

Table 23 Summary Plasma Bupivacaine Concentrations Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Various Soft Tissue Surgeries (Overall) (PK Analysis Set)

DBl/ 129475967.2 146

NC = Not calculated

Plasma Bupivacaine Pharmacokinetic Parameter Tables

Table 24 Individual and Summary Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Open Ventral Hernia Repair (PK Analysis Set)

DBl/ 129475967.2 147

Table 25 Individual and Summary Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Abdominoplasty (PK Analysis Set)

DBl/ 129475967.2 148

NC = Not calculated

Table 26 Individual and Summary Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Open Abdominal Hysterectomy (PK Analysis Set)

DBl/ 129475967.2 149

NC = Not calculated

DBl/ 129475967.2 150

Table 27 Individual and Summary Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Laparoscopic- Assisted Colectomy (PK Analysis Set)

NC = Not calculated

Table 28 Individual and Summary Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Reduction Mammoplasty (PK Analysis Set)

DBl/ 129475967.2 151

DBl/ 129475967.2 152

NC = Not calculated

Table 29 Individual Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Unspecified Surgery (Subject 103-043) (PK Analysis Set)

. = Value missing or not reportable

Table 30 Summary Plasma Bupivacaine Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Various Soft Tissue Surgeries (Overall) (PK Analysis Set)

DBl/ 129475967.2 153

Table 31 Summary Bupivacaine Pharmacokinetic Parameters Following Administration of a Single Dose of POSIMIR 5 mL (660 mg)

^®t = last sampling time ' Median/ Range (mm -max)

* Drug leakage from the surgical site was suspected.

Plasma Bupivacaine Terminal Pharmacokinetic Parameter Tables

Table 32 Individual Plasma Bupivacaine Terminal Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Open Ventral Hernia Repair (PK Analysis Set)

DB1/ 129475967.2 -154-

DBl/ 129475967.2 155

Table 33 Individual Plasma Bupivacaine Terminal Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Abdominoplasty (PK Analysis Set)

NC = Not calculated

DBl/ 129475967.2 156

Table 34 Individual Plasma Bupivacaine Terminal Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Open Abdominal Hysterectomy (PK Analysis Set)

DBl/ 129475967.2 157

Table 35 Individual Plasma Bupivacaine Terminal Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Laparoscopic- Assisted Colectomy (PK Analysis Set)

NC = Not calculated

Table 36 Individual Plasma Bupivacaine Terminal Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Reduction Mammoplasty (PK Analysis Set)

DB1/ 129475967.2 158

NC = Not calculated

Table 37 Individual Plasma Bupivacaine Terminal Pharmacokinetic Parameters Following Placement of INL-001 Bupivacaine HC1 Implants (300 mg) in Patients Following Unspecified Surgery (PK Analysis Set)

. = Value missing or not reportable

DBl/ 129475967.2 159

[0568] In some embodiments, any of the clauses herein may depend from any one of the independent clauses or any one of the dependent clauses. In one aspect, any of the clauses (e.g., dependent or independent clauses) may be combined with any other one or more clauses (e.g., dependent or independent clauses). In one aspect, a claim may include some or all of the words (e.g., steps, operations, means or components) recited in a clause, a sentence, a phrase or a paragraph. In one aspect, a claim may include some or all of the words recited in one or more clauses, sentences, phrases or paragraphs. In one aspect, some of the words in each of the clauses, sentences, phrases or paragraphs may be removed. In one aspect, additional words or elements may be added to a clause, a sentence, a phrase or a paragraph. In one aspect, the subject technology may be implemented without utilizing some of the components, elements, functions or operations described herein. In one aspect, the subject technology may be implemented utilizing additional components, elements, functions or operations.

[0569] The foregoing description is provided to enable a person skilled in the art to practice the various configurations described herein. While the subject technology has been particularly described with reference to the various figures and configurations, it should be understood that these are for illustration purposes only and should not be taken as limiting the scope of the subject technology.

[0570] There may be many other ways to implement the subject technology. Various functions and elements described herein may be partitioned differently from those shown without departing from the scope of the subject technology. Various modifications to these configurations will be readily apparent to those skilled in the art, and generic principles defined herein may be applied to other configurations. Thus, many changes and modifications may be made to the subject technology, by one having ordinary skill in the art, without departing from the scope of the subject technology.

[0571] It is understood that the specific order or hierarchy of steps in the processes disclosed is an illustration of exemplary approaches. Based upon design preferences, it is understood that the specific order or hierarchy of steps in the processes may be rearranged. Some of the steps may be performed simultaneously. The accompanying method claims present elements of the various steps in a sample order, and are not meant to be limited to the specific order or hierarchy presented. [0572] As used herein, the term “about” preceding a quantity indicates a variance from the quantity. The variance may be caused by manufacturing tolerances or may be based on differences in measurement techniques. The variance may be up to 10% from the listed value in some instances. Those of ordinary skill in the art would appreciate that the variance in a particular quantity may be context dependent and thus, for example, the variance in a dimension at a micro or a nano scale may be different than variance at a meter scale.

[0573] As used herein, the phrase “at least one of’ preceding a series of items, with the term “and” or “or” to separate any of the items, modifies the list as a whole, rather than each member of the list (i.e., each item). The phrase “at least one of’ does not require selection of at least one of each item listed; rather, the phrase allows a meaning that includes at least one of any one of the items, and/or at least one of any combination of the items, and/or at least one of each of the items. By way of example, the phrases “at least one of A, B, and C” or “at least one of A, B, or C” each refer to only A, only B, or only C; any combination of A, B, and C; and/or at least one of each of A, B, and C.

[0574] Terms such as “top,” “bottom,” “front,” “rear” and the like as used in this disclosure should be understood as referring to an arbitrary frame of reference, rather than to the ordinary gravitational frame of reference. Thus, a top surface, a bottom surface, a front surface, and a rear surface may extend upwardly, downwardly, diagonally, or horizontally in a gravitational frame of reference.

[0575] Furthermore, to the extent that the term “include,” “have,” or the like is used in the description or the claims, such term is intended to be inclusive in a manner similar to the term “comprise” as “comprise” is interpreted when employed as a transitional word in a claim.

[0576] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0577] A reference to an element in the singular is not intended to mean “one and only one” unless specifically stated, but rather “one or more.” Pronouns in the masculine (e.g., his) include the feminine and neuter gender (e.g., her and its) and vice versa. The term “some” refers to one or more. Underlined and/or italicized headings and subheadings are used for convenience only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subj ect technology. All structural and functional equivalents to the elements of the various configurations described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein by reference and intended to be encompassed by the subject technology. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the above description.

Claims

1. A method of performing a soft tissue surgery procedure in a subject in need thereof, comprising placing a drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising a type I fibrillar collagen matrix and about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day.

2. The method of claim 1, wherein the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

3. The method of claim 1, wherein the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure.

4. The method of claim 1, wherein the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement.

5. The method of claim 1, wherein the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

6. The method of claim 1, wherein the surgery procedure is open ventral hernia repair comprising onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath.

7. The method of claim 1, wherein the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

8. The method of claim 1, wherein the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

9. The method of claim 1, wherein the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets.

10. The method of any one of claims 1 to 9, wherein the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

11. The method of any one of claims 1 to 10, wherein the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

12. The method of any one of claims 1 to 11, further comprising partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently.

13. The method of any one of claims 1 to 12, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

14. The method of claim 12 or 13, wherein the release dissolution profde of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

15. The method of claim 12 or 13, wherein the release dissolution profde of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profde of the unpartitioned drug delivery device.

16. Use of a type I fibrillar collagen matrix and bupivacaine hydrochloride for the manufacture of a drug delivery device for a soft tissue surgery procedure in a subject in need thereof, the procedure comprising placing the drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day.

17. The use of claim 16, wherein the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

18. The use of claim 16, wherein the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure.

19. The use of claim 16, wherein the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement.

20. The use of claim 16, wherein the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

21. The use of claim 16, wherein the surgery procedure is open ventral hernia repair comprising onlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath.

22. The use of claim 16, wherein the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

23. The use of claim 16, wherein the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

24. The use of claim 16, wherein the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets.

25. The use of any one of claims 16 to 24, wherein the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

26. The use of any one of claims 16 to 25, wherein the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

27. The use of any one of claims 16 to 26, further comprising partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently.

28. The use of any one of claims 16 to 27, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

29. The use of claim 27 or 28, wherein the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

30. The use of claim 27 or 28, wherein the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profile of the unpartitioned drug delivery device.

31. A kit for performing a soft tissue surgery procedure in a subject in need thereof, the kit comprising a drug delivery device, and instructions for placement of the drug delivery device at a surgical site for controlled and/or sustained release of bupivacaine hydrochloride, the drug delivery device comprising a type I fibrillar collagen matrix and about 1.0 to about 20.0 mg/cm³ bupivacaine hydrochloride, wherein the bupivacaine hydrochloride is substantially homogeneously dispersed in the collagen matrix and is present in the delivery device in an amount sufficient to provide a duration of local analgesia, local anesthesia or nerve blockade which lasts for at least about one day.

32. The kit of claim 31, wherein the surgery procedure is an abdominoplasty comprising one or more of rectus sheath plication, general anesthesia, making an incision that does not extend above the umbilicus, an anterior approach, making an incision from one anterior superior iliac spine (ASIS) to the other, placing one or more delivery devices on the rectus diastasis at the site of rectus sheath plication, or placing a delivery device below the abdominal incision between Scarpa’s fascia and the subcutaneous fat.

33. The kit of claim 31, wherein the surgery procedure is unilateral inguinal hernia repair comprising placing a drug delivery device into the hernia repair site below the site of mesh placement, closing the muscle/fascial layer, placing a drug delivery device between the fascia/muscle closure and the skin closure.

34. The kit of claim 31, wherein the surgery procedure is open ventral hernia repair comprising mesh placement at different subcutaneous layers, including intraperitoneal placement.

35. The kit of claim 31, wherein the surgery procedure is open ventral hernia repair comprising underlay or inlay mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part subcutaneously lying in direct contact with the closed anterior rectus sheath with the subcutaneous tissue closed over the matrices.

36. The kit of claim 31, wherein the surgery procedure is open ventral hernia repair comprising mesh repair, wherein the drug delivery device is placed in part in the preperitoneal space between the closed peritoneum and posterior rectus sheath, and in part laid in direct contact with the closed anterior rectus sheath.

37. The kit of claim 31, wherein the surgery procedure is open abdominal hysterectomy comprising placing the drug delivery device in part at the vaginal vault, in part at the site of the peritoneal incision between the visceral peritoneum and muscle, and in part on the fascia immediately below the subcutaneous fat under the site of the incision.

38. The kit of claim 31, wherein the surgery procedure is laparoscopic-assisted colectomy comprising placing the drug delivery device in part at the site of fascial repair, and in part superficially above the abdominal wall musculature and beneath extraction site incision.

39. The kit of claim 31, wherein the surgery procedure is reduction mammoplasty comprising placing the drug delivery device in part in one or both breast pockets.

40. The kit of any one of claims 31 to 39, wherein the drug delivery device comprises about 1.0 to about 20.0 mg/cm³ type I collagen.

41. The kit of any one of claims 31 to 40, wherein the drug delivery device comprises one or more collagen sponges, wherein a collagen sponge comprises about 50 to about 150 mg bupivacaine hydrochloride.

42. The kit of any one of claims 31 to 41, further comprising instructions for partitioning the drug delivery device into segments with a predetermined size, wherein each segment is placed at the surgical site independently.

43. The kit of any one of claims 31 to 42, wherein the drug delivery device has a length of about 45 to about 55 mm, a width of about 45 to about 55 mm, and a thickness of about 2.5 to about 7.5 mm, or a length of about 50 mm, a width of about 50 mm, and a thickness of about 5 mm.

44. The kit of claim 42 or 43, wherein the release dissolution profile of the sum of drug delivery device segments is substantially similar to the release dissolution profde of the unpartitioned drug delivery device.

45. The kit of claim 42 or 43, wherein the release dissolution profile of the sum of drug delivery device segments is within about 1% and about 15% at any point in time substantially similar to the release dissolution profde of the unpartitioned drug delivery device.