Abstract: The present invention refers to a controlled release system of phytocannabinoids formulation soluble in aqueous media comprising phytocannabinoids, or derivatives thereof, a non-ionic surfactant and a cross-linked polymer, wherein the pH of the compositions ranges between 4 and 9, and wherein the weight ratio of cannabinoid/hyaluronic acid is 50:1 to 1:50, and the weight ratio cannabinoid/non-ionic surfactant is 1:30 to 1:1. The invention also refers to methods of producing the controlled release system of cannabinoids formulation soluble in aqueous medium and the pharmaceutical, cosmetic and nutraceutical applications thereof. The methods of the present invention allow the cross-linking of hyaluronic acid containing encapsulated or vehiculized phytocannabinoids at neutral pH, avoiding the degradation of the phytocannabinoids and preserving its functionality.