Injectable cross-linked collagen with improved flow properties.

Aqueous suspensions of glutaraldehyde cross-linked fibrillar collagen and non-cross-linked fibrillar collagen were examined by rheometry, particle size analysis, and microscopic techniques. Although cross-linked collagen suspensions were similar to non-cross-linked suspensions by microscopic and size analyses, they differed in rheometric properties. Concentric cylinder Couette flow, shear creep, uniaxial creep, and porous bed flow all revealed that cross-linked collagen was more resistant to deformation and flow than non-cross-linked collagen. These results were in agreement with in vivo dermal implantation studies, both in pig and human; i.e., compared to non-cross-linked collagen, the cross-linked formulation was more difficult to inject into tissue and did not spread uniformly, sometimes giving rise to palpable lumps or large masses evident in histological sections. When hyaluronic acid was blended with cross-linked collagen to achieve a final hyaluronate concentration of 5 mg/mL, there was a significant improvement in ease of injection into tissue. Rheometry on blends of hyaluronate and cross-linked collagen demonstrated that the blend required lower forces to achieve deformation and flow, compared to cross-linked collagen alone. Particle size analysis on the blend showed a reduction in fiber aggregate dimensions, compared to cross-linked collagen alone.

Injectable collagen: a six-year clinical investigation.

An injectable form of bovine dermal collagen has been developed for use in correcting cutaneous contour deficiencies. This material is a sterile device composed predominantly of highly purified type I collagen dispersed in phosphate-buffered physiological saline containing 0.3% lidocaine. The safety and efficacy of injectable collagen, which is now in widespread clinical use in the United States, Canada, England, Germany, France, Switzerland, Brazil, and 11 other countries, were evaluated in a 6 1/2-year investigation in which 5,109 patients were evaluated by 728 dermatologists and plastic surgeons. The incidence of adverse treatment reactions was 1.3%, most of which manifested with localized swelling and erythema. Current data covering an estimated 100,000 patients indicate that the incidence of treatment reactions has not increased during the 3 1/2 years since the material was cleared for marketing by the United States Food and Drug Administration. Subjective assessment of efficacy indicated that the material may be employed successfully to elevate dermal contour defects associated with various etiological factors.

Local effects of intrauterine contraceptives placed within the peritoneal cavities of rabbits.

Two studies were conducted to evaluate local surface tissue responses to seven different intrauterine contraceptive units placed within the peritoneal cavities of rabbits, either near the uterus or in contact with the hepatic capsule. One or six weeks after insertion, the animals were killed and tissue responses evaluated. All local tissue responses were inflammatory although in some animals tissue responses were also associated with a mechanical component related to pressure of the contraceptive units on the hepatic capsule. Control animals revealed no response. One-week tissue responses among the treated rabbits ranged from minimal to moderate for the Progestasert Intrauterine Progesterone Contraceptive System (IPCS), placebo (nonhormonal) IPCS, Lippes Loop and Saf-T-Coil; moderate for the Dalkon Shield; and severe for the Gyne-T and Cu-7. After six weeks the inflammatory responses to the IPCS, placebo (nonhormonal) IPCS, Lippes Loop and Saf-T-Coil consisted of well-organized fibrous tissue, while the responses to the Gyne-T and Cu-7 were aggressive, invasive and characterized by necrosis and fibroplasia.

The effect of exogenous intrauterine progesterone on the amount and prostaglandin F2alpha content of menstrual blood in dysmenorrheic women.

Women with complaints of moderate or severe dysmenorrhea received intrauterine progesterone contraceptive system (16 patients) or placebo systems releasing no hormone (8 patients). Tampons were collected during the period prior to insertion and from 11 and 6 women, respectively, in the two groups at the second and fourth postinsertion periods. Prostaglandins in menstrual blood were extracted, and the amount and concentration of PGF2alpha analyzed for each patient. The menstrual blood loss (MBL) was determined by the method of Hallberg and Nilsson. The total PGF2alpha content was significantly lower in the group using progesterone systems than in the placebo group at collections 2 and 4 and was well below the preinsertion level; in placebo users the content tended to be slightly higher than it had been before insertion. The MBL increased approximately 60% above preinsertion levels in five of the six women using placebo units and decreased approximately 40% in 10 of 11 women with progesterone systems. Of the eight women in the progesterone group who had reported severe dysmenorrhea prior to insertion, seven reported an improvement; three of six in the placebo group reported a lower degree of improvement. These findings suggest that the decreased biosynthesis of PGF2alpha is a concomitant of intrauterine progesterone administration and may be a basis for the ability of the Progestasert system to diminish menstrual pain.

Steroid delivery systems for contraception.

Scientific disciplines not normally associated with pharmaceutical development have been employed to enhance the effectiveness and attractiveness of two approaches to steroidal contraception. The use of a bioerodible polymeric carrier for predictable systemic steroidal administration has removed the largest hurdle to the development of a subcutaneous contraceptive implant. A polymeric progesterone delivery system has provided a method for localizing hormonal contraception in the uterine cavity. Extensions of these technologies may provide two useful tools in limiting fertility in an already overcrowded world.

Endometrial morphology in women exposed to uterine systems releasing progesterone.

A blind study was done in 402 endometrial biopsies of women who had intrauterine devices releasing different daily amounts of progesterone or a placebo (empty device): 175 were obtained in what presumably was the proliferative phase and 227 in the secretory stage, as all these subjects were normal, healthy women with a history of previous fertility. With all dose levels of the progesterone-releasing devices there was variation of the endometrium general pattern and the over-all picture varied from normal secretory to suppressed endometrium. In addition to these changes of the endometrial pattern, in 231 specimens there was significant inflammatory infiltration and in six cases even plasma cells were seen. Predecidual reaction was frequently seen and in 45 cases it was diffuse and marked. The significance of these data is discussed on the grounds of the frequent similarities of the changes here reported with those in women using combined oral steroids for contraception.

Progestasert: a uterine therapeutic system for long-term contraception: I. Philosophy and clinical efficacy.

PIP: An intrauterine steroid delivery system the Progestasert system, is described and studies of its clinical efficacy are reported. The Progestasert system combines the advantageous features of IUDs and oral minidose progestogen preparations. An internal device continuously delivers progesterone for 1 year to the uterine lumen and endometrium. A T-shaped Progestasert which releases 65 mcg/day has been selected for wide scale clinical use. A total of 3121 parous women used Progestasert systems for 25,389 woman-months. The pregnancy rate was 1%, the expulsion rate 2.8%, and the total removal rate was 13%. The total continuation rate of the Progestasert system of 83.2% compares favorable with that of the Tatum-T-shaped IUD of 68.7%. These initial results aft er 1 year of use are most encouraging and suggest that the goals originally set for a contraceptive approach using intrauterine progester one are well within reach.^ieng

Progress in the development of the Progestasert TM 65 progesterone therapeutic system for contraception.

PIP: The primary objective in the design of the Progestasert 65 system, a progesterone uterine therapeutic system, has been to influence the intrauterine environment and produce fertility control by means of local steroid action. It has an average release rate of 65 mcg progesterone/day to the uterine lumen for a period of 400 days. Although the system was developed as a method of local steroid contraception rather than as an intrauterine device (IUD), information gained from experience with IUDs guided certain aspects of the design specifications; e.g., the T configuration was selected and modified for easier insertion. The progesterone core composition is contained within the verticle system of the T maintaining the flexibility and softness of this portion. The inserter is a smooth cylindrical unit, precurved and malleable so the angle can be changed if necessary. This inserter design has provided over 3000 insertions with no perforations. Clinical data come from 32 clinics. It is concluded that this development is a highly efficacious local hormonal system of contraception.^ieng