Title

Insulin Complexation With Hydroxypropyl-beta-cyclodextrin: Use of the Complex in Gel for Healing of Pressure Ulcers
Insulin Complexation With Hydroxypropyl-beta-cyclodextrin: Spectroscopic Evaluation of Molecular Inclusion and Use of the Complex in Gel for Healing of Pressure Ulcers
  • Phase

    Phase 1/Phase 2
  • Study Type

    Interventional
  • Study Participants

    15
The coprecipitation method was used to prepare hydroxypropyl-beta-cyclodextrin complexed with insulin (HPβCD-I) by mixing insulin with hydroxypropyl-beta-cyclodextrin (HPβCD) in the molar ratio of 1:5 with the addition of 10 mL of purified water for every 100 mg of the complex. After complete dissolution of the material, the mixture was stirred for 30 min at room temperature (25°C), then left to rest for 60 min and lyophilized.

The gel was prepared by dispersing the Carbopol 940® polymer in a known amount of purified water. Under mild heating the methylparaben (0.02%, w/v), propylparaben (0.01%, w/v) and propylene glycol were dissolved and incorporated in the dispersion of Carbopol 940® and left to rest for a period of 12h. After this time, the prepared gel was stirred and pH corrected to a range of 5.0 to 7.0 with triethanolamine. A set amount of insulin and the HPβCD-I complex were incorporated into the control gel for the preparation of other formulations.

A randomized, double-blind, prospective clinical trial was conducted from March 2013 to April 2014 at the Hospital Universitário Regional de Maringá (HUM), Paraná, Brazil, in order to determine the safety and efficacy of gel in patients hospitalized in the Intensive Care Unit.

Hyperglycemic volunteers and those with pressure ulcers other than grade II were excluded from the study. Grade II pressure ulcers were selected as they are a superficial lesion, with little tissue loss, and allow easy visualization of healing.

A letter of free and informed consent was obtained. The study was conducted with each patient for a period of 15 days.

The volunteers were divided equally into three groups A, B and C, with each group being formed by five volunteers (n=5). Group A was randomly selected for treatment with gel with HPβCD-I complex, group B for treatment with gel with insulin, and group C with the control gel.

Blood glucose tests were performed in order to assess whether the insulin complexed or otherwise with HPβCD could cause an increase in the rate of insulin in the blood in patients, leading to hypoglycemia.

An identical standardized procedure for gel placement was used for all patients. Initially, the pressure ulcer was cleaned with saline. With the aid of a paper ruler, the ulcer was measured and photographed, as the ruler included the date and the initials of the patient. After measuring, a quantity of 5 grams of gel was placed on the pressure ulcer and covered with sterile gauze and a transparent film.

The curative was changed once a day during the treatment period, unless there was leakage of fluid, contamination, or signs of infection. Every three days the pressure ulcers of all patients were measured and photographed again, resulting in a total of six measurements per patient. The photos of pressure ulcers were evaluated for measurement of pressure ulcers and any kind of irritation. At the end of this stage, the properly gathered study data was interpreted using the analysis software Mobile Wound Analyzer® (MOWA).

Data was evaluated by variance analysis (ANOVA), and means were compared with the Tukey test (p < 0.05) using the software Statistica 8.0/2008 (Stat Soft Inc., Tulsa, USA).

Mixed model repeated measures methodology with some covariance structures was adopted for statistical analysis of the clinical trial (p < 0.05). The Statistical Analysis System (SAS) for Windows, version 9.3 (SAS Inc., Chicago, IL) program was used for statistical analysis.
Study Started
Mar 31
2013
Primary Completion
Apr 30
2014
Study Completion
Jul 31
2014
Results Posted
Jan 14
2016
Estimate
Last Update
Jan 14
2016
Estimate

Drug Gel with HPβCD-I complex

Initially, the pressure ulcer was cleaned with saline. With the aid of a paper ruler, the ulcer was measured and photographed, as the ruler included the date and the initials of the patient. After measuring, a quantity of 5 grams of gel with hydroxypropyl-beta-cyclodextrin complexed with insulin (HPβCD-I) was placed on the pressure ulcer and covered with sterile gauze and a transparent film. The curative was changed once a day during the treatment period, unless there was leakage of fluid, contamination, or signs of infection. Every three days the pressure ulcers of all patients were measured and photographed again, resulting in a total of six measurements per patient. The photos of pressure ulcers were evaluated for measurement of pressure ulcers and any kind of irritation.

Drug Gel with insulin

Initially, the pressure ulcer was cleaned with saline. With the aid of a paper ruler, the ulcer was measured and photographed, as the ruler included the date and the initials of the patient. After measuring, a quantity of 5 grams of gel with insulin was placed on the pressure ulcer and covered with sterile gauze and a transparent film. The curative was changed once a day during the treatment period, unless there was leakage of fluid, contamination, or signs of infection. Every three days the pressure ulcers of all patients were measured and photographed again, resulting in a total of six measurements per patient. The photos of pressure ulcers were evaluated for measurement of pressure ulcers and any kind of irritation.

Drug Control gel

Initially, the pressure ulcer was cleaned with saline. With the aid of a paper ruler, the ulcer was measured and photographed, as the ruler included the date and the initials of the patient. After measuring, a quantity of 5 grams of control gel was placed on the pressure ulcer and covered with sterile gauze and a transparent film. The curative was changed once a day during the treatment period, unless there was leakage of fluid, contamination, or signs of infection. Every three days the pressure ulcers of all patients were measured and photographed again, resulting in a total of six measurements per patient. The photos of pressure ulcers were evaluated for measurement of pressure ulcers and any kind of irritation.

Gel with HPβCD-I complex Experimental

A quantity of 5 grams of gel with hydroxypropyl-beta-cyclodextrin complexed with insulin (HPβCD-I) was placed on the pressure ulcer, previously cleaned with saline, and covered with sterile gauze and a transparent film.

Gel with insulin Active Comparator

A quantity of 5 grams of gel with insulin was placed on the pressure ulcer, previously cleaned with saline, and covered with sterile gauze and a transparent film.

Control gel Placebo Comparator

A quantity of 5 grams of gel without active was placed on the pressure ulcer, previously cleaned with saline, and covered with sterile gauze and a transparent film.

Criteria

Inclusion Criteria:

Brazilian,
bedridden,
of both genders,
aged between 45 and 75 years old, and
diabetic or not.

Exclusion Criteria:

hyperglycemic volunteers, and
those with pressure ulcers other than grade II.

Summary

Gel With HPβCD-I Complex

Gel With Insulin

Control Gel

All Events

Event Type Organ System Event Term

Efficacy Index (%EI)

Every three days the pressure ulcers (PUs) of all patients were measured and photographed again, resulting in a total of six measurements per patient. The photos were evaluated for measurement of PUs and any kind of irritation. At the end of this stage, the properly gathered study data was interpreted using the analysis software Mobile Wound Analyzer® (MOWA). Healing efficacy indices (% EI) were calculated as percentage reduction in the wound size at days 3, 6, 9, 12 and 15 from treatment beginning (d0). The % EI of the wound size was calculated by the following equation: %EI= ((Vsp.day-Vi)/Vi))x100. Vsp.day refers to the diameter (mm) values measured at day 3, 6, 9,12 and 15, while Vi refers to the baseline value measured before treatment (d0). The most representative result of treatment efficacy was observed on day 15, therefore it was used to calculate the % EI. For each group assessed, it was calculated the mean % EI of the five patients, resulting in a single value.

Gel With HPβCD-I Complex

82.76
percentage (%) (Mean)
95% Confidence Interval: 78.25 to 86.15

Gel With Insulin

43.66
percentage (%) (Mean)
95% Confidence Interval: 39.73 to 47.03

Control Gel

14.58
percentage (%) (Mean)
95% Confidence Interval: 12.53 to 16.25

Blood Glucose Tests in Order to Assess Whether the Gel With Hydroxypropyl-beta-cyclodextrin Complexed With Insulin (HPβCD-I) or With Insulin Could Cause an Increase in the Rate of Insulin in the Blood of Patients

Dosages were provided four times daily (04h, 10h, 16h and 22h) to each patient during the 15-day study period, giving a total of 60 doses. To obtain these dosages, a drop of blood of patients was placed on a colorimetric strip and blood glucose was measured with the use of an Accu Check Active® glucose meter. The mean of 60 dosages was calculated for each patient at the end of 15 days. For each group assessed, it was calculated the mean of the measurements of the five patients, resulting in a single value.

Gel With HPβCD-I Complex

167.2
mg/dL (Mean)
95% Confidence Interval: 153.92 to 208.9

Gel With Insulin

168.88
mg/dL (Mean)
95% Confidence Interval: 155.12 to 209.39

Control Gel

196.07
mg/dL (Mean)
95% Confidence Interval: 103.0 to 325.0

Total

15
Participants

Age, Customized

Sex: Female, Male

Overall Study

Gel With HPβCD-I Complex

Gel With Insulin

Control Gel